Our experience of repeat laparoscopic liver resection in patients with recurrent hepatocellular carcinoma.

BACKGROUND: Repeat liver resection is an effective treatment approach for patients with recurrent hepatocellular cell carcinoma (HCC). However, the surgical feasibility and oncological significance of repeat laparoscopic liver resection (r-LLR) remain unproven. This study evaluates and compares the clinical outcomes of non-anatomic r-LLR applied towards recurrent HCC, with those of primary LLR (p-LLR) for primary HCC. METHODS: This retrospective study reports 104 patients with HCC, treated with LLR between 2014 and 2018. Twenty eight of these patients underwent r-LLR for recurrent HCC. The clinical and surgical variables were reviewed for all cases. RESULTS: The analysis was limited to non-anatomic resection across both groups (r-LLR: 89% (25/28) vs. p-LLR: 80% (61/76)). There were no statistically significant differences about patient background between the two groups, with the exception of Child-Pugh classification. r-LLR surgical techniques included single-site laparoscopic adhesiolysis (32%, 8/25), Pringle maneuver (8%, 2/25), and crush-clamp method using BiClamp for hepatic parenchymal transection (72%, 18/25). No severe postoperative complications were observed in the r-LLR group. Postoperative hospital stays and procedure-related postoperative survival were similar for both groups. CONCLUSIONS: Non-anatomical r-LLR renders comparable surgical and oncological outcomes. Our data suggest that non-anatomical r-LLR is a safe and feasible therapeutic approach to recurrent HCC.

[Improvement of Pain Control after Dealing with Chemical Coping-A Case of Local Recurrence of Rectal Cancer].

A 57-year-old female underwent abdominoperineal resection for rectal cancer. Although she received postoperative adjuvant chemotherapy, she had presacral recurrence with pain 26 months postoperatively. We provided palliative care in parallel with systemic chemotherapy, but she had difficulty controlling pain despite using high-dose opioids at 43 months after surgery. Multimodal therapy contributed to a reduction in opioid use for a brief time. Nevertheless, she required high-dose opioid therapy again at 50 months after the procedure. Since she used a rescue dose for relieving anticipatory anxiety for pain, we estimated that she developed chemical coping. After we tried analgesic adjuvant therapy and psychotherapy, her opioid use was reduced. For 10 months afterward, her disease worsened with time, but her pain was well-controlled. In cases where it is difficult to control pain, protection against exacerbation or opioid dose escalation should be considered. Furthermore, psychological contexts, including chemical coping, should also be considered. It may lead to the use of a proper dose of opioids and improve quality of life for patients.

Platelet count is more useful for predicting posthepatectomy liver failure at surgery for hepatocellular carcinoma than indocyanine green clearance test.

BACKGROUND AND OBJECTIVES: Preoperatively evaluating reserved liver function is critical in preventing posthepatectomy liver failure (PHLF) in patients undergoing liver resection. The commonly used indocyanine green (ICG) clearance test has several drawbacks. Patients would benefit from a more reliable and straightforward means of assessing the risk of PHLF. METHODS: This study included 277 patients with hepatocellular carcinoma (HCC) undergoing liver resection. The predictive value of known risk factors for PHLF was compared to that of ICG. RESULTS: PHLF was identified in 25 out of 277 patients (9.0%). Multivariate logistic regression analysis for identifying predictors for the PHLF development revealed platelet count and resected liver volume as significant independent predictors. In a subgroup analysis based on resected liver volume, platelet count was significantly correlated with PHLF in both larger volume (≥100 g) and smaller volume resection groups (<100 g), although ICG R15 level was associated with PHLF only in larger volume group. CONCLUSIONS: Platelet count is superior to ICG R15 level in predicting PHLF development in HCC patients. J. Surg. Oncol. 2016;113:565-569. © 2016 Wiley Periodicals, Inc.

Preoperative Chemoradiation Followed by Extensive Pelvic Surgery Improved the Outcome of Posterior Invasive Locally Recurrent Rectal Cancer without Deteriorating Surgical Morbidities: A Retrospective, Single-Institution Analysis.

