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Chemotherapy has been developed for many years for malignancies, including advanced pancreatic cancer, downsizing the primary site, thereby enabling complete cure with the combination of conversion surgery. Pathological complete remission from operation samples was usually identified as a promising indication for a good prognosis for many carcinomas. Several case reports consisting of pathological complete remission after chemotherapy application have been reported but no case of pathological complete remission that resulted from successful extensive resection by surgery after S-1, irinotecan, and oxaliplatin (SIROX) chemotherapy. A 48-year-old male patient was hospitalized due to abdominal pain which turned out to be a 25 mm-sized advanced uncinate process of pancreatic cancer with possible duodenum invasion and hepatic metastasis. The tumor had decreased after administering 23 sessions of modified SIROX chemotherapy, and he underwent pylorus-preserving pancreaticoduodenectomy with portal vein resection. He was successfully managed with conservative treatment and discharged 12 days postoperatively despite his postoperative weakness. He had been taking S-1 pills for 6 months and until now, 3 years postoperatively, with no relapse. The final pathology reported complete tumor regression. Therefore, we emphasize the oncologic significance of chemotherapy in the uncinate process of pancreatic cancer and the potential role of conversion surgery., (© 2024. Japanese Society of Gastroenterology.)

The function of a biomacromolecule is not only determined by its three-dimensional structure but also by its electronic state. Quantum chemical calculations are promising non-empirical methods available for determining the electronic state of a given structure. In this study, we used the fragment molecular orbital (FMO) method, which applies to biopolymers such as proteins, to provide physicochemical property values on representative structures in the SCOP2 database of protein families, a subset of the Protein Data Bank. Our dataset was constructed by over 5,000 protein structures, including over 200 million inter-fragment interaction energies (IFIEs) and their energy components obtained by pair interaction energy decomposition analysis (PIEDA) using FMO-MP2/6-31 G*. Moreover, three basis sets, 6-31 G*, 6-31 G**, and cc-pVDZ, were used for the FMO calculations of each structure, making it possible to compare the energies obtained with different basis functions for the same fragment pair. The total data size is approximately 6.7 GB. Our dataset will be useful for functional analyses and machine learning based on the physicochemical property values of proteins., (© 2024. The Author(s).)

A seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol -1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases., (open access.)

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures., (open access.)

A 54-year-old man with resectable pancreatic cancer and abnormally high levels of carbohydrate antigen 19-9 (CA19-9) underwent 6 months of platinum-based chemotherapy. This treatment substantially reduced the primary tumor size and normalized CA19-9 levels. Subsequently, radical surgery was conducted. However, eight months post-surgery, CA19-9 levels re-elevated, and lymph-node recurrence was observed. The patient underwent treatment with poly(adenosine diphosphate ribose) polymerase inhibitors (PARPi) following the detection of frameshift L1904fs*5 via BRACAnalysis CDx. This mutation revealed a stop codon, leading to the inactivation of the BRCA function. Additionally, the patient tested positive for a mutation in the breast cancer susceptibility gene 2 ( BRCA2 ). Two months after starting PARPi, there was evidence of tumor shrinkage. Nevertheless, 5 months later, CA19-9 levels increased again, and new metastatic tumors in the liver were identified. Genomic profiling test (FoundationOne CDx) of surgically resected specimens revealed a BRCA2 pL1908fs*2 mutation, indicating its location in the cis position on the same allele as the germline BRCA2 mutation. The pL1908fs*2 deletion, alongside the original L1904fs*5, resulted in three deletions, equating to one amino acid deletion. This deletion ultimately reversed the stop codon, leading to the restoration of BRCA2 functionality. Despite treatment with PARPi for postoperative recurrence, a sustained response was not achieved owing to BRCA reversion mutations. It is essential to acknowledge the rarity of BRCA reversion mutations, which limit the effectiveness of PARPi., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: Recently, artificial intelligence (AI) has been applied to clinical diagnosis. Although AI has already been developed for gastrointestinal (GI) tract endoscopy, few studies have applied AI to endoscopic ultrasound (EUS) images. In this study, we used a computer-assisted diagnosis (CAD) system with deep learning analysis of EUS images (EUS-CAD) and assessed its ability to differentiate GI stromal tumors (GISTs) from other mesenchymal tumors and their risk classification performance., Materials and Methods: A total of 101 pathologically confirmed cases of subepithelial lesions (SELs) arising from the muscularis propria layer, including 69 GISTs, 17 leiomyomas and 15 schwannomas, were examined. A total of 3283 EUS images were used for training and five-fold-cross-validation, and 827 images were independently tested for diagnosing GISTs. For the risk classification of 69 GISTs, including very-low-, low-, intermediate- and high-risk GISTs, 2,784 EUS images were used for training and three-fold-cross-validation., Results: For the differential diagnostic performance of GIST among all SELs, the accuracy, sensitivity, specificity and area under the receiver operating characteristic (ROC) curve were 80.4%, 82.9%, 75.3% and 0.865, respectively, whereas those for intermediate- and high-risk GISTs were 71.8%, 70.2%, 72.0% and 0.771, respectively., Conclusions: The EUS-CAD system showed a good diagnostic yield in differentiating GISTs from other mesenchymal tumors and successfully demonstrated the GIST risk classification feasibility. This system can determine whether treatment is necessary based on EUS imaging alone without the need for additional invasive examinations.

