Prognostic impact of pre- and postoperative tumor markers in patients with intrahepatic cholangiocarcinoma.

PURPOSE: The present study assessed the impact of pre- and postoperative tumor markers on the survival of patients with intrahepatic cholangiocarcinoma. METHODS: Medical records of 73 patients with intrahepatic cholangiocarcinoma were reviewed retrospectively. The pre- and postoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels were assessed. Patient characteristics, clinicopathological factors, and prognostic factors were analyzed. RESULTS: The median recurrence-free survival and overall survival were 30.0 and 90.9 months, respectively. A multivariate survival analysis revealed that elevated postoperative carbohydrate antigen 19-9 (p = 0.023) was the only independent poor prognostic factor. The median overall survival of patients with normal and elevated postoperative carbohydrate antigen 19-9 levels was 101.4 and 15.7 months (p < 0.001), respectively. Multivariate logistic regression identified elevated preoperative carbohydrate antigen 19-9 as an independent preoperative risk factor for elevated postoperative carbohydrate antigen 19-9. The optimal cutoff value of preoperative carbohydrate antigen 19-9 for predicting elevated postoperative carbohydrate antigen 19-9 was 40 U/mL, with a sensitivity and specificity of 92% and 87%, respectively (area under curve = 0.915). CONCLUSIONS: Elevated postoperative carbohydrate antigen 19-9 was an independent poor prognostic factor. Preoperative predictors, such as elevated preoperative carbohydrate antigen 19-9, may indicate the need for neoadjuvant therapies to improve the survival.

A Multicenter, Open-Label, Single-Arm Phase I Trial of Dual-Wield Parenchymal Transection: A New Technique of Liver Resection Using the Cavitron Ultrasonic Surgical Aspirator and Water-Jet Scalpel Simultaneously (HiSCO-14 Trial).

PURPOSE: This study evaluated the safety and feasibility of a technique of liver resection named dual-wield parenchymal transection technique (DWT), using cavitron ultrasonic surgical aspirator (CUSA) and water-jet scalpel simultaneously. METHODS: This multicenter, prospective, open-label, and single-arm phase I trial included patients aged 20 years or older with hepatic tumors indicated for surgical resection and scheduled for open radical resection. This study was conducted at two institutions affiliated with the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). The primary endpoint was the proportion of massive intraoperative blood loss (≥ 1000 mL). The secondary endpoints were the amount of blood loss, operative time, parenchymal transection speed, postoperative complications, and mortality. The safety endpoints were device failure and adverse events associated with devices. RESULTS: From June 2022 to May 2023, 20 patients were enrolled; one was excluded and 19 were included in the full analysis set (FAS). In the FAS, segmentectomy was performed in nine cases, sectionectomy in four cases, and hemihepatectomy in six cases. Radical resection was achieved in all patients. Intraoperative blood loss greater than 1000 mL was observed in five patients (26.3%). The median amount of blood loss was 545 mL (range, 180-4413), and blood transfusions were performed on two patients (10.5%). The median operative time was 346 minutes (range, 238-543) and the median parenchymal transection speed was 1.2 cm2/minute (range, 0.5-5.1). Postoperative complications of Clavien-Dindo classification ≥ Grade 3 occurred in four patients (21.1%). No mortalities occurred in this study. In the safety analysis, there were no device failures or adverse events associated with devices. CONCLUSIONS: This study demonstrated the safety and feasibility of DWT for liver resection. The efficacy of the DWT will be evaluated in future clinical trials.

The efficacy and safety of pure laparoscopic liver resection for hepatocellular carcinoma in super-elderly patients over 80 years: A multicenter propensity analysis.

BACKGROUND: Very few reports have evaluated the safety of laparoscopic liver resection in super-elderly patients. We assessed the short-term outcomes of laparoscopic liver resection in patients with hepatocellular carcinoma aged ≥80 years, using propensity score matching. METHODS: We retrospectively analyzed the data of 287 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at eight hospitals belonging to Hiroshima Surgical study group of Clinical Oncology, between January 2012 and December 2021. The perioperative outcomes were compared between laparoscopic and open liver resection, using propensity score matching. RESULTS: Of the 287 patients, 83 and 204 were included in the laparoscopic and open liver resection groups, respectively. Propensity score matching was performed, and 52 patients were included in each group. The operation (p = .68) and pringle maneuver (p = .11) time were not different between the groups. There were no significant differences in the incidences of bile leakage or organ failure. The laparoscopic liver resection group had significantly less intraoperative bleeding and a lower incidence of cardiopulmonary complications (both p < .01). CONCLUSIONS: Laparoscopic liver resection can be safely performed in elderly patients aged ≥80 years.