PURPOSE: The main feature of locally recurrent rectal cancer (LRRC) is infiltrating growth; thus, preoperative chemoradiation therapy (preCRT) is recommended to improve patient outcomes. However, no studies have reported the potential impact of preCRT on oncological and surgical outcomes in posterior invasive LRRC (piLRRC) that requires sacrectomy. METHODS: Forty-one patients with piLRRC were treated with (n = 25) or without (n = 16) preCRT. Oncological outcomes regarding local re-recurrence-free survival, distant metastasis-free survival, and overall survival (OS) were analyzed. Surgical complications were assessed using the Clavien-Dindo scale. RESULTS: The preCRT group had higher 5-year local re-recurrence-free survival (24.4 vs. 0 %) and OS (46.6 vs. 29.3 %) than the non-preCRT group. Univariate analysis demonstrated that preCRT (p = 0.03) and microlymphatic involvement (p = 0.01) were significantly related to local re-recurrence. Microlymphatic involvement occurred less frequently in the preCRT group than in the non-preCRT group (23.8 vs. 71.4 %; p = 0.01) despite the similarity in primary cancers between groups. Major infectious complications occurred with similar frequency in the preCRT and non-preCRT groups (24 vs. 18.8 %, p = 1). CONCLUSIONS: PreCRT significantly benefited oncological outcome without compromising surgical results for piLRRC.

A Cancer Reprogramming Method Using MicroRNAs as a Novel Therapeutic Approach against Colon Cancer: Research for Reprogramming of Cancer Cells by MicroRNAs.

BACKGROUND: We previously generated induced pluripotent stem cells by reprograming adipose stem cells through the introduction of microRNAs targeting four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4). In this study, we aimed to reprogram cancer cells using microRNAs to explore their therapeutic potential. METHODS: Mature microRNAs (mir-302a-d, 369-3p and 5p, and mir-200c, as needed) were introduced into colon cancer cells (DLD-1, RKO, and HCT116) using lipofection. RESULTS: The transfected cells exhibited an embryonic stem cell-like morphology and expressed the undifferentiated marker genes Nanog, Oct3/4, SOX2, and Klf4, as well as tumor-related antigen-1-60. These cells expressed neurogenic or adipogenic markers, indicating that reprogramming of the cancer cells was partially successful. Moreover, we found that miRNA-expressing DLD-1 cells showed low proliferative activity in vitro and in vivo, accompanied by increased expression of the tumor suppressor genes p16 (ink4a) and p21 (waf1) . miRNA-expressing DLD-1 cells also exhibited enhanced sensitivity to 5-fluorouracil, possibly through the downregulation of multidrug-resistant protein 8. The reprogrammed cells from DLD-1, RKO, and HCT116 cells exhibited reduced c-Myc expression, in contrast to the high c-Myc expression in the induced pluripotent cancer cells that were generated using four transcription factors. CONCLUSIONS: Our cancer reprogramming method employing simple lipofection of mature microRNAs is safe and well suited for clinical application, because it avoids integration of exogenous genes into the host genome and allows escape from augmentation of c-Myc gene expression.

Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND: Development of cancer has been linked to inflammatory cytokines such as interleukin (IL)-6 and IL-17. In this study, we assessed the expression of these cytokines in intrahepatic cholangiocarcinoma (ICC) and determined their correlation to the survival probability. METHODS: A total of 72 consecutive patients who underwent curative resection of ICC at Osaka University Hospital from March 1998 to November 2014 were enrolled. Immunohistochemical analysis was performed for IL-17 and its receptor A (IL-17RA), as well as IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed for preoperative plasma levels of IL-6 and IL-17 in 32 patients with ICC. RESULTS: Immunohistochemical analysis showed that the IL-6(high) (n = 34) and IL-17RA(high) (n = 29) groups had significantly worse disease-free survival (DFS) than IL-6(low) (n = 38) and IL-17RA(low) (n = 43) groups, respectively. Although IL-17(+) cells were abundant in the intratumoral area, patients with high peritumoral, but not intratumoral, IL-17(+) cells (n = 28) corresponded with a significantly lower overall survival (OS) and DFS (OS, p = 0.023; DFS, p = 0.026) than those with low group. Moreover, multivariate Cox proportional hazards analysis revealed that IL-6, peritumoral IL-17(+), and IL-17RA are independent prognostic factors for DFS (p = 0.023, p = 0.0088, p = 0.039, respectively). In addition, high preoperative plasma levels of IL-6 in patients with ICC corresponded with significantly lower DFS (p = 0.002). CONCLUSIONS: Our data suggested that IL-6, peritumoral IL-17(+) cells, and IL-17RA expression are postoperative useful markers for predicting recurrence in patients with ICC.

