Intragastric free cancer cells may be attached to automatic staplers during anastomosis in patients with gastric cancer.

BACKGROUND: Automatic staplers are often used to reconstruct the digestive tract during surgeries for gastric cancer. Intragastric free cancer cells adhering to automatic staplers may come in contact with the laparoscopic port area and progress to port site recurrence. This study aimed to investigate the presence/absence of cancer cells adhering to automatic staplers during gastric cancer surgery using cytological examinations. We further determined the positive predictive clinicopathological factors and clinical implications of free cancer cells attached to automatic staplers. METHODS: This study included 101 patients who underwent distal gastrectomy for gastric cancer. Automatic staplers used for anastomosis in gastric cancer surgeries were shaken in 150 ml of saline solution to collect the attached cells. Papanicolaou stains were performed. We tested the correlation between cancer-cell positivity and clinicopathological factors to identify risk factors arising from the presence of attached cancer cells to the staplers. RESULTS: Based on the cytology, cancer cells were detected in 7 of 101 (6.9%) stapler washing fluid samples. Univariate analysis revealed that circular staplers, type 1 tumors, and positive lymph nodes were significantly associated with higher detection of free cancer cells adhering to staplers. No significant differences in other factors were detected. Of the seven cases with positive cytology, one developed anastomotic recurrence. CONCLUSIONS: Exfoliated cancer cells adhered to the automatic staplers used for anastomoses in 6.9% of the staplers used for distal gastrectomies in patients with gastric cancer. Staplers used for gastric cancer surgeries should be handled carefully.

A multicenter validation study for determining the condition of nonanatomical or minor anatomical hepatectomies satisfying technical difficulty of current high-level hepatectomy certificated by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

BACKGROUND: The current high-level hepatectomy (HLH) is certified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS), comprising only anatomical hepatectomies above Couinaud's segmentectomy. This multicenter study aimed to identify the conditions of non-HLH that satisfy equivalent technical difficulties to HLH. METHODS: Between 2018 and 2021, 595 first open hepatectomies without biliary reconstruction (374 HLHs and 221 non-HLHs) were performed in the five institutions. Non-HLHs belonging to at least one of the three conditions; depth of hepatectomy ≥5 cm, number of resections ≥3 locations and at least one location with a depth of hepatectomy ≥3 cm, and hepatectomy involving the paracaval portion of the caudate lobe was proposed as the candidate for difficult non-HLH. The technical difficulty was estimated by the operative time and blood loss. RESULTS: Difficult non-HLHs were neither associated with shorter operative time (373 min vs. 354 min, p = .184) nor lesser blood loss than those with HLHs (503 mL vs. 436 mL, p = .126). Postoperative complications such as Clavien-Dindo classification grade III or more were not significant between the two groups (18.6% vs. 13.4%, p = 0212). CONCLUSIONS: Difficult non-HLHs were associated with no lesser technical difficulty than those with HLH.

Physical frailty recovery is slower than mental frailty recovery after non-cardiac surgery in older adult patients.

PURPOSE: Frailty is characterized by fragility and decline in physical, mental, and social activities; it is commonly observed in older adults. No studies have reported frailty status changes between the preoperative and postoperative periods, including mental and cognitive factors. Therefore, this study investigated frailty factors, including mental and cognitive functions, that change after non-cardiac surgery in older adults. METHODS: Patients aged ≥ 75 years who underwent non-cardiac surgery were surveyed using five tools (Eastern Cooperative Oncology Group-Performance Status (PS); handgrip strengths; Japan-Cardiovascular Health Study index (J-CHS index); Mini-Mental State Examination (MMSE); and Geriatric Depression Scale) for comprehensive evaluation of perioperative functions. The results before surgery, at discharge, and during follow-up at the outpatient clinic were compared. RESULTS: Fifty-three patients with a median age of 80 (IQR, 77-84) years were evaluated. MMSE scores did not change during the perioperative period. The PS and J-CHS index worsened significantly at discharge and did not improve at the outpatient clinic follow-up. The dominant handgrip strength decreased after surgery (p < 0.001) but improved during follow-up. Additionally, nondominant handgrip strength decreased after surgery (p < 0.001) but did not recover as much as the dominant handgrip strength during follow-up (p = 0.015). CONCLUSION: Changes in physical frailty and mental and cognitive functions were not identical perioperatively in older adult patients undergoing non-cardiac surgery. Physical frailty did not improve 1 month after surgery, mental function recovered early, and cognitive function did not decline. This study may be important for frailty prevention in older adult patients.

