Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Full-Circumference Prosthetic Grafts for Replacing a Retrohepatic Inferior Vena Cava Segment During Hepatectomy for Tumor.

BACKGROUND: Although hepatectomy including inferior vena cava (IVC) resection is becoming more common, some details remain uncertain such as use of artificial materials to replace a tumor-involved, damaged, or narrowed retrohepatic IVC segment. METHODS: Surgical outcomes of 12 patients who underwent hepatectomy with IVC resection including reconstruction using synthetic tubular grafts were investigated to clarify safety and feasibility. RESULTS: Operative time (median, 573 min; range, 268 to 774) and the blood loss (1076 mL; 155 to 2960) were acceptable. In-hospital mortality was 8% (1/12), and morbidity was 42% (5/12). Among the 12 patients, 2 were planned to undergo IVC reconstruction without an artificial graft. In one patient, prosthetic repair was adopted because of massive bleeding from the IVC wall during dissection of tumor from the IVC. In the other, severe stricture became evident during attempted direct closure of the partially resected IVC wall. DISCUSSION: Ongoing experience has increased our acceptance of combined liver and IVC resection. We believe that segmental IVC resection and reconstruction with a prosthetic tubular graft could be chosen more frequently in managing liver tumors suspected to involve the IVC.

Failure of peritoneal lavage to prevent operative site infection and peritoneal tumor recurrence in pancreatic surgery.

BACKGROUND: Although intraoperative peritoneal lavage often is performed routinely with the aim of reducing peritoneal contamination, evidence of lavage benefit in elective pancreatic surgery is limited. METHODS: We retrospectively classified patients who had undergone pancreatic surgery to groups given or not given peritoneal lavage, then comparing clinical results. This saline lavage was performed at the end of the operation. The primary endpoint was rate of surgical site infection. Frequency of peritoneal recurrence also was evaluated. RESULTS: Among all 104 patients in the study, incidence of infectious complications in the lavage group (n = 65) was significantly higher than in the non-lavage group (n = 39; 35% vs. 15%, P = 0.041), while incidences of postoperative complications overall and surgical site infection did not differ between lavage (80% and 26%) and non-lavage groups (67% and 10%, P = 0.162 and 0.076, respectively). Among 63 patients undergoing pancratoduodenectomy, frequencies of positive bacterial cultures of drainage fluids on postoperative days 1 and 3 were greater in the non-lavage group (P < 0.001 and P = 0.012), but surgical site infection was significantly more frequent in the lavage group (P = 0.043). Among patients with pancreatic and biliary cancers, lavage did not affect frequency of peritoneal recurrence. CONCLUSION: Intraoperative lavage did not prevent surgical site infection or peritoneal recurrence of pancreatobiliary cancer.

Depletion of plasma thymidine results in growth retardation and mitochondrial myopathy in mice overexpressing human thymidine phosphorylase.

Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.

Prognostic implications of histologic growth patterns and tumor-infiltrating macrophages in colorectal liver metastases.

PURPOSE: Histopathologic patterns at the invasion fronts of tumors predict metastatic potential and prognosis in several cancers. We examined whether such patterns at the interface between colorectal liver metastases and hepatic parenchyma have similar prognostic value. METHODS: Microscopic growth patterns at edges of metastases including desmoplasia, pushing borders, and replacement of hepatocytes were retrospectively analyzed with respect to surgical outcomes in 142 patients who underwent hepatectomy for colorectal metastases. RESULTS: Patterns included desmoplasia in 58 patients (41%), hepatocyte replacement in 41 (29%), and pushing borders in 43 (30%). Maximum metastasis diameter and serum carcinoembryonic antigen concentration in patients showing desmoplastic tumor growth were lower than those in others (P < 0.05 and P < 0.01). Disease-free survival and overall survival were better in patients showing desmoplastic growth, while a non-desmoplastic tumor growth pattern showed a negative influence. More cluster of differentiation (CD) 68-positive M1 macrophages and fewer CD206-positive M2 macrophages were demonstrated at interfaces of tumors with hepatic parenchyma when desmoplasia was present, although markers for proliferative activity (MIB1 index) and metastatic potential (E-cadherin expression) appeared uninfluenced by desmoplasia. CONCLUSION: Better long-term results were associated with metastatic tumors showing desmoplastic growth patterns at invasion fronts, which may reflect local immune state in a prognostically useful manner.

