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Hiroshi Matsuda,1 Kota Yokoyama,2 Noriko Sato,2 Kengo Ito,3 Kiyotaka Nemoto,4 Hiroshi Oba,5 Haruo Hanyu,6 Hidekazu Kanetaka,6 Sunao Mizumura,7 Shin Kitamura,8 Hitoshi Shinotoh,9 Hitoshi Shimada,9 Tetsuya Suhara,9 Hitoshi Terada,10 Tomoya Nakatsuka,10 Shinobu Kawakatsu,11 Hiroshi Hayashi,12 Takashi Asada,13 Tetsutaro Ono,14 Tomoaki Goto,14 Keiko Shigemori14 1Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 2Department of Radiology, National Center Hospital of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 3Innovation Center for Clinical Research, National Center for Geriatrics and Gerontology, Obu, Japan; 4Department of Psychiatry, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan; 5Department of Radiology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan; 6Department of Geriatric Medicine, Tokyo Medical University Hospital, Shinjuku-ku, Tokyo, Japan; 7Department of Radiology, Toho University Omori Medical Center, Oota-ku, Tokyo, Japan; 8Department of Internal Medicine, Nippon Medical School Musashi Kosugi Hospital, Kawasaki, Japan; 9Department of Functional Brain Imaging Research, Clinical Research Cluster, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; 10Department of Radiology, Toho University Sakura Medical Center, Sakura, Japan; 11Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan; 12Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan; 13Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo, Japan; 142nd Group, 2nd Planning Department, 1st Integrated Communication Division, Communication and Information Center, Information Innovation Operations, Dai Nippon Printing Co., Ltd., Tokyo, JapanCorrespondence: Hiroshi MatsudaIntegrative Brain Imaging Center, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, JapanTel +81 42 341 2711Email matsudah@ncnp.go.jpBackground: The differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is particularly important because DLB patients respond better to cholinesterase inhibitors but sometimes exhibit sensitivity to neuroleptics, which may cause worsening of clinical status. Antemortem voxel-based morphometry (VBM) using structural MRI has previously revealed that patients with DLB have normal hippocampal volume, but atrophy in the dorsal mesopontine area.Objectives: The aim of this multicenter study was to determine whether VBM of the brain stem in addition to that of medial temporal lobe structures improves the differential diagnosis of AD and DLB.Methods: We retrospectively chose 624 patients who were clinically diagnosed with either DLB (239 patients) or AD (385 patients) from 10 institutes using different MR scanners with different magnetic field strengths. In all cases, VBM was performed on 3D T1-weighted images. The degree of local atrophy was calculated using Z-score by comparison with a database of normal volumes of interest (VOIs) in medial temporal lobe (MTL) and the dorsal brain stem (DBS). The discrimination of DLB and AD was evaluated using Z-score values in these two VOIs. MRI data from 414 patients were used as the training data set to determine the classification criteria, with the MRI data from the remaining 210 patients used as the test data set.Results: The DLB and AD patients did not differ with respect to mean age or Mini-Mental State Examination scores. Z-index scores showed that there was significantly more atrophy in MTL of AD patients, compared to DLB patients and in DBS of DLB patients, compared to AD patients. The discrimination accuracies of VBM were 63.3% in the test data set and 73.4% in the training data set.Conclusion: VBM of DBS in addition to that of MTL improves the differentiation of DLB and AD.Keywords: dementia with Lewy bodies, Alzheimer’s disease, MRI, voxel-based morphometry

Aims: Globular glial tauopathy (GGT) is a new category within the 4‐repeat tauopathies that is characterised neuropathologically by tau‐positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau‐positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. Methods: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three‐dimensional imaging, and biochemical and genetic analysis of tau. Results: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process‐like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord‐like, and round/horseshoe‐shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe‐shaped NCIs were observed only in Type III cases. Conclusions: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity. [ABSTRACT FROM AUTHOR]

Purposes: We performed a conversation analysis of the speech conducted among the surgical team during three-dimensional (3D)-printed liver model navigation for thrice or more repeated hepatectomy (TMRH)., Methods: Seventeen patients underwent 3D-printed liver navigation surgery for TMRH. After transcription of the utterances recorded during surgery, the transcribed utterances were coded by the utterer, utterance object, utterance content, sensor, and surgical process during conversation. We then analyzed the utterances and clarified the association between the surgical process and conversation through the intraoperative reference of the 3D-printed liver., Results: In total, 130 conversations including 1648 segments were recorded. Utterance coding showed that the operator/assistant, 3D-printed liver/real liver, fact check (F)/plan check (Pc), visual check/tactile check, and confirmation of planned resection or preservation target (T)/confirmation of planned or ongoing resection line (L) accounted for 791/857, 885/763, 1148/500, 1208/440, and 1304/344 segments, respectively. The utterance's proportions of assistants, F, F of T on 3D-printed liver, F of T on real liver, and Pc of L on 3D-printed liver were significantly higher during non-expert surgeries than during expert surgeries. Confirming the surgical process with both 3D-printed liver and real liver and performing planning using a 3D-printed liver facilitates the safe implementation of TMRH, regardless of the surgeon's experience., Conclusions: The present study, using a unique conversation analysis, provided the first evidence for the clinical value of 3D-printed liver for TMRH for anatomical guidance of non-expert surgeons., (© 2024. The Author(s).)