A Prospective Study of Neoadjuvant Gemcitabine Plus Nab-paclitaxel in Patients with Borderline-resectable Pancreatic Cancer.

Objectives Neoadjuvant therapy followed by radical resection improves the borderline-resectable pancreatic cancer (BRPC) prognosis; however, the optimal therapeutic regimen remains unclear. Gemcitabine plus nab-paclitaxel (GnP) showed a high anti-tumor effect in primary lesions in a prospective study for metastatic disease. However, evidence concerning its feasibility is still lacking in patients with BRPC. We therefore evaluated the tolerability of neoadjuvant GnP (NAC-GnP) for BRPC. Methods This single-center prospective study evaluated 10 patients with BRPC who were treated with two cycles of NAC-GnP. The primary endpoint was feasibility for NAC-GnP. Treatment feasibility was defined as a successful outcome in at least eight patients. Results Ten patients who had BRPC in contact with the celiac artery (n=5), superior mesenteric artery (n=3), or hepatic artery (n=2) were enrolled. The median age was 75 (range, 40-82) years old. Grade 3 anorexia and grade 2 pneumonia occurred in one patient each, so treatment was feasible in eight patients. The median primary tumor reduction and response rates were 33% (range, 0-68%) and 60%, respectively. Six of eight patients who had abnormal CA19-9 levels at the time of enrolment showed a decrease in CA19-9 levels, with a median decrease of 72%. Five patients underwent radical resection, including R0 resection in four. Postoperative grade IIIa Clavien-Dindo complications occurred in one patient (upper gastrointestinal bleeding and pancreatic fistula). Conclusion Two-cycle NAC-GnP is a feasible treatment for patients with BRPC. Further studies on NAC-GnP in patients with BRPC are warranted.

Right hemihepatectomy preserving the fluorescently visible paracaval portion of the caudate lobe.

The paracaval portion (PC) of the caudate lobe is a small area of the liver located in front of the inferior vena cava. Conventional right hemihepatectomy (RH) along the Rex-Cantlie line involves resection of not only the anterior and posterior sections but also the PC behind the middle hepatic vein (MHV). However, to preserve the future liver remnant volume as much as possible, PC-preserving RH may be beneficial in selected patients. We injected an indocyanine green (ICG) solution in the PC portal branch under intraoperative ultrasonography (IOUS) guidance and performed an RH preserving the fluorescently visible PC in a patient with liver metastasis. The patient was a 47-year-old male with a 24 ×10 cm metastatic hepatic tumor from sigmoid colon cancer. CT volumetry revealed that the left hemiliver excluding the caudate lobe was 55%, and the caudate lobe was 5.3%. Before hepatic transection, the ICG solution was injected into the PC portal branch under IOUS guidance. During hepatic transection, the PC was identified as a fluorescent area behind the MHV using a near-infrared imaging system. Thus, the anatomical right-side boundary of the caudate lobe was clearly found. Following RH, the PC was preserved as a fluorescently visible area. The patient had an uneventful recovery. RH preserving the fluorescently visible PC of the liver is a feasible procedure.

Efficacy and safety of regorafenib in combination with immune checkpoint inhibitor therapy as second-line and third-line regimen for patients with advanced hepatocellular carcinoma: a retrospective study.