Background: The cutoff value for stereomicroscopic on-site evaluation (SOSE) in endoscopic ultrasound-guided tissue acquisition (EUS-TA) has high diagnostic sensitivity when a Franseen needle is employed for upper gastrointestinal subepithelial lesions (SELs) (stereomicroscopically visible white core [SVWC] ≥ 4 mm)., Aim: We aimed to determine whether high diagnostic sensitivity could be obtained when EUS-TA was performed using a Fork-tip needle., Methods: Twenty-one patients were prospectively registered. Patients underwent EUS-TA using a Fork-tip needle for upper gastrointestinal SELs at Kitasato University Hospital between January and November 2022. Punctures were made twice using the needle, and SOSE was conducted for each specimen. Blood and physical examination were performed to assess adverse events. Pathological diagnosis was made using hematoxylin and eosin-stained sections and immunohistochemical staining. Statistical comparisons were completed using Fisher's exact tests., Results: The diagnostic rate of EUS-TA was 100% (21/21 cases). The final diagnosis was gastrointestinal stromal tumor in 17 (81.0%) and leiomyoma in 4 (19.0%) patients. SOSE was conducted on all 42 punctures, and the tissue sampling rate was 100% (42/42 punctures). Specimens with SVWC ≥ 4 mm were collected in 97.6% punctures (41/42 punctures) and the diagnostic sensitivity for these specimens was 100% (41/41 punctures), which is significantly higher (p < 0.0238) compared to the absence of cutoff value (diagnostic sensitivity of 0%). No EUS-TA-related adverse events occurred., Conclusions: EUS-TA combined with SOSE for upper gastrointestinal SEL using a fork-tip needle had a high diagnostic rate, and the cutoff value of SVWC ≥ 4 mm had high diagnostic sensitivity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aims: To validate endoscopic ultrasound-guided tissue acquisition (EUS-TA) used in conjunction with stereomicroscopic on-site evaluation (SOSE) as a preoperative diagnostic tool for resectable pancreatic cancer (R-PC) and borderline resectable PC (BR-PC)., Methods: Seventy-eight consecutive patients who underwent EUS-TA for suspected R-PC or BR-PC were enrolled. The primary endpoint was the sensitivity of EUS-TA together with SOSE based on the stereomicroscopically visible white core (SVWC) cutoff value. One or two sites were punctured by using a 22-gauge biopsy needle for EUS-TA, based on the SOSE findings., Results: We collected 99 specimens from 56 and 22 patients with R-PC and BR-PC, respectively. Based on the SOSE results, we performed 57 procedures with one puncture. The SVWC cutoff values were met in 73.7% and 73.1% of all specimens and in those obtained during the first puncture, respectively. The final diagnoses were malignant and benign tumors in 76 and two patients, respectively. The overall sensitivity, specificity, and accuracy of EUS-TA for the 78 lesions were 90.8%, 100%, and 91.0%, respectively. The sensitivity for malignant diagnosis based on the SVWC cutoff value were 89.5% and 90.4% for the first puncture and all specimens, respectively., Conclusions: The sensitivity of EUS-TA in conjunction with SOSE for malignancy diagnosis in patients with suspected R-PC or BR-PC was 90.4%.

Energy decomposition analysis is one of the most attractive features of fragment molecular orbital (FMO) calculations from the point of view of practical applications. Here we report some enhancements for PIEDA in the ABINIT-MP program. One is a separation of the dispersion-type stabilization from the electron correlation energy, traditionally referred to as the "dispersion interaction" (DI). Another is an alternative evaluation of the electrostatic (ES) interaction using the restrained electrostatic potential (RESP) charges. The GA:CT stacked base pair and the Trp-Cage miniprotein were used as illustrative examples., (© 2023 Wiley Periodicals LLC.)

Bovine serum albumin (BSA) has a uranyl(VI) binding hotspot where uranium is tightly bound by three carboxylates. Uranyl oxygen is "soaked" into the hydrophobic core of BSA. Isopropyl hydrogen of Val is trapped near UO 2 2+ and upon photoexcitation, C-H bond cleavage is initiated. A unique hydrophobic contact with "yl"-oxygen, as observed here, can be used to induce C-H activation.