Objective: To reappraise whether preoperative autologous blood donation reduces post-hepatectomy liver failure (PHLF) in major hepatectomy for perihilar malignancy., Summary Background Data: Autologous blood storage and transfusion are carried out to reduce the use of allogeneic blood transfusion during hepatectomy and prevent postoperative complications. However, the clinical benefit in major hepatectomy has been controversial., Methods: This randomized clinical trial included patients who underwent major hepatectomy with extrahepatic bile duct resection for perihilar malignancy. Eligible patients were randomly assigned (1:1) to undergo surgery with or without the use of autologous blood transfusion. The primary outcome was the incidence of clinically relevant PHLF (grade B/C according to the International Study Group of Liver Surgery definition)., Results: Between February 6, 2019, and May 12, 2023, 138 consecutive patients were enrolled in the study (blood storage group n=68, non-storage group n=70). Twenty-five patients who did not undergo resection were excluded; the remaining 113 patients were investigated as the full analysis set (blood storage group n=60, non-storage group n=53). Surgical procedures, operative time, and blood loss were not significantly different between the two groups. The incidence of PHLF was comparable (blood storage group n=10 [17%], non-storage group n=10 [19%]; P=0.760). There were also no between-group differences in other postoperative outcomes, including the incidence of Clavien-Dindo Grade Ⅲ or higher (72% vs. 72%, P=0.997) and median duration of hospital stay (25 vs. 29 d, P=0.277)., Conclusions: Autologous blood storage did not contribute to reducing the incidence of PHLF in patients undergoing major hepatectomy., Competing Interests: Disclosure of potential conflicts of interest: The authors declare no potential conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A 21-year-old man was diagnosed with segmental adenomyomatosis of the gallbladder based on ultrasonography and computed tomography images. Computed tomography with drip infusion cholangiography revealed that the cystic duct joined the infraportal type of the left lateral bile duct (IPLLBD), which runs caudal to the umbilical portion, and that the left medial bile duct joined the right hepatic duct without forming the left hepatic duct. We planned a single-incision laparoscopic cholecystectomy with fluorescent cholangiography. The fluorescent cholangiography visualized the anatomic variant of the biliary system, and the cystic duct was divided safely. Fluorescent cholangiography is a suitable procedure to depict complex biliary anatomic variations in this patient. IPLLBD without the formation of the left hepatic duct is potentially hazardous during cholecystectomy., (© 2024 The Author(s). Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [ 14 C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [ 14 C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP ( n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background and Aims: Mild cognitive impairment (MCI) is a widespread condition in older individuals, posing significant risk of dementia. However, limited research has been conducted to explore effective interventions and clarify their impact at the neural level. Therefore, this study aimed to investigate the effects of computerized cognitive training (CCT) and explore the associated neural mechanisms in preventing dementia in older individuals with MCI, with a view to inform future intervention efforts., Methods: We reviewed the effects of CCT on biomarker outcomes in older adults with MCI. The search was conducted for studies published between 2010 and May 10, 2023, using three search engines: PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature. The inclusion criteria were as follows: studies that involved participants diagnosed with MCI, included CCT, included quantitative assessment of biomarker results, and conducted randomized controlled trials., Results: Sixteen studies that used biomarkers, including magnetic resonance imaging, electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and blood or salivary biomarkers, were extracted. The results showed that CCT caused changes in structure and function within the main brain network, including the default mode network, and decreased both theta rhythm activity on EEG and prefrontal activity on fNIRS, with improvement in cognitive function. Furthermore, CCT combined with physical exercise showed more significant structural and functional changes in extensive brain regions compared with CCT alone. Virtual reality-based cognitive training improved not only executive function but also instrumental activities of daily living., Conclusion: CCT causes functional and structural changes in extensive brain regions and improves cognitive function in older adults with MCI. Our findings highlight the potential of individualized intervention methods and biomarker assessment according to the specific causes of MCI. Future research should aim to optimize these personalized therapeutic strategies to maximize the benefits of CCT in older adults with MCI., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy. However, few studies have predicted the presence of comorbid LB pathology with AD using indicative biomarkers of dementia with Lewy bodies or by collecting detailed clinical symptoms. We report the clinical progression of a 67-year-old patient diagnosed with AD who developed rapid eye movement sleep disorder-like symptoms and transient visual hallucinations 10 years after AD onset and was considered to have comorbid LB pathology based on imaging indicative biomarkers of dementia with Lewy bodies., Competing Interests: Ryota Kobayashi received honoraria for lectures from PDRadiopharma Inc. and Nihon Medi-physics Co., Ltd., and research support from Nihon Medi-physics Co., Ltd. All other authors have no conflicts of interest to report., (© 2024 – The authors. Published by IOS Press.)