Background: Despite the emergence of immune checkpoint inhibitors (ICIs) as first-line treatment for advanced hepatocellular carcinoma (HCC), there is an unmet need regarding subsequent treatments in patients that fail ICI. Regorafenib is a vascular endothelial growth factor receptor (VEGFR) inhibitor, which could increase programmed death-ligand 1 (PD-L1) expression in tumors and increase intra-tumoral CD8+ T-cell infiltration by normalizing the cancer vasculature and improving the efficacy of the programmed cell death protein 1 (PD-1) antibody. Thus, we evaluated the combination of regorafenib and a PD-1 inhibitor for advanced HCC patients that had failed combined tyrosine kinase inhibitors (TKIs) plus ICI. Methods: Data of patients with advanced HCC who had failed combined TKIs plus ICI treatment and were afterwards treated with combined regorafenib plus a PD-1 inhibitor were reviewed. All patients had received PD-1 inhibitors as part of the first-line treatment and regorafenib every 4 weeks until disease progression, intolerable toxicities, or physician/patient withdrawal. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events (AEs) during follow-ups were recorded. Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 was used to evaluate AEs and Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 was used to evaluate response. The primary endpoint was safety, and the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and duration of response (DOR). Results: From November 15, 2020, to January 31, 2022, data of 17 patients with advanced HCC that met the criteria were reviewed. The cohort included 16 men and 1 woman with a median age of 54 years (interquartile range, 46 to 63 years). Sixteen patients had Child-Pugh class A (n=16, 94.12%) and one with class B (n=1, 15.9%) liver disease. Thirteen patients received second-line treatment, and the remaining patients received third-line treatment. All patients received at least 1 dose of PD-1 inhibitors. The median follow-up duration was 7.62 months. Twelve recipients experienced treatment-related AEs. The most frequent AE (≥5%) included fatigue (17.64%), diarrhea (17.65%), proteinuria (5.88%), bleeding gums (11.76%), and hypertension (11.76%). No grade-4 AE or new safety signals were identified. The ORR and DCR were 41.2% and 64.7%, respectively, and the median PFS was 5.09 months. Conclusions: Regorafenib combined with PD-1 inhibitor is a promising regimen in treating patients with advanced HCC owing to its safety and effectiveness as well as low incidence of serious AEs with its use.

Liver Cancer Study Group of Japan Clinical Practice Guidelines for Intrahepatic Cholangiocarcinoma.

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.

Intraoperative Colonoscopy in Laparoscopic Rectal Cancer Surgery Reduces Anastomotic Leakage.

Objectives: Anastomotic leakage (AL) is the most severe complication of colorectal surgery and is a frequent cause of postoperative mortality. This study aimed to identify the risk factors for AL, including the type of air leak test (ALT) performed, in patients undergoing laparoscopic colorectal cancer surgery. Methods: This study involved a retrospective review of 201 patients who underwent elective laparoscopic procedures using circular stapled anastomosis for colorectal cancer between January 2015 and December 2020 at Kyorin University Hospital, Tokyo, Japan. In all cases, the distance from the anal verge to the anastomotic site was within 15 cm. Results: Overall, AL was observed in 16 patients (8.0%). Univariate analysis revealed that the risk factors for AL included diabetes (P = 0.068), tumor location (P = 0.049), level of anastomosis (P = 0.002), number of linear stapler firings (P = 0.007), and intraoperative colonoscopy (IOCS; P = 0.069). Multivariate analysis revealed that the level of anastomosis (P = 0.029) and IOCS (P = 0.039) were significant and independent risk factors for AL. One of the 107 patients undergoing ALT without IOCS and 3 of the 94 patients undergoing ALT with IOCS were proven to be positive for air leak. However, these four patients underwent additional suturing intraoperatively and developed no AL following surgery. Conclusions: This study identified the level of anastomosis and ALT with IOCS as predictors for AL. The results of our study indicate that ALT with IOCS may be more effective than ALT without IOCS in the diagnosis and prevention of AL.