Background and Aim: Stereomicroscopic on-site evaluation (SOSE) is a rapid evaluation method for endoscopic ultrasound-guided tissue acquisition (EUS-TA) with a high diagnostic sensitivity when the stereomicroscopically visible white core (SVWC) cut-off value (≥ 11 mm) is met. We prospectively examined the association between SVWCs and the adequacy of tissue specimens, assuming subsequent comprehensive genome profiling (CGP)., Methods: This study included 66 consecutive patients with suspected unresectable pancreatic cancer who underwent EUS-TA. The primary endpoint was the frequency of combined samples with ≥ 20% tumor cell content that met over twice the SVWC (T-SVWC) cut-off value, achieved through multiple punctures. The secondary endpoints were the number of punctures, the percentage of SVWC cut-off values, adverse events, the positive diagnosis rate, and the tissue section area., Results: The median number of EUS-TA punctures for suspected unresectable pancreatic cancer was 3 (range, 3-4); SVWC and T-SVWC cut-off values were obtained in 171/206 specimens and 65/66 patients, respectively. There were no EUS-TA-related adverse events. The positive diagnosis rate of EUS-TA was 95.5%. Among the 63 patients meeting the T-SVWC cut-off value in pathological diagnoses, the median tumor cell content was 40% (range, 5-80%), with 57 patients having tumor cell content ≥ 20%. The median tissue section area was 15 (range, 3-40) mm 2 ., Conclusions: When performing EUS-TA for unresectable pancreatic cancer with the intention of subsequent CGP, obtaining a high tumor cell content (≥ 20%) by assessing the T-SVWC cut-off value via SOSE may serve as a novel indicator for on-site estimation of CGP suitability for EUS-TA specimens., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

A novel in silico drug design procedure is described targeting the Main protease (Mpro) of the SARS-CoV-2 virus. The procedure combines molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. The binding structure and properties of Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through drug repositioning, targeting Mpro. Several poses of the Mpro and NFV complexes were generated by docking, from which four docking poses were selected by scoring with FMO energy. Then, each pose was subjected to MD simulation, 100 snapshot structures were sampled from each of the generated MD trajectories, and the structures were evaluated by FMO calculations to rank the pose based on binding energy. Several residues were found to be important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NFV. Asn142 is presumably regarded to form hydrogen bonds or CH/π interaction with NFV; however, in the present calculation, their interactions were transient. Moreover, the tert -butyl group of NFV had no interaction with Mpro. Identifying such strong and weak interactions provides candidates for maintaining and substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Besides the interaction between NFV and the amino acid residues of Mpro, the desolvation effect of the binding pocket also affected the ranking order. A similar procedure of drug design was applied to Lopinavir, and the calculated interaction energy and experimental inhibitory activity value trends were consistent. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained.

Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events-BRCA1 (n = 3), BRCA2 (n = 18)-including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion-insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aims: In stereomicroscopic sample isolation processing, the cutoff value (≥4 mm) of stereomicroscopically visible white cores indicates high diagnostic sensitivity. We aimed to evaluate endoscopic ultrasound-guided tissue acquisition (EUS-TA) using a simplified stereomicroscopic on-site evaluation of upper gastrointestinal subepithelial lesions (SELs)., Methods: In this multicenter prospective trial, we performed EUS-TA using a 22-gauge Franseen needle in 34 participants with SELs derived from the upper gastrointestinal muscularis propria, requiring pathological diagnosis. The presence of stereomicroscopically visible white core (SVWC) in each specimen was assessed using stereomicroscopic on-site evaluation. The primary outcome was EUS-TA's diagnostic sensitivity with stereomicroscopic on-site evaluation based on the SVWC cutoff value (≥4 mm) for malignant upper gastrointestinal SELs., Results: The total number of punctures was 68; 61 specimens (89.7%) contained stereomicroscopically visible white cores ≥4 mm in size. The final diagnoses were gastrointestinal stromal tumor, leiomyoma, and schwannoma in 76.5%, 14.7%, and 8.8% of the cases, respectively. The sensitivity of EUS-TA with stereomicroscopic on-site evaluation based on the SVWC cutoff value for malignant SELs was 100%. The per-lesion accuracy of histological diagnosis reached the highest level (100%) at the second puncture., Conclusion: Stereomicroscopic on-site evaluation showed high diagnostic sensitivity and could be a new method for diagnosing upper gastrointestinal SELs using EUS-TA.

Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is more common in patients with asymptomatic common bile duct stones (CBDSs) and normal anatomy than in those with symptomatic CBDS; however, studies on the effect of surgically altered anatomy are lacking. We aimed to investigate whether asymptomatic CBDS in balloon enteroscopy-assisted ERCP cases for surgically altered anatomy also has a high incidence of PEP and analyze the risk factors for PEP., Methods: We retrospectively analyzed 108 consecutive patients who underwent initial ERCP for CBDS with surgically altered anatomies and with naive papilla at Kitasato University Hospital from April 2015 to December 2022., Results: Study participants were as follows: 92 (85%) patients with symptomatic CBDS and 16 (15%) patients asymptomatic CBDS. The overall bile duct cannulation success rate was 89.8%, with PEP occurring in 7.4% of patients (symptomatic CBDS: 3.3%, asymptomatic CBDS: 31.3%). PEP incidence was significantly higher for asymptomatic CBDS (p = .0017). Multivariate analysis identified asymptomatic CBDS and precut sphincterotomy as significant risk factors for PEP., Conclusions: Asymptomatic CBDS may be a risk factor for PEP onset in balloon enteroscopy-assisted ERCP with surgically altered anatomy. Therefore, the procedure should be performed after obtaining sufficient informed consent and adequate preparation., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective The effect of sarcopenia on the prognosis of patients undergoing chemotherapy for unresectable pancreatic ductal adenocarcinoma remains largely unexplored. In this retrospective study, we investigated the relationship between sarcopenia and the prognosis of patients receiving first-line nanoparticle albumin-bound paclitaxel plus gemcitabine for unresectable pancreatic ductal adenocarcinoma. Methods We enrolled 251 patients with unresectable metastatic or locally advanced pancreatic ductal adenocarcinoma who had received chemotherapy between January 2015 and December 2020 at Kitasato University Hospital. Univariate and multivariate analyses were performed using the stratified Cox proportional hazards model to determine variables significantly associated with the progression-free and overall survival. Propensity score matching was performed to mitigate selection bias effects. Results In the propensity score-matched cohort, the progression-free and overall survival were not significantly different between the sarcopenia and non-sarcopenia groups (p=0.335, and 0.679 respectively). The skeletal muscle index decreased by 4.4% and 6.5% in the sarcopenia and non-sarcopenia groups, respectively, during the early treatment phase (p=0.084). There were no significant differences between groups with regard to major adverse events or drug toxicity occurrences. Both the progression-free and overall survival were significantly shorter in the skeletal muscle index loss group than in the non-skeletal muscle index loss group (p=0.026 and 0.045, respectively). Conclusion Skeletal muscle index loss during the initial treatment phase may be an early marker for the long-term prognosis of patients receiving nanoparticle albumin-bound paclitaxel plus gemcitabine as first-line treatment for unresectable pancreatic ductal adenocarcinoma.

Over 4 billion years of evolution, multiple mutations, including nucleotide substitutions, gene and genome duplications and recombination, have established de novo genes that translate into proteins with novel properties essential for high-order cellular functions. However, molecular processes through which a protein evolutionarily acquires a novel function are mostly speculative. Recently, we have provided evidence for a potential evolutionary mechanism underlying how, in mammalian cells, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) evolved into a GTP sensor from ATP-utilizing kinase. Mechanistically, PI5P4Kβ has acquired the guanine efficient association (GEA) motif by mutating its nucleotide base recognition sequence, enabling the evolutionary transition from an ATP-dependent kinase to a distinct GTP/ATP dual kinase with its K M for GTP falling into physiological GTP concentrations-the genesis of GTP sensing activity. Importantly, the GTP sensing activity of PI5P4Kβ is critical for the manifestation of cellular metabolism and tumourigenic activity in the multicellular organism. The combination of structural, biochemical and biophysical analyses used in our study provides a novel framework for analysing how a protein can evolutionarily acquire a novel activity, which potentially introduces a critical function to the cell., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: We prospectively investigated whether cells derived from pancreatic cancers adhered to the puncture needle's external surface after endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and whether wiping the needle with alcohol swabs removed residual cancer cells., Methods: The participants were 100 consecutive patients who underwent EUS-FNA for suspected pancreatic ductal adenocarcinoma. In the first pass of EUS-FNA, we prepared aspiration and lavage cytological diagnosis materials from the lumen and external surface of the puncture needle, respectively. This was repeated in the second pass, although the needle's external surface was wiped with an alcohol swab., Results: The positivity rates of aspiration cytological diagnosis for the first and second passes were 67% and 72%, respectively. The positivity rates of lavage cytological diagnosis of the needle's external surface on the first and second passes were 20% and 3%, respectively. Wiping the needle's external surface with alcohol swabs significantly reduced the proportion of cancer cells detected ( P < 0.001). The accuracy rate based on all the collected specimens was 90%. There were no EUS-FNA-related adverse events., Conclusion: Pancreatic cancer cells may adhere to the puncture needle's external surface after EUS-FNA. Wiping the needle with alcohol swabs after each puncture effectively removes residual cancer cells., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Sample isolation processing by stereomicroscopy (SIPS) was recently introduced as an alternative to rapid on-site cytologic evaluation and showed high accuracy for use in pathologic diagnoses. SIPS is a useful, but slightly complicated procedure; therefore, a new, more straightforward method for the objective estimation of the core tissue amount required during the sampling is desirable. We evaluated the usefulness of the automated multiband imaging system (AMUS) for calculating whitish core amounts in EUS-FNA biopsy (EUS-FNAB) samples from patients with subepithelial lesions (SELs)., Methods: Four EUS-FNAB specimens per patient were obtained from 20 patients with upper gastrointestinal SELs. The correlation between the whitish core amount calculated by AMUS, length of the manually measured whitish cores (stereomicroscopically visible white core [SVWC]), and sample suitability for pathologic evaluation were analyzed., Results: We identified 13 patients with gastrointestinal stromal tumors, five with leiomyomas, one with a schwannoma, and one with an ectopic pancreas. The histological diagnostic accuracy was 100%, median SVWC length was 9 mm, and median whitish core area, calculated using AMUS, was 10 mm 2 . SVWC length correlated with whitish core amount (ρ = 0.81, P < 0.01) and adequacy score (ρ = 0.54, P < 0.01). Whitish core amount correlated with adequacy score (ρ = 0.54, P < 0.01). The area under the receiver-operating characteristic curve calculated for whitish core amount with respect to the histological diagnosis was 0.83 (P < 0.01; cutoff ≥4 mm 2 , sensitivity 98.4%)., Conclusions: AMUS, a simple on-site verification instrument, is an alternative to SIPS for determining the appropriate SEL tissue sampling quantity with high diagnostic accuracy., Competing Interests: None

Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience). However, the genesis and evolution of its GTP responsiveness remain unknown. Here, we reveal that PI5P4Kβ has acquired GTP preference by generating a short dual-nucleotide-recognizing motif called the guanine efficient association (GEA) motif. Comparison of nucleobase recognition with 660 kinases and 128 G proteins has uncovered that most kinases and PI5P4Kβ use their main-chain atoms for adenine recognition, while the side-chain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of GTP reactivity is accompanied by an extended activity toward inosine triphosphate (ITP) and xanthosine triphosphate (XTP). Along with the evolutionary analysis data that point to strong negative selection of the GEA motif, these results suggest that the GTP responsiveness of PI5P4Kβ has evolved from a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Aim: Endoscopic bilateral self-expandable metallic stent (SEMS) placement for unresectable malignant hilar biliary obstruction (MHBO) is widely performed; however, re-intervention after recurrent biliary obstruction (RBO) is often challenging. We compared stent-in-stent (SIS) and side-by-side (SBS) SEMS placement for MHBO considering re-intervention for RBO., Methods: One hundred five consecutive patients with MHBO who underwent endoscopic bilateral SEMS placement in our hospital and its affiliated institutions were enrolled in this study; 75 patients underwent partial SIS deployment between December 2005 and December 2012; and 30 underwent SBS deployment between January 2013 and March 2019. Initial treatments and re-interventions in each group were retrospectively evaluated., Results: Technical success rate (92% vs 100%, P = 0.179), procedure duration (46 vs 35 min, P = 0.382), functional success rate (97.1% vs 100%, P = 1.00), complication rate (24.6% vs 20.0%, P = 0.797), time to RBO (260 vs 312 days; Gray test, P = 0.815), and rate of RBO (59.4% vs 70.0%, P = 0.371) were not significantly different between the SIS and SBS groups. However, bilateral re-stenting with plastic stents through SEMS was successful in 63.4% of patients in the SIS group compared with 100% of patients in the SBS group (P = 0.0013). Median time to RBO upon first re-stenting with a plastic stent was 75 days (range, 11-195 days)., Conclusions: Endoscopic re-stenting after RBO was significantly more successful in the SBS group than in the SIS group. SBS method is suitable for MHBO considering revisionary stent placement., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Stone removal using endoscopic papillary large balloon dilation (EPLBD) is extremely effective. However, limited research exists regarding the risk factors for perforation of the duodenal papilla and bile duct, which may be fatal., Aims: We aimed to investigate the risk factors for perforation during EPLBD + stone removal., Methods: We included patients who underwent EPLBD + stone removal at four medical facilities between January 2008 and December 2018. We retrospectively analyzed the risk factors for perforation and their relationship between overdilation and adverse events. Overdilation was defined as a ratio of the balloon diameter to the diameter of the bile duct that exceeded 100%. The diameter of the distal bile duct was measured using the diameter of the intrapancreatic bile duct at a point 10 mm toward the liver from the narrow distal segment on a cholangiogram., Results: We included 310 patients (177 males; median age: 79 years [range: 46-102 years]). Perforation occurred in five patients (1.6%). Multivariate analysis indicated that no surrounding-pancreas (half or less of the circumference of the intrapancreatic bile duct was surrounded by the pancreatic parenchyma) was a significant risk factor (perforation rate: 8.3%, p = 0.011, odds ratio: 12.7 [95% confidence interval: 1.8-90.5]). No significant difference was found between the overdilation and non-overdilation groups regarding the occurrence of pancreatitis, bleeding, and cholangitis. Perforation rate in patients with no surrounding pancreas + overdilation was 16.7% (2/12). Patients with perforation underwent conservative therapy, which improved their conditions., Conclusions: EPLBD + stone removal should be avoided in patients with no surrounding pancreas. Overdilation is not a risk factor for adverse procedural events; however, it should be limited in patients with surrounding pancreas., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Variational quantum eigensolver (VQE)-based quantum chemical calculations have been extensively studied as a computational model using noisy intermediate-scale quantum devices. The VQE uses a parametrized quantum circuit defined through an "ansatz" to generate approximated wave functions, and the appropriate choice of an ansatz is the most important step. Because most chemistry problems focus on the energy difference between two electronic states or structures, calculating the total energies in different molecular structures with the same accuracy is essential to correctly understand chemistry and chemical processes. In this context, the development of ansatzes that are capable of describing electronic structures of strongly correlated systems accurately is an important task. Here we applied a conventional unitary coupled cluster (UCC) and a newly developed multireference unitary coupled cluster with partially generalized singles and doubles (MR-UCCpGSD) ansatzes to the quasi-reaction pathway of Be insertion into H 2 , LiH molecule under covalent bond dissociation, and a rectangular tetra-hydrogen cluster known as a P4 cluster; these are representative systems in which the static electron correlation effect is prominent. Our numerical simulations revealed that the UCCSD ansatz exhibits extremely slow convergence behaviour around the point where an avoided crossing occurs in the Be + H 2 → BeH 2 reaction pathway, resulting in a large discrepancy of the simulated VQE energy from the full-configuration interaction (full-CI) value. By contrast, the MR-UCCpGSD ansatz can give more reliable results with respect to total energy and the overlap with the full-CI solution, insisting the importance of multiconfigurational treatments in the calculations of strongly correlated systems. The MR-UCCpGSD ansatz allows us to compute the energy with the same accuracy regardless of the strength of multiconfigurational character, which is an essential property to discuss energy differences of various molecular systems.