Background: The standard procedure for middle-third cholangiocarcinoma (MCC) is pancreaticoduodenectomy (PD); hepatopancreaticoduodenectomy (HPD) is often performed despite its high risk. There is no clear selection guidance for these procedures., Methods: Patients with MCC who underwent HPD or PD were retrospectively evaluated. The conventional PD was modified (mPD) to transect the bile duct beyond or close to the cranial level of the portal bifurcation., Results: The mPD group (n = 55) was characterized by older age, shorter operation time, less blood loss, and less frequent complications than were observed in the HPD group (n = 34). The median grossly tumor-free margin of the proximal bile duct (GM) was 13 mm vs 20 mm (P = 0.006). Overall survival did not differ significantly between groups (48% vs 53% at 5 years, P = 0.399). Multivariate analysis identified positive surgical margin as a sole independent prognostic factor (hazard ratio, 1.89; P = 0.043), which was statistically associated with GM length. Five-year survival for mPD patients with GM ≥15 mm was significantly better than that for those who had GM <15 mm (69% vs 33%, P = 0.011) and comparable to that of HPD patients (53%, P = 0.450)., Conclusion: The mPD may be recommended in patients with MCC, provided that GM ≥15 mm is expected from the preoperative radiological imaging. Otherwise, HPD should be considered., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Natural language processing (NLP) is a branch of artificial intelligence, which combines computational linguistics, machine learning, and deep learning models to process human language. Although there is a surge in NLP usage across various industries in recent years, NLP has not been widely evaluated and utilized to support drug development. To demonstrate how advanced NLP can expedite the extraction and analyses of information to help address clinical pharmacology questions, inform clinical trial designs, and support drug development, three use cases are described in this article: (1) dose optimization strategy in oncology, (2) common covariates on pharmacokinetic (PK) parameters in oncology, and (3) physiologically-based PK (PBPK) analyses for regulatory review and product label. The NLP workflow includes (1) preparation of source files, (2) NLP model building, and (3) automation of data extraction. The Clinical Pharmacology and Biopharmaceutics Summary Basis of Approval (SBA) documents, US package inserts (USPI), and approval letters from the US Food and Drug Administration (FDA) were used as our source data. As demonstrated in the three example use cases, advanced NLP can expedite the extraction and analyses of large amounts of information from regulatory review documents to help address important clinical pharmacology questions. Although this has not been adopted widely, integrating advanced NLP into the clinical pharmacology workflow can increase efficiency in extracting impactful information to advance drug development., (© 2024 Genentech, Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the β phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues., (© 2023, The American College of Clinical Pharmacology.)