[A Case of Surgical Resection of a Liver Metastasis from Colorectal Cancer with a Macroscopic Portal Vein Tumor Thrombus].

The patient was a 65-year-old man. In July 2014, he was diagnosed with rectal cancer in a different hospital and underwent high anterior resection(type 2, T3N0M0, StageⅡ [TMN classification, 7th edition]). During the operation, a small nodule was detected in segment 4 of the liver. Contrast-enhanced abdominal CT revealed a tumor measuring 5 cm in diameter located in segment 4/8 of the liver with a tumor thrombus in the main trunk of the portal vein. In August 2014, the patient was referred to our hospital for further examination and treatment. MR imaging showed a lobulated tumor located in segment 4/8 of the liver. Gadoxeticac id-enhanced hepatobiliary phase MR imaging showed that the tumor was less enhanced than was the adjacent liver parenchyma. 18F-FDG-PET/CT demonstrated abnormal accumulation of 18F-FDG in the main tumor(SUVmax=18.3). There was no obvious abnormal accumulation in the other organs. In September 2014, he underwent extended left hepatectomy and portal vein tumor thrombectomy. The resected specimen showed a well-differentiated adenocarcinoma. Immunohistochemical staining results were CK7/CK20 (-/+) and CDX2 (+), which suggested that the tumor was derived from the gastrointestinal tract rather than the liver. The pathological diagnosis was a liver metastasis from rectal cancer. In the 6 months after the operation, intrahepatic recurrence was detected, and the patient was treated with systemicchemotherapy.

[A Successful Curative Resection Including Replacement with a Ringed Gore-Tex Tube Graft for Local Recurrence after Right Adrenalectomy and Liver Metastasis of Colon Cancer with Inferior Vena Cava Invasion].

A 65-year-old woman underwent sigmoidectomy for colon cancer in January 2002. She had multiple liver metastases and received systemic chemotherapy (UFT-E plus CPT-11) for 6 months. She underwent partial hepatectomy of S7 and S3 and cholecystectomy in July 2003. After 4 years without recurrence, right adrenal and para-aortic lymph nodes metastases were detected and she underwent right adrenalectomy and para-aortic lymphadenectomy in July 2007. In July 2008, local recurrence (1 cm in size) was identified in the cavity of the right adrenal gland. She received chemotherapy (mFOLFOX6 plus bevacizumab) for 5 years. In May 2013, PET-CT showed abnormal accumulation of FDG in S7 of the liver (SUVmax 6.7). The enhanced EOB-MRI showed a mass lesion in S7 (3 cm in size) and 2 nodules (1 cm in size) in S3 and S4. We scheduled for liver surgery with reconstruction of the inferior vena cava (IVC) after systemic chemotherapy (FOLFIRI plus cetuximab). The patient underwent partial hepatectomy of the tumor in S7 combined with resection of the diaphragm and IVC. Reconstruction of the IVC was performed using a ringed Gore-Tex tube graft in February 2014. The patient is still alive without recurrence 18 months after surgery.

[Three Resected Cases of Metachronous Pancreatic Cancer Successfully Treated with Repeated Pancreatectomy].