Objective: In sample isolation processing by stereomicroscopy (SIPS), a technique used to assess the quality of specimens collected during endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA), the cutoff value of stereomicroscopically visible white core (SVWC) (≥11 mm) indicates high diagnostic sensitivity. However, the procedure of SIPS is complicated and time-consuming. Therefore, we devised the stereomicroscopic on-site evaluation (SOSE), a new rapid assessment method that is simpler than SIPS and only determines if the SVWC cutoff value is attained. We aimed to examine the usefulness of SOSE in a multicenter, prospective setting., Methods: Seventy patients from multiple institutions with solid pancreatic masses suspected to be pancreatic cancer were included. EUS-TA was performed using a 22-gauge Franseen needle. SVWCs were measured on-site using stereomicroscopy. The primary outcome was the sensitivity of SVWC cutoff value in EUS-TA with SOSE., Results: The total number of punctures was 214 and SOSE was performed on 150 punctures. The SVWC cutoff value collection rate was 100% per lesion, with 80% in the first pass, 79% in the second pass, and 78% per puncture in all passes. The median time taken to determine the SVWC cutoff value for SOSE was 47 s. The sensitivity of the SVWC cutoff value was 93.2% for histology and 96.6% for cytology + histology. The per-lesion accuracy of pathological diagnosis reached the highest level (98.6%) at the second puncture., Conclusions: SOSE showed high diagnostic sensitivity and may be a new rapid assessment method for the diagnosis of malignant pancreatic cancer using EUS-TA., Competing Interests: Declaration of competing interest Authors declare no conflict of interest for this article., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with complications such as post-ERCP pancreatitis (PEP). Protease inhibitors, including nafamostat mesylate (NM), have been evaluated for prophylaxis against PEP., Aim: We describe the first multicenter randomized controlled trial assessing the prophylactic efficacy of NM against PEP., Methods: In this multicenter prospective study, we aimed to enroll 800 patients aged ≥ 20 years with a planned ERCP between December 2012 and March 2019. The primary outcome was the incidence and severity of PEP in patients who did not receive NM (non-NM) versus those who did (NM; 20 mg). Secondary outcomes included the incidence of PEP by NM initiation (pre- and post-ERCP), risk factors for PEP, and NM-related adverse events., Results: Only 441 of the planned 800 patients were enrolled (non-NM: n = 149; NM: n = 292 [pre-ERCP NM: n = 144; post-ERCP NM: n = 148]). Patient characteristics were balanced at baseline with no significant differences between groups. PEP occurred in 40/441 (9%) patients (non-NM: n = 15 [10%]; NM: n = 25 [9%]), including 17 (12%) and eight (8%) in the pre-ERCP and post-ERCP NM groups, respectively. In the NM group, the incidence of PEP was lower in the low-risk group than in the high-risk group. Pancreatic injection and double-guidewire technique were independent risk factors for PEP. NM-related adverse events of hyperkalemia occurred in two (0.7%) patients., Conclusions: We found no evidence for the prophylactic effect of NM against PEP, regardless of the timing of administration; however, further studies are needed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

A 76-year-old man with epigastric pain developed 1 month earlier was referred to our department for additional screening and treatment after abdominal ultrasound revealed a mass shadow in the pancreatic head and liver. Blood biochemistry revealed signs of mild jaundice and hepatic dysfunction. Abdominal contrast-computed tomography revealed an irregular hypodense mass with poor enhancement in the pancreatic head and several hypodense nodules in the liver. Endoscopic examination revealed duodenal infiltration signs. The biopsied duodenal mucosa contained atypical cells with high nuclear-to-cytoplasmic ratios; the cells stained positive for CD56, chromogranin, and synaptophysin, and the Ki-67 index was 90%. Accordingly, pancreatic neuroendocrine carcinoma (PanNEC) was diagnosed. Platinum-based chemotherapy (6 courses) and streptozotocin (10 courses) were adopted as the first- and second-line regimens, respectively. However, the patient showed progressive disease (PD). Pembrolizumab was added as a third-line regimen (13 courses) after confirming PanNEC with high microsatellite instability (MSI-high). Despite a temporary partial response (PR), the patient showed PD by the end of the 13 courses and died 1 year and 7 months after diagnosis. Although there is no established PanNEC therapy, those with MSI-high may respond favorably to pembrolizumab. Therefore, we should ascertain the MSI status of any PanNEC in routine practice., (© 2021. Japanese Society of Gastroenterology.)