Absence of a weekday effect on short- and long-term oncologic outcomes of gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: Day of the week when elective gastrointestinal surgery is performed may be influenced by various background and tumor-related factors. Relationships between postoperative outcome and when in the week gastrectomy is performed remain controversial. We undertook this study to evaluate whether weekday of gastrectomy influenced outcomes of gastric cancer treatment ("weekday effect"). METHODS: Patients who underwent curative surgery for gastric cancer between 2004 and 2017 were included in this retrospective study. To obtain 2 cohorts well balanced for variables that might influence clinical outcomes, patients whose gastrectomy was performed early in the week (EW group) were matched 1:1 with others undergoing gastrectomy later in the week (LW group) by use of propensity scores. RESULTS: Among 554 patients, 216 were selected from each group by propensity score matching. Incidence of postoperative complications classified as Clavien-Dindo grade II or higher was similar between EW and LW groups (20.4% vs. 24.1%; P = 0.418). Five-year overall and recurrence-free survival were 86.0% and 81.9% in the EW group, and 86.2% and 81.1% in the LW group (P = 0.981 and P = 0.835, respectively). CONCLUSIONS: Short- and long-term outcomes were comparable between gastric cancer patients who underwent gastrectomy early and late in the week.

Modification of ALPPS to avoid ischemia and congestion after stage 1: a case report.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been advocated for treating advanced liver tumors, but the devascularized ischemic area resulting from liver parenchymal division can become a nidus for sepsis. We present a patient who underwent ALPPS modified to avoid ischemia and congestion after liver partitioning during stage 1. CASE PRESENTATION: ALPPS was carried out for a patient with multiple bilobar liver metastases from rectosigmoid colon cancer. The 2-stage treatment included 3 partial resections within the left lateral section and parenchymal division at the umbilical fissure with right portal vein ligation as stage 1, followed by right trisectionectomy as stage 2. During parenchymal division at the umbilical fissure, Segment 4 portal pedicles and the middle hepatic vein had to be resected at their roots. To safely accomplish this, combined resection of Segment 4 and the drainage area of the middle hepatic vein was performed after parenchymal partition, aiming to avoid ischemia and congestion within the remnant liver. Successful stage 2 hepatectomy followed later. No ischemia or congestion occurred during stage 1 or 2. CONCLUSIONS: During ALPPS, ischemia and congestion after stage 1 must be avoided to reduce morbidity and mortality. The modification described here should reduce likelihood of severe postoperative complications.

Benefit of laparoscopic compared to standard open gastric cancer surgery for sarcopenic patients: a propensity score-matching analysis.

BACKGROUND: Laparoscopic gastrectomy (LG) is performed widely, but whether LG is the optimal treatment for sarcopenic gastric cancer patients is unclear. This study aimed to determine whether LG is particularly beneficial for gastric cancer patients with sarcopenia. METHODS: We collected data concerning 604 consecutive patients who underwent gastrectomy for gastric cancer between January 2003 and December 2019. After adjustment using one-to-one propensity score matching, short-term and long-term outcomes were compared between LG and open gastrectomy (OG) groups among patients with sarcopenia and those without. RESULTS: Among patients with and without sarcopenia, the LG group had a significantly longer operative time but less blood loss than the OG group. The two groups showed no significant differences regarding complications. Although 5-year overall and disease-specific survival were similar between LG and OG groups among patients with and without sarcopenia, LG was associated with greater 5-year non-gastric cancer-related survival than OG among patients with sarcopenia (88.3% vs. 78.1%, P = 0.048), but not those without. CONCLUSION: LG for resectable gastric cancer was not inferior to OG regarding complications and outcomes in patients with or without sarcopenia. No difference in overall survival was evident between these approaches, but LG may lessen mortality from conditions unrelated to gastric cancer in sarcopenic patients.

Impact of body fat and muscle quantity on short- and long-term outcome after gastrectomy for cancer.