Future prospects for cancer immunotherapy using induced pluripotent stem cell-derived dendritic cells or macrophages.

Cancer immunotherapy is now the first-line treatment for many unresectable cancers. However, it remains far from a complete cure for all patients. Therefore, it is necessary to develop innovative methods for cancer immunotherapy, and immune cell therapy could be an option. Currently, several institutions are attempting to generate immune cells from induced pluripotent stem cells (iPSCs) for use in cancer immunotherapy. A method for generating dendritic cells (DCs) and macrophages (MPs) from iPSC has been established. iPSC-derived DCs (iPS-DCs) can activate T cells via antigen presentation, and iPSC-derived macrophages (iPS-MPs) attack cancer. Since iPSCs are used as the source, genetic modification is easy, and various immune functions, such as the production of anti-tumour cytokines, can be added. Furthermore, when iPS-DCs and iPS-MPs are immortalized, cost reduction through mass production is theoretically possible. In this review, the achievements of cancer research using iPS-DCs and iPS-MPs are summarized, and the prospects for the future are discussed.

Prospective Exploratory Phase I Clinical Trial Assessing the Safety of Preoperative Marking for Small Liver Tumors.

Background Small tumors in liver cirrhosis are difficult to distinguish using intraoperative ultrasonography. In addition, preoperative chemotherapy for metastatic liver cancer may diminish tumor size, thus making tumors difficult to identify intraoperatively. To address such difficulties, we devised a method to mark liver tumors preoperatively to facilitate intraoperative identification. This study aimed to investigate the safety of a preoperative liver tumor marking method. Methodology This exploratory prospective clinical trial included patients with liver tumors measuring ≤20 mm requiring resection. Preoperative marking was performed by placing a coil for embolization of blood vessels near the tumor using either the transcatheter or percutaneous approach. The tumor was identified and resected by intraoperative ultrasonography based on the marker. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028608). Results Overall, 19 patients (9 with primary liver cancer and 10 with metastatic tumors) were recruited. The transcatheter and percutaneous methods were used in 13 and 6 patients, respectively. Marking was not possible in two patients in the transcatheter group because the catheter could not be guided to the vicinity of the tumor. There were no marking-related complications. Hepatectomy was performed in all but one patient who was not fit for hepatectomy owing to the development of a metastatic liver tumor. The markers were adequately identified during hepatectomy. Additionally, there were no difficulties in the surgical procedure or postoperative complications. Conclusions Preoperative marking with embolization coils can be performed safely for intraoperative identification of liver nodules.

[A Case of Postoperative Peritoneal Dissemination Recurrence of CY1 Gastric Cancer with cCR after Nab-PTX Therapy].

A 72-year-old man visited his local doctor for gastric discomfort. Esophagogastroduodenoscopy revealed a type 3 tumor on the gastric antrum, and histopathological examination revealed a moderately differentiated adenocarcinoma(tub2). The patient was referred to our hospital and CT scan revealed wall thickening with contrast effect in the gastric angle but no enlarged lymph nodes in the region. The patient was diagnosed as cT3N0M0, Stage ⅡB gastric cancer and underwent open distal gastrectomy and D2 lymph node dissection. No peritoneal dissemination was observed, but intraoperative laparoscopic cytology showed Class Ⅴ. The patient was diagnosed as CY1 Stage Ⅳ gastric cancer, and treated with S-1 plus Tmab therapy starting 1 month after surgery. One year postoperative follow-up CT revealed recurrence of peritoneal disseminations, and the patient was treated with nab-PTX as a second-line therapy. Tumor shrinkage was achieved steadily, and the peritoneal disseminations disappeared at the CT after 12 courses, resulting in cCR. Thereafter, cCR continued and treatment was terminated at the 17th course. Seven years have passed since the end of chemotherapy, and the patient is still alive without recurrence.

[A Case of Postoperative Recurrence of Liver Metastasis after Gastrectomy for Gastric Cancer-No Recurrence for Five Years after Twice Liver Resections].