Background: Previous studies have suggested the utility of an indocyanine green plasma clearance rate of the future liver remnant (FLR) (ICGK-F) ≥0.05 in hepatobiliary resection to reduce the surgical risk. The present study aimed to verify whether future liver remnant size rather than ICGK-F matters in extended hepatobiliary resection., Methods: Between 2004 and 2021, patients who underwent right hepatic trisectionectomy with bile duct resection were included. The effect of the FLR volume-to-body weight ratio (FLR/BW) and ICGK-F on posthepatectomy liver failure was evaluated along with other parameters., Results: Among 91 study patients, the median ICGK-F, FLR, and FLR/BW were 0.057 (range, 0.027-0.099), 392 mL (145-705), and 0.78% (0.40-1.37), respectively. Posthepatectomy liver failure occurred in 23 patients. The incidence was 10 (40%) in 25 patients with an ICGK-F <0.05 and 12 (18%) in 65 patients with an ICGK-F ≥0.05 (P = .053); 13 (52%) in 25 patients with a FLR/BW <0.65% and 10 (15%) in 66 patients with a FLR/BW ≥0.65% (P = .001). Multivariate analysis showed that a FLR/BW <0.65% (odds ratio, 11.7; P = .005), age ≥65 years (odds ratio, 31.7; P < .001), and blood loss ≥25 mL/kg (odds ratio, 22.1; P = .004) were independent predictors of posthepatectomy liver failure, but ICGK-F <0.05 was not (P = .499). According to the meeting number of 3 factors, posthepatectomy liver failure incidence was 0 of 22 (0%) in patients with 0 factors, 6 of 43 (14%) in patients with 1, and 17 of 26 (65%) in patients with 2 or 3 (P < .001)., Conclusion: A FLR/BW ≥0.65% may serve as a volumetric basis to reduce posthepatectomy liver failure after extended hepatobiliary resection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dementia with Lewy bodies (DLB) is strongly associated with Alzheimer disease (AD)-type pathology and tends to mask the core clinical features of DLB. Therefore, there may be cases of undiagnosed DLB without suggestive biomarkers of DLB. We describe the case of a 63-year-old woman who was initially diagnosed as having AD and later diagnosed with DLB based on suggestive biomarkers of DLB. In this case, transient sleep talking with physical movements for several days led to the assessment of suggestive biomarkers for DLB in the absence of the core clinical features of DLB. For clinicians, diagnosing DLB in patients with AD-type pathology is challenging. However, the application of biomarkers suggestive of DLB to all patients with dementia is not realistic. To overcome the difficulties of clinical diagnosis of DLB, further research is needed regarding strategies for the application of suggestive biomarkers for DLB to appropriately diagnose DLB., Competing Interests: R.K. has received honoraria for lectures from PDRadiopharma Inc. and Nihon Medi-physics Co., Ltd. and research support from Nihon Medi-physics Co., Ltd. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Retroperitoneal liposarcoma (RPLS) is a rare but challenging neoplasm, which is frequently associated with iliac vessel invasion. We describe how we used a two-step arterial reconstruction technique to perform en bloc resection of a large RPLS involving the iliac arteries in three patients. A temporal long in situ graft bypass was established using a prosthetic vascular graft during dissection of the tumor. This bypass provided an unobscured surgical field, while maintaining blood flow in the lower limb during the operation. After removal of the tumor and washing out the abdominal cavity, the new prosthetic vascular graft of a suitable length was placed. No graft-related complications, including vascular graft infection or graft occlusion, occurred during the follow-up period. This novel technique appears to provide a safe and effective way to remove large RPLSs involving the retroperitoneal major vessels., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Objective: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities., Background: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures., Methods: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient., Results: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months., Conclusion: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the goal of intraoperative blood loss in hepatectomy for perihilar cholangiocarcinoma., Background: Although massive bleeding can negatively affect the postoperative course, the target value of intraoperative bleeding to reduce its adverse impact is unknown., Methods: Patients who underwent major hepatectomy for perihilar cholangiocarcinoma between 2010 and 2019 were included. Intraoperative blood loss was adjusted for body weight [adjusted blood loss (aBL)], and the overall postoperative complications were evaluated by the comprehensive complication index (CCI). The impact of aBL on CCI was assessed by the restricted cubic spline regression., Results: A total of 425 patients were included. The median aBL was 17.8 (interquartile range, 11.8-26.3) mL/kg, and the CCI was 40.6 (33.7-49.5). Sixty-three (14.8%) patients had an aBL<10 mL/kg, nearly half (45.4%) of the patients were in the range of 10 ≤aBL<20 mL/kg, and 37 (8.7%) patients had an aBL >40 mL/kg. The spline regression analysis showed a nonlinear incremental association between aBL and CCI; CCI remained flat with an aBL under 10 mL/kg; increased significantly with an aBL ranging from 10 to 20 mL/kg; grew gradually with an aBL over 20 mL/kg. These inflection points of ~10 and 20 mL/kg were almost consistent with the cutoff values identified by the recursive partitioning technique. After adjusting for other risk factors for the postoperative course, the spline regression identified a similar model., Conclusions: aBL had a nonlinear aggravating effect on CCI after hepatectomy for perihilar cholangiocarcinoma. The primary goal of aBL should be <10 mL/kg to minimize CCI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)