BACKGROUND & AIMS: Preoperative low skeletal muscle mass and obesity have been identified as poor prognostic factors after gastrectomy for cancer, but the predictive value of combined quantitation of skeletal muscle mass and obesity remains unclear. This study examined the impact of combined body compositions on outcomes after gastrectomy for cancer. METHODS: 518 patients who had undergone gastric resection for cancer between 2004 and 2017 were analyzed retrospectively. Skeletal muscle mass (skeletal muscle mass index (SMI)) and visceral obesity (visceral fat area) were measured in preoperative computed tomographic images to categorize patients as outlined below. Impacts of these body compositions on outcomes after gastrectomy were investigated. RESULTS: Body composition was classified as high SMI without obesity in 231 patients (45%), high SMI with obesity in 202 (39%), low SMI without obesity in 55 (11%), and low SMI with obesity in 30 (6%). Postoperative complications developed in 128 patients (25%). Multivariate analysis identified low SMI with obesity as an independent risk factor for postoperative complications (odds ratio, 3.27; P = 0.010). Moreover, patients with low SMI without obesity had lower 5-year overall survival rates than patients with high SMI without obesity (64.4% vs. 88.0%; P < 0.001) and worse 5-year relapse-free survival rates (61.3% vs. 81.3%; P = 0.002). Multivariate analysis identified low SMI without obesity as a significant risk factor for overall survival (hazard ratio, 3.033; P < 0.001) and relapse-free survival (hazard ratio, 2.144; P = 0.008) after gastrectomy. CONCLUSION: Preoperative low SMI with obesity was an independent risk factor for postoperative complications, while low SMI without obesity was an independent risk factor for overall and relapse-free survival following gastrectomy for cancer.

Superior mesenteric vein reconstruction during pancreatoduodenectomy using a dilated right ovarian vein in a patient at future risk for pelvic congestion syndrome: a case report.

BACKGROUND: Pancreatoduodenectomy including resection of the superior mesenteric vein (SMV) is increasingly performed for right-sided pancreatic ductal adenocarcinoma invading the wall of that vessel. Various venous grafts may be chosen for reconstruction. We present a woman with pancreatic cancer who underwent such a pancreatoduodenectomy with venous reconstruction using a dilated right ovarian vein. CASE PRESENTATION: A 71-year-old woman with cancer involving the pancreatic head, uncinate process, and SMV underwent pancreatoduodenectomy with SMV resection. Reconstruction used a portion of the right ovarian vein that was markedly dilated and had placed her at risk for pelvic congestion syndrome (PCS). Graft patency was confirmed 8 months after surgery. She now finished receiving adjuvant chemotherapy and has no symptoms of PCS. CONCLUSION: If an ovarian vein has sufficient diameter, it can be used to reconstruct the resected segment of the SMV during pancreatoduodenectomy in suitable patients.

[Prehepatectomy Chemotherapy Using Circadian Chrono-HAI for Liver Metastases from Colorectal Cancer].

We investigated the safety and efficacy of circadian chronotherapy via the hepatic artery(chrono-HAI)as a prehepatectomy chemotherapy for initially unresectable colorectal liver metastases. Five-day course of chrono-HAI using 5-FU, l-LV, and L-OHP plus systemic panitumumab with 9-day interval were administered to 24 patients with failure for previous chemotherapy. Response rate and Grade 3 adverse effect(AE) were 63% and 54%, respectively. Among 22 patients( excluding 2 CR patients), conversion surgery could be performed in 10(45%). Two-year overall survival of patients with surgery (58%)was longer in those without(20%, p=0.057). Although incidence of AE was a bit high, chrono-HAI plus systemic panitumumab is an effective prehepatectomy chemotherapy for patients with aggressive colorectal liver metastases.

Comparative Study of an Ultrasound-guided Percutaneous Biopsy and Endoscopic Ultrasound-guided Fine-needle Aspiration for Liver Tumors.