Repeated pancreatectomy for metachronous pancreatic cancer has rarely been reported. We report 3 cases with metachronous pancreatic ductal carcinoma that developed after pancreatectomy for the first pancreatic cancer. They were successfully resected by removal of the remnant pancreas. In all 3 cases, the cancers in the remnant pancreas were treated with repeated pancreatectomy. The histological margin of the first pancreatic resection was cancer-free in all the cases. Furthermore, the second cancer tissue contained carcinoma lesions in situ adjacent to invasive ductal carcinoma. Based on these findings, the 3 patients were diagnosed with metachronous pancreatic cancers.

[A case of pathological complete response with neoadjuvant XELOX chemotherapy for locally advanced rectal cancer].

A 70-year-old man presenting with melena was referred to our clinic. A clinical examination revealed a bulky tumor in the lower rectum. After ileostomy, 4 courses of capecitabine plus oxaliplatin (XELOX) therapy were administered as neoadjuvant chemotherapy. Computed tomography (CT) revealed significant reduction of the tumor. Laparoscopic super-low anterior resection with lateral lymph node dissection was performed. The pathological examination revealed no residual cancer cells, and a diagnosis of pathological complete response was made. The patient has been disease-free for 1 year after the operation. Neoadjuvant chemotherapy with XELOX might be promising for patients with locally advanced rectal cancer.

Adipose-derived mesenchymal stem cells and regenerative medicine.

Adipose tissue-derived mesenchymal stem cells (ADSCs) are multipotent and can differentiate into various cell types, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic ß-cells, and hepatocytes. Compared with the extraction of other stem cells such as bone marrow-derived mesenchymal stem cells (BMSCs), that of ADSCs requires minimally invasive techniques. In the field of regenerative medicine, the use of autologous cells is preferable to embryonic stem cells or induced pluripotent stem cells. Therefore, ADSCs are a useful resource for drug screening and regenerative medicine. Here we present the methods and mechanisms underlying the induction of multilineage cells from ADSCs.

[Cancer stem cells depend on their own niche].

It is considered that cancer stem cells have the same characteristics as normal stem cells, such as drug-resistance, self-renewal, differentiation, and tissue-formation. Normal stem cells depend on their surroundings, a niche. Cancer stem cells may also depend on their own niche. Because cancer stem cells are resistant to present remedies, it is important to find a remedy targeting cancer stem cells. The remedy must not only target cancer stem cells themselves but also target the niche surrounding the cancer stem cells.

SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction.

Sarcoma is a rare type of cancer for which new therapeutic agents are required. Ferroptosis is a nonapoptotic cell death triggered by iron-mediated lipid peroxidation. We found that TFRC, an iron uptake protein, was expressed at higher levels in sarcoma cell lines than in noncancer and carcinoma cell lines. Glutathione peroxidase 4 (GPX4) protects cells against ferroptosis, and its inhibition using RAS-selective lethal 3 (RSL3) had an antitumor effect that was more pronounced in sarcoma cell lines, particularly synovial sarcoma cells, compared to non-sarcoma cells. Because NF-κB can provoke ferroptosis, we examined the role of SHARPIN, an activator of NF-κB, in sarcoma. We found that SHARPIN expression was significantly associated with reduced survival in cohorts of patients with cancer, including sarcoma. In addition, SHARPIN promoted the sensitivity of sarcoma cells to ferroptosis. Further analyses revealed that the PGC1α/NRF2/SLC7A11 axis and BNIP3L/NIX-mediated mitophagy are regulated through NF-κB and PRMT5 downstream of SHARPIN. Our findings suggest that ferroptosis could have a therapeutic effect in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression.

Establishment of Organoids From Human Epithelioid Sarcoma With the Air-Liquid Interface Organoid Cultures.