Trends in the surgical treatment for pancreatic cancer in the last 30 years.

Pancreatic cancer has the poorest prognosis among digestive cancers. During the 1990s, the 5-year survival rate of surgical patients with pancreatic cancer was 14% in Japan. However, survival rates have increased to 40% in the 2020s due to the refinement of surgical procedures and the introduction of perioperative chemotherapy. Several pivotal randomized controlled trials have played an indispensable role to establish each standard treatment strategy. Resectability of pancreatic cancer can be classified into resectable, borderline resectable, and unresectable based on the anatomic configuration, and multidisciplinary treatment strategies for each classification have been revised rapidly. Investigation of superior perioperative adjuvant treatments for resectable and borderline resectable pancreatic cancer and the establishment of optimal conversion surgery for unresectable pancreatic cancer are the progressive subjects.

Predictive factors for subsequent intrahepatic cholangiocarcinoma associated with hepatolithiasis: Japanese National Cohort Study for 18 years.

BACKGROUND: Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the predictive factors for developing intrahepatic cholangiocarcinoma in hepatolithiasis. METHODS: This cohort is comprised of 401 patients registered in a nationwide survey of hepatolithiasis for 18 years of follow-up. Cox regression analysis was used to elucidate predictive factors for developing intrahepatic cholangiocarcinoma. RESULTS: The median follow-up period of patients was 134 months. Twenty-two patients developed intrahepatic cholangiocarcinoma and all died. Identified independent significant factors were as follows: age 63 years or older (hazard ratio [HR] 3.344), residual stones at the end of treatment (HR 2.445), and biliary stricture during follow-up (HR 4.350). The incidence of intrahepatic cholangiocarcinoma in patients with three factors was significantly higher than that in patients with one or two factors. The incidence in the groups with one or two predictive factors was not different. In 88.9% of patients with both biliary stricture and intrahepatic cholangiocarcinoma, the duration between the diagnoses of biliary stricture and intrahepatic cholangiocarcinoma was ≥ 5 years. However, once intrahepatic cholangiocarcinoma developed, 77.8% of patients died within 1 year. Of 24 patients with no symptoms, no previous choledocoenterostomy, no signs of malignancy, no biliary stricture, and no treatment for hepatolithiasis during follow-up, only one developed intrahepatic cholangiocarcinoma. CONCLUSIONS: Regarding carcinogenesis, complete stone clearance and releasing biliary stricture can prevent the development of intrahepatic cholangiocarcinoma and improve the prognosis of hepatolithiasis.

In vitro ballooned hepatocytes can be produced by primary human hepatocytes and hepatic stellate cell sheets.

Despite the increasing prevalence of Nonalcoholic steatohepatitis (NASH) worldwide, there is no effective treatment available for this disease. "Ballooned hepatocyte" is a characteristic finding in NASH and is correlated with disease prognosis, but their mechanisms of action are poorly understood; furthermore, neither animal nor in vitro models of NASH have been able to adequately represent ballooned hepatocytes. Herein, we engineered cell sheets to develop a new in vitro model of ballooned hepatocytes. Primary human hepatocytes (PHH) and Hepatic stellate cells (HSC) were co-cultured to produce cell sheets, which were cultured in glucose and lipid containing medium, following which histological and functional analyses were performed. Histological findings showed hepatocyte ballooning, accumulation of fat droplets, abnormal cytokeratin arrangement, and the presence of Mallory-Denk bodies and abnormal organelles. These findings are similar to those of ballooned hepatocytes in human NASH. Functional analysis showed elevated levels of TGFß-1, SHH, and p62, but not TNF-α, IL-8. Exposure of PHH/HSC sheets to a glucolipotoxicity environment induces ballooned hepatocyte without inflammation. Moreover, fibrosis is an important mechanism underlying ballooned hepatocytes and could be the basis for the development of a new in vitro NASH model with ballooned hepatocytes.

Demonstration of the right-side boundary of the caudate lobe in a liver cast.