Objective Both a percutaneous biopsy and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) have been widely performed for liver tumors. However, no studies have compared these two biopsy methods. Method A retrospective study was conducted using medical records for patients who underwent a liver tumor biopsy from 2012 to 2019. The cases were classified into two groups for a comparison: an ultrasound-guided percutaneous biopsy group (percutaneous group) and an EUS-FNA group (EUS group). Results A total of 106 patients (47 in the percutaneous group and 59 in the EUS group) were included. The final diagnosis was malignant in 100 cases and benign in the remaining 6 cases. While the median lesion diameter was 62 mm in the percutaneous group, it was significantly smaller (34 mm) in the EUS group (p <0.01). The EUS group had more left lobe tumors than right lobe tumors. All cases of caudate lobe tumor (four cases) underwent EUS-FNA. The sensitivity, specificity, and accuracy of the procedure were 95%, 100%, and 96% in the percutaneous group and 100%, 100%, and 100% in the EUS group, respectively showing no significant difference. Adverse events were reported in 17% of the percutaneous group, which was significantly lower than in the EUS group (2%; p <0.01). Conclusion A percutaneous biopsy and EUS-FNA have equivalent diagnostic qualities for liver tumors, although EUS-FNA tends to be associated with fewer adverse events. A complete understanding of the characteristics of each procedure is essential when choosing the best biopsy method for each particular case.

A case of bile duct diverticulum with repeated acute cholangitis due to diverticular stone fall.

A 34-year-old man presented to the emergency department with a chief complaint of epigastric pain. Endoscopic ultrasound detected a 5 mm stone in the common bile duct. After endoscopic sphincterotomy, the black stones and debris were removed with balloon catheter. Abdominal ultrasonography detected no gallbladder stones; hence, the patient was followed up. However, 3 months later, the patient again developed acute cholangitis caused by common bile duct stones and underwent endoscopic stone removal. Cholangiography under balloon occlusion revealed a left hepatic duct diverticulum with an internal defect. Intraductal ultrasonography showed a hyperechoic lesion with acoustic shadow in the diverticulum, suggesting a stone or debris. Therefore, the patient was considered to have had repeated acute cholangitis because of the presence of falling diverticular stones. The patient underwent left hemihepatectomy plus segmentectomy 1 and cholecystectomy. Histopathologically, it was a true diverticulum without internal epithelial atypia. Many debris were seen in the diverticulum. Gallbladder stones were not observed. Eventually, the patient was discharged from the hospital with no postoperative complications and no recurrence of cholangitis after 20 months.

Performance evaluation of bactericidal effect and endotoxin inactivation by low-temperature ozone/hydrogen peroxide mixed gas exposure.

This study evaluated the performance of a new O3 /H2 O2 mixed gas sterilization instrument for killing microorganisms and inactivating bacterial endotoxin at low temperatures. Sterility assurance level was achieved by an over 6-log reduction of Geobacillus stearothermophilus ATCC 12980, and the decimal reduction value was 0.77 min in sterilization mode. A reduction of over 3 logs in Limulus amebocyte lysate coagulation activity of purified endotoxin from Escherichia coli was observed after treatment in endotoxin-inactivation mode. The same inactivation ability was observed when treating dried bacterial cells. Biomaterials made of polymer or metal did not exhibit cytotoxicity after gas exposure at O3 concentrations below 200 ppm. As the results of human cell-based pyrogen testing, significant amounts of endotoxin that were over the limit for medical devices contacting cerebrospinal fluid (2.15 EU/device) were detected on scissors washed with a washer-disinfector and sterilized with ethylene oxide or autoclaving. In contrast, endotoxin decreased to 0.29 ± 0.05 EU/device after O3 /H2 O2 mixed gas sterilization in endotoxin-inactivation mode. Compared to conventional gas sterilization methods, O3 /H2 O2 mixed gas has high sterilization ability and a strong capacity to inactivate endotoxin. It is expected that this sterilization technology will improve the safety of reusable medical devices and utensils for regenerative medicine.

Incidental Gallbladder Cancer on Cholecystectomy: Strategy for Re-resection of Presumed Benign Diseases from a Retrospective Multicenter Study by the Yokohama Clinical Oncology Group.