Background: Although biological resources are essential for basic and preclinical research in the oncological field, those of sarcoma are not sufficient for rapid development of the treatment. So far, some sarcoma cell lines have been established, however, the success rate was low and the established sarcoma types were frequently biased. Therefore, an efficient culture method is needed to determine the various types of sarcomas. Organoid culture is a 3-dimentional culture method that enables the recapitulation of the tumor microenvironment and the success rate reported is higher than the 2-dimentional culture. The purpose of this study was to report our newly established organoids from human epithelioid sarcoma using the air-liquid interface organoid culture method. Methods: We treated 2 patients with epithelioid sarcoma in our institute. The remaining sarcoma specimens after surgical resection were embedded in collagen type 1 gels according to the air-liquid interface organoid culture method. After serial passages, we xenografted the organoids to NOD-scid IL2Rgnull (NSG) mice. Using the developed tumors, we performed histological and genomic analyses to compare the similarities and differences with the original epithelioid sarcoma from the patient. Results: Organoids from the epithelioid sarcoma could be serially cultured and maintained in collagen type 1 gels for more than 3 passages. Developed orthotopic tumor xenografts were detected in the NSG mice. After the process was repeated severally, the patient derived organoid lines from the epithelioid sarcoma were established. The established organoids showed loss of integrase interactor 1 expression with polymerase chain reaction and immunohistochemical analyses. The xenografted organoids of the epithelioid sarcoma had histologically similar phenotypes with the original tumor and genetically resembled it to some degree. Conclusions: The present study demonstrated 2 novel established organoid models of epithelioid sarcoma, and our organoid models could be used to investigate the molecular pathogenesis and develop a novel treatment.

Establishment of organoids using residual samples from saline flushes during endoscopic ultrasound-guided fine-needle aspiration in patients with pancreatic cancer.

Background and study aims In patients with pancreatic cancer (PC), patient-derived organoid cultures can be useful tools for personalized drug selection and preclinical evaluation of novel therapies. To establish a less invasive method of creating organoids from a patient's tumor, we examined whether PC organoids can be established using residual samples from saline flushes (RSSFs) during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Methods Five patients with PC who underwent EUS-FNA were enrolled in a prospective study conducted at our institution. RSSFs obtained during EUS-FNA procedures were collected. An organoid culture was considered as established when ≥ 5 passages were successful. Organoid-derived xenografts were created using established organoids. Results EUS-FNA was performed using a 22- or 25-gauge lancet needle without complications. Patient-derived organoids were successfully established in four patients (80.0 %) with the complete medium and medium for the selection of KRAS mutants. Organoid-derived xenografts were successfully created and histologically similar to EUS-FNA samples. Conclusions Patient-derived PC organoids were successfully established using EUS-FNA RSSFs, which are produced as a byproduct of standard manipulations, but are usually not used for diagnosis. This method can be applied to all patients with PC, without additional invasive procedures, and can contribute to the development of personalized medicine and molecular research.

InBody 720 as a new method of evaluating visceral obesity.

BACKGROUND/AIMS: This study was conducted to assess the efficacy of bioelectrical impedance analysis by InBody 720 as a new tool for measuring visceral fat area. METHODOLOGY: A total of 53 consecutive patients elected to undergo surgical resection of primary gastric cancer received preoperative measurement of visceral fat area at the umbilical level with both computed tomography and bioelectrical impedance analysis by InBody 720. RESULTS: Visceral fat area values measured by InBody 720 significantly correlated with those by computed tomography (R = 0.759). CONCLUSION: Bioelectrical impedance analysis by InBody 720 was shown to be useful as a more convenient substitute for computed tomography when measuring visceral fat area.

[Hepatic metastasis from gastric GIST radically resected after imatinib mesylate therapy-a case report].

We report a case of hepatic metastasis from gastric gastrointestinal stromal tumor (GIST), which was safely resected with preoperative imatinib therapy. A 60-year-old woman was hospitalized and underwent a treatment for hepatic SOL at another hospital prior to gastric GIST resection. Computed tomography revealed a tumor compressing the right and middle hepatic vein. The tumor volume decreased after an initiation of imatinib therapy aimed at preserving the middle hepatic vein. Although tumor volume was further decreased over the course of twelve months, a new lesion appeared, suggesting a progressive disease. Our findings suggest that a radical resection of gastric GIST to preserve the middle hepatic vein is possible.