There have been historical arguments about the boundary of the caudate lobe of the liver. Kumon M first advocated the definition of the caudate lobe based on the portal segmentation of the liver in 1985, and classified it into three parts, Spiegel lobe, paracaval portion and caudate process. Prof. Couinaud defined the dorsal liver as a union of segments I and IX in 1994, based on the spatial position to the major hepatic veins, hilar plate and inferior vena cava. In Couinaud's classification, right-side of the dorsal liver is supplied by the branches from the posterior and anterior sections. In the present study using a liver cast, we found a paracaval branch of the portal vein branching from the right portal vein on the dissecting plain along the Rex-Cantlie's line. We also found several branches from the posterior portal vein to the right-side of the paracaval portion, but they should be defined to belong to the posterior sections.

Involvement of a skill-qualified surgeon favorably influences outcomes of laparoscopic cholecystectomy performed for acute cholecystitis.

OBJECTIVE: The Endoscopic Surgical Skill Qualification System (ESSQS) was developed by the Japan Society for Endoscopic Surgery as a means of subjectively assessing the proficiency of laparoscopic surgeons. We conducted a study to evaluate how involvement of an ESSQS skill-qualified (SQ) surgeon influences short-term outcomes of laparoscopic cholecystectomy performed for acute cholecystitis. Previous reports suggest that assessment of the video-rating system is a potential tool to discriminate laparoscopic surgeons' proficiency and top-rated surgeons face less surgical mortality and morbidity in bariatric surgery. METHODS: Data from the National Clinical Database regarding laparoscopic cholecystectomy performed for acute cholecystitis between January 2016 and December 2018 were analyzed. Outcomes were compared between patients grouped according to involvement vs. non-involvement of an SQ surgeon. Outcomes were also compared between patients grouped according to whether their operation was performed by biliary tract-, stomach-, or colon-qualified surgeon. RESULTS: Of the 309,998 laparoscopic cholecystectomies during the study period, 65,295 were suitable for inclusion in the study and 13,670 (20.9%) were performed by an SQ surgeon. Patients' clinical characteristics did not differ between groups. Thirty-day mortality was significantly lower in the SQ group (0.1%) 16/13,670 than in the non-SQ group (0.2%) 140/51,625 (P = 0.001). Thirty-day mortality was [0.1% (9/7173)] in the biliary tract-qualified group, [0.2% (5/3527)] in the stomach-qualified group, and [0.1% (2/3240)] in the colon-qualified group. CONCLUSION: Surgeons with ESSQS certification outperform the non-skilled surgeons in terms of surgical mortality in 30 and 90 days. Further verification of the value of the ESSQS is warranted and similar systems may be needed in countries across the world to ensure patient safety and control the quality of surgical treatments.

Expert Consensus Guidelines: How to safely perform minimally invasive anatomic liver resection.

BACKGROUND: The concept of minimally invasive anatomic liver resection (MIALR) is gaining popularity. However, specific technical skills need to be acquired to safely perform MIALR. The "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was developed as a special program during the 32nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS). METHODS: Thirty-four international experts gathered online for the consensus. A Research Committee performed a comprehensive literature review, classifying studies according to the Scottish Intercollegiate Guidelines Network method. Based on the literature review and experts' opinions, tentative recommendations were drafted and circulated among experts using online Delphi Rounds. Finally, formulated recommendations were presented online in the Expert Consensus Meeting of the JSHBPS on February 23rd, 2021. The final recommendations were validated and finalized by the 2nd Delphi Round in May 2021. RESULTS: Seven clinical questions were selected, and 22 recommendations were formulated. All recommendations reached more than 85% consensus among experts at the final Delphi Round. CONCLUSIONS: The Expert Consensus Meeting for safely performing MIALR has presented a set of clinical guidelines based on available literature and experts' opinions. We expect these guidelines to have a favorable effect on the safe implementation and development of MIALR.

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

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