BACKGROUND/AIM: Current expert consensus recommends re-resection for incidental gallbladder cancer (IGBC) of pT1b-3. This study examined whether this consensus was reasonably applicable to patients with IGBC in one Japanese region. PATIENTS AND METHODS: This was a multicenter, retrospective analysis of cholecystectomies for presumed benign diseases between January 2000 and December 2009. RESULTS: IGBC was diagnosed in 70 (1.0%) out of 6,775 patients undergoing cholecystectomy. Five-year disease-specific cumulative survival was 100% in 19 patients with pT1a, 80.0% in five with pT1b, 49.5% in 33 with pT2, and 23.1% in 13 with pT3. Re-resection was not performed for the 24 patients with pT1a/1b disease, whereas 24 out of 46 patients with pT2/3 underwent re-resection. Regardless of re-resection, independent factors associated with a poor prognosis on multivariate analysis were grade 2 or poorer disease and bile spillage at prior cholecystectomy. In the 24 patients with pT2/3 re-resection, 11 patients without either of these two factors had significantly better 5-year disease-specific cumulative survival than the 13 patients with one or two independent factors associated with a poor prognosis (72.7% vs. 30.8%, p=0.009). CONCLUSION: This Japanese regional study suggests that indication of re-resection for IGBC should not be determined by pT-factor alone and that much more attention should be paid to pathological and intraoperative findings at prior cholecystectomy.

Association between low preoperative skeletal muscle quality and infectious complications following gastrectomy for gastric cancer.

PURPOSE: It is known that sarcopenia affects the overall short- and long-term outcomes of patients with gastric cancer (GC); however, the effect of muscle quality on infectious complications after gastrectomy for GC remains unclear. We investigated the associations between the preoperative quantity and quality of skeletal muscle on infectious complications following gastrectomy for GC. METHODS: The subjects of this retrospective study were 353 GC patients who underwent radical gastrectomy between 2009 and 2018. We examined the relationships between their clinical factors, including skeletal muscle mass index and intramuscular adipose tissue content (IMAC), and infectious complications after gastrectomy. RESULTS: Infectious complications developed in 59 patients (16.7%). The independent risk factors for infectious complications identified by multivariate analysis were male gender (P < 0.001), prognostic nutritional index below 45 (P = 0.006), and high IMAC (P = 0.011). Patients with a high IMAC were older and had a higher body mass index, as well as a greater age-adjusted Charlson comorbidity index, than those with low or normal IMAC. CONCLUSIONS: Low skeletal muscle quality defined by a high IMAC is a risk factor for infectious complications following gastrectomy. When feasible, preoperative nutritional intervention and rehabilitation aiming to improve muscle quality could reduce infectious complications after gastrectomy for GC.

Liver regeneration after performing associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) is histologically similar to that occurring after liver transplantation using a small-for-size graft.

PURPOSE: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT). METHODS: The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12). RESULTS: Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups. CONCLUSIONS: The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.

Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

Can the location of the mural nodule indicate benign or malignant in branch duct-type intraductal papillary mucinous neoplasm of the pancreas?

BACKGROUND/OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are classified into main duct (MD)-type IPMNs, branch duct (BD)-type IPMNs, and mixed type IPMNs. While MD-type IPMN has a high risk of malignancy and should therefore be considered for resection if the patient is fit, BD-type IPMN needs to be carefully judged for surgical indication. The decision to resect BD-type IPMN is often based on international consensus Fukuoka guidelines 2017, but further investigation is required. In this study, we focused on whether the location of the mural nodule (MN) could be an indicator of malignancy. METHODS: We enrolled 17 cases who had been diagnosed BD-type IPMNs which were surgically resected from January 2016 to December 2019. These cases were classified into benign and malignant group. Subsequently, a clinicopathological study was conducted based on the localization of MN (MN-central type or MN-peripheral type). RESULTS: Although MN was found in 57% (4/11) in the benign group, 88% (7/8) was noted in the malignant group, indicating the presence of MN to be more common in the malignant group. Those with MN consisted of 6 cases of MN-central type and 5 cases of MN-peripheral type. All cases of central type were malignant compared to only one case of the peripheral group being confirmed on histology as cancer. CONCLUSION: BD-IPMN with central mural nodule should be considered high risk for malignancy.