The patient was an 89-year-old man. He underwent laparoscopic distal gastrectomy for gastric cancer and was diagnosed as T1bN1M0, Stage ⅠB. Eight months after surgery, a CT scan showed an 18 mm-sized hypodense mass in S6 of the liver, and the patient was diagnosed with recurrent liver metastasis. He was treated with 3 courses of CapeOX therapy, and the response was judged as partial response(PR). Laparoscopic partial hepatic S6 resection was performed for the single liver metastasis. The pathological results showed liver metastasis of gastric cancer. Capecitabine was started as adjuvant chemotherapy. Nine months after surgery for liver metastasis, CT scan showed a 12 mm-sized single tumor in S5 and the patient was diagnosed with recurrent liver metastasis. The patient underwent laparoscopic partial hepatectomy after 3 courses of weekly paclitaxel plus ramucirumab therapy. The pathological result showed liver metastasis of gastric cancer. After the surgery, adjuvant chemotherapy was not administered according to the patient's request. Seven years have passed since the resection of the gastric cancer, and 5 years have passed since the resection of the second liver metastasis, and the patient has not had any recurrence.

Usefulness and safety of midline incision for right-sided hepatectomy: Cohort study.

BACKGROUND: While the adoption rates of laparoscopic hepatectomy are increasing, most patients still undergo open hepatectomy. Open hepatectomies use inverted L-shaped or Mercedes incisions for right-sided liver tumor. To decrease procedural invasiveness, we performed midline incisions in such cases, excluding those of laparoscopic hepatectomy. This retrospective study examined the effects of this change in treatment policy on overall patient surgical outcomes. MATERIALS AND METHODS: From 2012 to 2018, 374 patients who underwent hepatectomy for right-sided hepatocellular carcinoma were enrolled, and short-term patient outcomes were compared following stratification into the 1st (n = 157) or 2nd (n = 217) Era group based on whether procedures occurred before or after the policy change, respectively. RESULTS: Short-term outcomes were mostly comparable between the two groups, with significantly increased postoperative aspartate aminotransferase maximum values found in the 2nd Era group relative to the 1st Era group (median: 393 vs. 331, p < 0.05). Pain scores at rest during postoperative day 1 and while moving on postoperative days 1, 2, and 3 were significantly lower in the 2nd Era group than in the 1st Era group (p < 0.05, <0.01, <0.05, <0.01, respectively). CONCLUSIONS: Utilization of midline incisions may provide some benefits in postoperative outcomes for right-sided open hepatectomy cases.

Improved safety of induced pluripotent stem cell-derived antigen-presenting cell-based cancer immunotherapy.

The tumorigenicity and toxicity of induced pluripotent stem cells (iPSCs) and their derivatives are major safety concerns in their clinical application. Recently, we developed granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing proliferating myeloid cells (GM-pMCs) from mouse iPSCs as a source of unlimited antigen-presenting cells for use in cancer immunotherapy. As GM-pMCs are generated by introducing c-Myc and Csf2 into iPSC-derived MCs and are dependent on self-produced GM-CSF for proliferation, methods to control their proliferation after administration should be introduced to improve safety. In this study, we compared the efficacy of two promising suicide gene systems, herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) and inducible caspase-9 (iCasp9)/AP1903, for safeguarding GM-pMCs in cancer immunotherapy. The expression of HSV-TK or iCasp9 did not impair the fundamental properties of GM-pMCs. Both of these suicide gene-expressing cells selectively underwent apoptosis after treatment with the corresponding apoptosis-inducing drug, and they were promptly eliminated in vivo. iCasp9/AP1903 induced apoptosis more efficiently than HSV-TK/GCV. Furthermore, high concentrations of GCV were toxic to cells not expressing HSV-TK, whereas AP1903 was bioinert. These results suggest that iCasp9/AP1903 is superior to HSV-TK/GCV in terms of both safety and efficacy when controlling the fate of GM-pMCs after priming antitumor immunity.

PD1 gene polymorphism is associated with a poor prognosis in hepatocellular carcinoma following liver resection, cohort study.

BACKGROUND: This study examined whether single nucleotide polymorphism (SNP) in programmed cell death protein (PD)-1 is related to the postoperative prognosis of patients with hepatocellular carcinoma (HCC). The immune checkpoint protein PD-1 is an important inhibitor of T cell responses. SNP in the promoter region of PD-1 -606 G/A has been reported to result in high activation and expression of PD-1 associated with cancer risk. MATERIALS AND METHODS: We analyzed 321 patients with HCC who underwent hepatectomy between 2010 and 2015. PD-1 SNP was analyzed by polymerase chain reaction, and the prognosis after surgical treatment of patients with HCC was analyzed. RESULTS: The PD-1 SNP statuses were as follows: 90 AA (28.1%), 163 GA (50.8%), 68 GG (21.2%). The baseline parameters did not statistically differ between the three groups. The overall survival (OS) of patients with the GG genotype was significantly lower than that of those with the other genotypes (P = 0.031). The GG genotype was an independent risk factor for OS (P = 0.009; HR 2.201). There was no significant difference between the GG genotype and other genotypes in recurrent-free survival. The extrahepatic recurrence (EHR) rate of those with the GG genotype was significantly higher than that of those with the other genotypes (P = 0.036). The GG genotype was an independent risk factor for EHR (P = 0.008; HR 2.037). CONCLUSIONS: The PD-1 SNP GG genotype is associated with poor survival and increased EHR in HCC. Furthermore, the GG genotype is an independent predictive factor for OS and EHR.

Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response.

Immunotherapy using dendritic cells (DCs) is a promising treatment modality for cancer. However, the limited number of functional DCs from peripheral blood has been linked to the unsatisfactory clinical efficacies of current DC-based cancer immunotherapies. We previously generated proliferating antigen-presenting cells (APCs) by genetically engineering myeloid cells derived from induced pluripotent stem cells (iPSC-pMCs), which offer infinite functional APCs for broad applications in cancer therapy. Herein, we aimed to further enhance the antitumor effect of these cells by genetic modification. GM-CSF gene transfer did not affect the morphology, or surface phenotype of the original iPSC-pMCs, however, it did impart good viability to iPSC-pMCs. The resultant cells induced GM-CSF-dependent CD8+ T cell homeostatic proliferation, thereby enhancing antigen-specific T cell priming in vitro. Administration of the tumor antigen-loaded GM-CSF-producing iPSC-pMCs (GM-pMCs) efficiently stimulated antigen-specific T cells and promoted effector cell infiltration of the tumor tissues, leading to an augmented antitumor effect. To address the potential tumorigenicity of iPSC-derived products, irradiation was applied and found to restrict the proliferation of GM-pMCs, while retaining their T cell-stimulatory capacity. Furthermore, the irradiated cells exerted an antitumor effect equivalent to that of bone marrow-derived DCs obtained from immunocompetent mice. Additionally, combination with immune checkpoint inhibitors increased the infiltration of CD8+ or NK1.1+ effector cells and decreased CD11b+/Gr-1+ cells without causing adverse effects. Hence, although GM-pMCs have certain characteristics that differ from endogenous DCs, our findings suggest the applicability of these cells for broad clinical use and will provide an unlimited source of APCs with uniform quality.

In Vitro Detection of Cellular Adjuvant Properties of Human Invariant Natural Killer T Cells.

Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that play a crucial role in the tumor surveillance. The activation of iNKT cells by their specific ligand α-galactosylceramide (α-GalCer) induces the activation of dendritic cells (DCs) via reciprocal interaction, which results in the generation of cellular immunity against cancer. Here we describe a method to detect DC-mediated cellular adjuvant properties of human iNKT cells in vitro.

Clinical significance of glypican-3-positive circulating tumor cells of hepatocellular carcinoma patients: A prospective study.

The utility of glypican-3 (GPC3) expression for the detection of circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC) patients has not been elucidated. The aim of this study was to identify associations between the presence of GPC3-positive CTCs and clinicopathological factors of these patients, furthermore, to evaluate whether CTC can predict microscopic portal vein invasion (mPVI). This study was done on 85 patients who underwent hepatectomy as the first-line treatment and whose preoperative imaging showed no evidence of macroscopic PVI and distant metastases. Peripheral blood was collected from all patients immediately before surgery. Cells were purified initially by density gradient centrifugation followed by immunomagnetic positive enrichment based upon the expression of GPC3. The numbers of CTCs contained in the enriched samples were enumerated via flow cytometry. Protocol validation using HepG2 cells spiked into 8.0 mL of blood from a healthy volunteer indicated that we were able to recover 12.1% of the tumor cells. A median number of 3 CTCs (range: 0-27) was detected in the 8.0 mL of peripheral blood of the 85 analyzed HCC patients. Thirty-three patients had CTCs ≥5, and these patients had a higher incidence of mPVI (p < 0.001), a lower disease-free survival (p = 0.015), and a lower overall survival (p = 0.047) than those with CTCs <5. Multivariate analysis identified CTCs ≥5 as an independent predictor of mPVI (p < 0.001). In conclusion, preoperative GPC3-positive CTCs ≥5 was a risk factor of mPVI and poor prognosis, and therefore may be a useful biomarker for HCC patient outcomes.

Independent risk factors that predict bile leakage after hepatectomy for hepatocellular carcinoma: Cohort study.