Successful management of aberrant right hepatic duct during laparoscopic cholecystectomy: a rare case report.

BACKGROUND: Anatomic variants of the biliary tree present challenges to surgical management during laparoscopic cholecystectomy and affect perioperative outcomes. An aberrant right hepatic duct connecting into the cystic duct is a practically important variation because of the susceptibility to serious postoperative refractory bile leakage. We report a successful case of laparoscopic cholecystectomy in the aberrant right hepatic duct of a patient diagnosed with chronic cystitis. CASE PRESENTATION: A 49-year-old man was referred to our department for treatment of chronic cholecystitis. Magnetic resonance cholangiopancreatography indicated that the cystic duct branched from the common bile duct and an aberrant bile duct connected to the cystic duct. Intraoperative cholangiography revealed that the bile duct was not confluent to the major right branch of the intrahepatic bile duct and drained a narrow area. Preoperative magnetic resonance cholangiopancreatography had diagnostic value. Furthermore, intraoperative cholangiography with the Critical View of Safety method was paramount to achieving safe cholecystectomy based on confirmation of the biliary anatomy and the drainage area of the aberrant right hepatic duct. CONCLUSION: We encountered a rare but clinically significant case of laparoscopic cholecystectomy. This case suggests that precise understanding of the anatomy and drainage area of the aberrant right hepatic duct preoperatively and intraoperatively can lead to safe cholecystectomy.

Laparoscopic resection of retroperitoneal paraganglioma behind the Spiegel lobe in a kyphotic patient: A rare case report.

Extra-adrenal paraganglioma is a rare form of neuroendocrine neoplasm capable of catecholamine secretion. The surgical risks associated with the tumor location are compounded in this case of a kyphotic patient. This report presents the successful application of laparoscopy on extra-adrenal paraganglioma located behind the Spiegel lobe in a kyphotic patient. The operation was performed after 1 week of α-blocker administration. The laparoscopic approach, with the patient in the left hemilateral decubitus position on a rotating table, provided optimal access for safe tumor resection after complete hepatic right lobe mobilization. The patient's postoperative course was uneventful. Based on the results, the laparoscopic approach can be a safe and effective method for resecting extra-adrenal paraganglioma in the challenging case of a kyphotic patient.

[A case report of pseudomyxoma peritonei demonstrating complete response after intensive therapy consisting of cytoreductive surgery and adjuvant chemotherapy with paclitaxel and S-1].

A 74-year-old male with diffuse gelatinous ascites underwent cytoreductive surgery including ileocecal resection and greater omentectomy. Pathology revealed mucinous adenocarcinoma with low-grade malignancy originating in the appendix with disseminated peritoneal adenomucinosis, which was diagnostic of pseudomyxoma peritonei. A subcutaneous reservoir was implanted intraoperatively for intraperitoneal chemotherapy initiated at the time of operation. The patient received intraperitoneal chemotherapy with weekly paclitaxel at a dose of 60 mg/m(2) for 3 weeks, followed by a 1-week rest, repeated every 4 weeks for 2 months. Subsequently, paclitaxel was given intravenously at the same dose every 2 weeks for 2 months, and then the patient was placed on oral S-1 at a dose of 100 mg/body/day, administered daily for 2 consecutive weeks, followed by a 1-week rest, repeated every 3 weeks for 9 months. The patient tolerated the chemotherapy well, developing grade 1 anemia and grade 2 neutropenia plus elevation of total bilirubin. Tumor markers, CEA and CA19-9, fell to the normal range postoperatively, and have remained stable so far. A follow-up computed tomography (CT) scan revealed small ascites only in the right pelvis 8 months later after the initial operation, and complete disappearance of ascites 17 months later. Two years later, the patient presented with ileus, and required adhesionlysis as well as partial resection of adhesive ileum. No evidence of recurrent disease was confirmed intraoperatively as a second look. To date, the patient has been free of recurrence.