Visualization of the interfacial electrostatic complementarity (VIINEC) is a recently developed method for analyzing protein-protein interactions using electrostatic potential (ESP) calculated via the ab initio fragment molecular orbital method. In this Letter, the molecular interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with human angiotensin-converting enzyme 2 (ACE2) and B38 neutralizing antibody were examined as an illustrative application of VIINEC. The results of VIINEC revealed that the E484 of RBD has a role in making a local electrostatic complementary with ACE2 at the protein-protein interface, while it causes a considerable repulsive electrostatic interaction. Furthermore, the calculated ESP map at the interface of the RBD/B38 complex was significantly different from that of the RBD/ACE2 complex, which is discussed herein in association with the mechanism of the specificity of the antibody binding to the target protein.

Background/aims: Cholecystitis can occur after the placement of covered self-expandable metallic stents for distal malignant biliary obstructions. We aimed to identify risk factors for cholecystitis following covered self-expandable metallic stent placement., Methods: We investigated risk factors related to cholecystitis following covered self-expandable metallic stent placement in 118 patients with distal malignant biliary obstructions between January 1, 2015 and April 30, 2019. Endoscopic assessments and tumor invasion to the arteries feeding the gallbladder were determined by a pancreaticobiliary endoscopist and a radiologist, respectively., Results: The median patient age was 72 years (men, 61.0%). The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct were observed in 35 (29.7%) and 35 (29.7%) patients, respectively. During the observation period (median, 179 days), cholecystitis occurred in 18 (15.3%) patients. Multivariate analysis revealed the flow of the contrast agent into the gallbladder (p=0.023) and tumor involvement in the orifice of the cystic duct (p=0.005) as significant independent risk factors associated with cholecystitis., Conclusion: The flow of the contrast agent into the gallbladder and tumor involvement in the orifice of the cystic duct are potential independent risk factors for cholecystitis following the placement of covered self-expandable metallic stents. A follow-up prospective study is warranted to validate their influence.

Background: Information on whether a fine-needle biopsy (FNB) needle can improve histopathological specimen quality or the amount of core tissue collected in the diagnosis of subepithelial lesions (SELs) remains insufficient. In this study, we aimed to compare the procedure outcomes and adequacy of histopathological specimens of fine-needle aspiration (FNA) and FNB needles in endoscopic ultrasound-guided tissue acquisition (EUS-TA) using sample isolation processing by stereomicroscopy (SIPS) in patients with SELs., Methods: We performed a retrospective comparison of SEL cases registered in two previously conducted prospective studies. Of 61 cases, we identified 56 cases of SELs that involved the muscularis propria layer. Of these, 27 patients who underwent EUS-TA using a 22-gauge FNA needle between July 2016 and December 2017, and 29 patients who underwent the procedure using a 22-gauge FNB needle between March 2018 and January 2019 were included in the FNA and FNB group, respectively., Results: Patient background characteristics did not differ between the groups. The technical success rate was 100% in both groups. The median adequacy score was significantly higher in the FNB group than in the FNA group (P < .01). The histological diagnosis showed no significant difference in the accuracy rate between the groups., Conclusions: In EUS-TA using the SIPS procedure to target SELs derived from the muscularis propria layer, FNB needles collect more core tissues and significantly improve histopathological specimen quality compared with FNA needles. When combined with SIPS, a high tissue diagnosis rate may be obtained regardless of the type of puncture needle used., (© 2021 Wiley Periodicals LLC.)

By the splendid advance in computation power realized with the Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamic structures of protein-ligand complexes in a parallel way. We thus carried out electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (M pro ) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated conditions. Along with a statistical evaluation of the interfragment interaction energies (IFIEs) between the N3 ligand and the surrounding amino-acid residues for 1000 dynamic structure samples, in this study we applied a novel approach based on principal component analysis (PCA) and singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and the residues. We found that the relative importance of each residue is modified via the structural fluctuations and that the ligand is bound in the pharmacophore in a dynamic manner through collective interactions formed by multiple residues, thus providing new insight into structure-based drug discovery.