BACKGROUND: Bile leakage is a major cause of morbidity after hepatectomy. This study aimed to identify the predictive factors for bile leakage after hepatectomy. MATERIALS AND METHODS: Between January 2011 and December 2016, 556 patients underwent a liver resection for hepatocellular carcinoma with curative intent, and were enrolled to participate in this study. The incidence of postoperative bile leakage (POBL) was determined and the predictive factors for POBL were identified using univariate and multivariate analysis. RESULTS: POBLs occurred in 28 patients (5.0%). The multivariate analysis identified a history of stereotactic body radiotherapy, a body mass index <20 kg/m2, Child-Pugh class B cirrhosis, a central hepatectomy, and an operation time ≥375 min as risk factors that were associated with POBL. When the study cohort was grouped according to the number of the predictive factors present, the incidence of POBL increased as the number of the extant independent predictive factors increased. The POBL rate was 45.0% in patients with ≥3 predictive factors. CONCLUSION: We determined that POBL was associated with operative mortality and identified five independent predictive factors associated with POBL. Risk stratification using these predictive factors may be useful for identifying patients at a high risk of POBL.

De Garengeot hernia with perforated appendicitis and a groin subcutaneous abscess: A case report.

INTRODUCTION: De Garengeot hernia is rare. Although previous reports have suggested various surgical options according to patient condition, comorbidities, surgeon preference, and clinical findings during surgery, a treatment strategy has not been established. PRESENTATION OF CASE: An 81-year-old woman presented with an irreducible tender mass that was subsequently diagnosed as an incarcerated femoral hernia with a subcutaneous abscess in the right groin. Intraoperative findings revealed a necrotic and perforated appendix strangulated by the femoral ring for which an appendectomy and herniorrhaphy was performed concurrently through the hernia sac. The subcutaneous abscess cavity was washed thoroughly and a drainage tube was placed within it. The patient recovered uneventfully. DISCUSSION: We suggest that the approach through the inguinal incision in both appendectomy and herniorrhaphy with drainage may be useful in avoiding intra-abdominal contamination in cases of de Garengeot hernia with subcutaneous abscess. CONCLUSION: Here, we described a case of de Garengeot hernia with a subcutaneous abscess in the groin. Clinicians should consider de Garengeot hernia in patients with a groin hernia, make an early diagnosis, and promptly provide surgical treatment to reduce the risk of complications.

A small intestine volvulus caused by strangulation of a mesenteric lipoma: a case report.

BACKGROUND: An emergency department encounters a variety of cases, including rare cases of the strangulation of a mesenteric lipoma by the greater omentum band. CASE PRESENTATION: A 67-year-old Japanese man presented with nausea, vomiting, and upper abdominal pain. There were no abnormalities detected by routine blood tests other than a slight rise in his white cell count. A contrast-enhanced computed tomography scan of his abdomen revealed a dilated intestine, a small intestine volvulus, and a well-capsulated homogeneous mass. He was suspected of having a small intestine volvulus that was affected by a mesenteric lipoma; therefore, single-port laparoscopic surgery was performed. Laparoscopy revealed a small intestine volvulus secondary to the strangulation of a mesenteric lipoma. The band and tumor were removed. He had no postoperative complications and was discharged on postoperative day 6. CONCLUSIONS: Although this case was an emergency, it showed that single-port laparoscopic surgery can be a safe, useful, and efficacious procedure.

[Estimation of peritoneal dissemination in patients with unresectable advanced or recurrent colorectal cancer who underwent curative resection after combination chemotherapy].

In a group of 209 colorectal cancer patients with unresectable tumors, 10 patients underwent curative resection after combination chemotherapy at our hospital between 2006 and 2012. Of these 10 patients, 5 presented with peritoneal dissemination at the start of chemotherapy. With the exception of 1 patient with peritoneal recurrence, peritoneal dissemination and liver metastasis were observed in all patients at the time of diagnosis of colorectal cancer. Computed tomography (CT) and/ or positron emission tomography-CT examination revealed disappearance of peritoneal dissemination in response to chemotherapy, except in 1 patient with peritoneal recurrence. After combination chemotherapy, surgical resection of liver metastases and peritoneal dissemination was performed. Pathological and intraoperative findings indicated disappearance of peritoneal dissemination in 3 patients and P2 grade peritoneal dissemination in 1 patient. In the patient with peritoneal recurrence, 1 tumor was completely resected. Interestingly, none of the 3 patients that exhibited complete disappearance of peritoneal dissemination showed peritoneal recurrence, although 1 patient exhibited metastases in the lung and non-regional lymph nodes. In contrast, the patient with P2 grade peritoneal dissemination showed peritoneal recurrence and lung metastasis. All 5 patients survived (duration from diagnosis of colorectal cancer, 31-83 months). Herein, we report the use of combination chemotherapy to achieve the disappearance of peritoneal dissemination, changing unresectable colorectal cancer with peritoneal dissemination into resectable cancer.