Objectives: We evaluated the usefulness of a newly developed system with which the total amount of whitish cores in endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) samples is automatically calculated (automated multiband imaging system [AMUS])., Methods: From 30 prospectively enrolled patients suspected of having pancreatic cancer, four EUS-FNAB specimens per patient were obtained. Following AMUS calculations, two specimens were prepared after stereomicroscopy-guided manual division into whitish and reddish sections (isolation group), and the other two were prepared without such division (no-isolation group). The relation of the AMUS results pertaining to the length of the manually measured whitish cores (stereo-microscopically visible white core [SVWC]) and the sample suitability for pathologic evaluation were analyzed., Results: Histological diagnostic accuracy was 90%; median SVWC length, 14 mm; and median area of whitish core calculated using the AMUS, 13 mm 2 . The SVWC length correlated with whitish core amount (ρ = 0.83, p < 0.01) and adequacy score (ρ = 0.50, p < 0.01). The whitish core amount correlated with the adequacy score (ρ = 0.40, p < 0.01). The area under the receiver-operating characteristic curve calculated for whitish core amount with respect to the histological diagnosis was 0.84 ( p < 0.01; cutoff ≥ 8 mm 2 , sensitivity 92.5%). Subgroup analysis (isolation vs. no-isolation group) revealed no significant between-group differences in the median histological adequacy ( p = 0.27) or tumor cell content ratio ( p = 0.28). The median scores for degree of blood contamination were significantly lower in the isolation group than in the no-isolation group ( p < 0.01)., Conclusion: AMUS is a simple on-site verification procedure for determining the appropriate sampling tissue quantity for high diagnostic accuracy., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

A schwannoma is a tumor originating from Schwann cells. It is occasionally observed in the abdominal viscera in the form of a submucosal tumor derived from the gastric or duodenal muscularis propria. To date, only a few studies have reported on pancreatic schwannomas. Furthermore, very few patients are preoperatively diagnosed with pancreatic schwannoma because of the lack of established imaging characteristics distinguishing this type of schwannoma from other conditions. We herein report the first English publication of pancreatic schwannoma in which surgery was avoided because a pathological diagnosis was made solely on the basis of endoscopic ultrasound-guided fine-needle aspiration findings.

We herein report the first case of metastatic pancreatic leiomyosarcoma derived from the urinary bladder diagnosed by an endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) in a 65-year-old woman. The patient had undergone total cystectomy for bladder leiomyosarcoma. Four years thereafter, a nodule was observed in her left lung on chest computed tomography. Suspecting primary lung cancer, pulmonologists at our hospital recommended a thoracoscopic lung biopsy, which the patient refused. Five years post-cystectomy, fluorodeoxyglucose positron emission tomography revealed enlargement of the left lung nodule and a new mass in the pancreatic head. She was referred to our department for the pathological diagnosis of a pancreatic head mass by an EUS-FNB. The EUS-FNB yielded adequate pancreatic tissue for an immunohistochemical analysis. A diagnosis of metastatic pancreatic lesion originating from the urinary bladder was made. In atypical pancreatic tumors, the utilization of an EUS-FNB and immunohistochemical analysis can help establish an accurate diagnosis.

At the stage of SARS-CoV-2 infection in human cells, the spike protein consisting of three chains, A, B, and C, with a total of 3300 residues plays a key role, and thus its structural properties and the binding nature of receptor proteins to host human cells or neutralizing antibodies has attracted considerable interest. Here, we report on interaction analyses of the spike protein in both closed (PDB-ID: 6VXX) and open (6VYB) structures, based on large-scale fragment molecular orbital (FMO) calculations at the level of up to the fourth-order Møller-Plesset perturbation with singles, doubles, and quadruples (MP4(SDQ)). Inter-chain interaction energies were evaluated for both structures, and a mutual comparison indicated considerable losses of stabilization energies in the open structure, especially in the receptor binding domain (RBD) of chain-B. The role of charged residues in inter-chain interactions was illuminated as well. By two separate calculations for the RBD complexes with angiotensin-converting enzyme 2 (ACE2) (6M0J) and B38 Fab antibody (7BZ5), it was found that the binding with ACE2 or antibody partially compensated for this stabilization loss of RBD., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Background and Objectives: Balloon enteroscopy-assisted ERCP (BE-ERCP) has become the first-line therapy for biliopancreatic anastomotic strictures. However, it is not always successful, and salvage methods have not been established. This study aimed to evaluate the outcomes of EUS-guided transanastomotic drainage using a forward-viewing (FV) echoendoscope., Patients and Methods: Of eight cases wherein BE-ERCP treatment failed due to severe or complete benign anastomotic stricture, seven cases underwent EUS-guided choledochojejunostomy, and EUS-guided pancreaticojejunostomy was applied in one case after intubating an FV echoendoscope into the anastomotic site., Results: The success rate of reaching the target site was 100% (8/8) for patients after modified Child resection. The median time to reach the anastomosis was 5 min (range: 3-17 min), and the technical success rate for drainage was 75% (6/8). The median total procedure time was 33.5 min (range: 22-45 min) for six successful cases. Cautery dilatation catheters were necessary to dilate the puncture site in all cases, and no early complications were observed. During the follow-up period (median: 13.3 months [range: 6.5-60.3]), recurrence of the stricture occurred in one case, and a stent-free status was achieved after 6-12 months of stent placement in five cases., Conclusions: EUS-guided transanastomotic drainage using an FV echoendoscope is a feasible and safe rescue technique for the management of benign severe biliopancreatic anastomotic strictures., Competing Interests: None

Background: Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN., Patients and Methods: A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy., Results: The methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277)., Conclusions: CDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma-carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.