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.

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.

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.

Fetal hepatocyte-derived culture medium elicits adipocyte differentiation to bile duct cell lineages in a mouse model.

Fetal cells in the developmental stages function with a distinct mechanism in comparison to adult tissues, which may be a useful source for regenerative medicine in postnatal medicine; however, the precise molecular mechanism remains to be elucidated fully. The present study investigated murine fetal hepatocytes, which were cultured in vitro, and the supernatants were used for the culture with murine adipose tissue-derived cells. Notably, the results indicated that fetal hepatocyte-derived culture medium elicits the induction of differentiation of adipose tissue-derived cells to bile duct cell lineages, but not to hepatocyte lineages in mice. This indicates that fetal cells possess the multi potentials, which are already absent in adults, and may be useful for regenerative medicine in future.

[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.

Selection criteria for hepatic resection in intermediate-stage (BCLC stage B) multiple hepatocellular carcinoma.

BACKGROUND: Several reports have suggested that hepatic resection provides a survival benefit in patients with hepatocellular carcinoma (HCC) at the intermediate stage of the Barcelona Clinic Liver Cancer classification (BCLC-B). The operative indications for multiple BCLC-B have not been established, however. The aim of this study was to clarify the survival benefit of hepatic resection for multinodular BCLC-B HCC. METHODS: We retrospectively analyzed 85 patients with BCLC-B HCC who underwent liver resection. To evaluate clinicopathologic factors and survival, we divided the patients into 3 types based on radiologic findings regarding tumor number and maximum tumor diameter: type 1, up to 3 lesions <5 cm; type 2, up to 3 lesions ≥5 cm or 4 nodules of any size; type 3, >4 nodules. RESULTS: Thirty-four patients were classified as type 1, 32 as type 2, and 19 as type 3. The 1-, 3-, and 5-year survival in type 1 were 97.1%, 87.4%, and 75.2%, respectively. Those in type 2 were 84.0%, 74.0%, and 63.0%, and those in type 3 were 64.9%, 55.7%, and 37.1%, respectively. The overall survival of type 1 patients was significantly better than that of type 3 patients. The prognosis of type 2 patients was worse than that of type 1 patients and better than that of type 3. Multivariate analysis identified radiologic tumor size and tumor number as independent prognostic factors. CONCLUSION: Our findings suggest that hepatic resection should be considered a radical treatment for multinodular BCLC-B HCC. Our subclassification can be applied to select the initial treatment and when making decisions regarding hepatic resection of BCLC-B HCC with multiple nodules.

A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma.

Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in HCC. In the present study, we explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs, fluorouracil (5-FU), cisplatin (CDDP), doxorubicin (DXR) and sorafenib (SOR), and we elucidated the mechanism of these combination therapies. We evaluated changes in the expression of CD13 before and after treatment with anticancer drugs and with or without ubenimex in the human HCC cell lines HuH7 and PLC/PRF/5. The interactions between the anticancer drugs and ubenimex were determined with isobologram analyses. We analyzed cell cycle, apoptosis, and intracellular reactive oxygen species (ROS) levels to explore the mechanisms of the combination therapies. In both cell lines, the expression of CD13 increased after a 72-h exposure to each anticancer drug alone (p<0.05), and the expression of CD13 decreased with ubenimex administration (p<0.05). Isobologram analyses indicated that ubenimex had synergistic effects with 5-FU, CDDP and DXR, and an additive effect with SOR. Cell cycle analyses showed that ubenimex decreased the proportion of cells in G0/G1. Ubenimex enhanced the effects of 5-FU, CDDP and DXR by increasing apoptosis and intracellular ROS levels. In combination therapies, ubenimex synergistically enhanced the antitumor effects of 5-FU, CDDP and DXR on cell cycle regulation and apoptosis induction in HCC cell lines. The effects of ubenimex were due to increased intracellular ROS levels.

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.

Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review).

Cancer stem cells (CSCs) are a small population of cells in cancer with stem-like properties such as cell proliferation, multiple differentiation and tumor initiation capacities. CSCs are therapy-resistant and cause cancer metastasis and recurrence. One key issue in cancer therapy is how to target and eliminate CSCs, in order to cure cancer completely without relapse and metastasis. To target CSCs, many cell surface markers, DNAs and microRNAs are considered as CSC markers. To date, the majority of the reported markers are not very specific to CSCs and are also present in non-CSCs. However, the combination of several markers is quite valuable for identifying and targeting CSCs, although more specific identification methods are needed. While CSCs are considered as critical therapeutic targets, useful treatment methods remain to be established. Epigenetic gene regulators, microRNAs, are associated with tumor initiation and progression. MicroRNAs have been recently considered as promising therapeutic targets, which can alter the therapeutic resistance of CSCs through epigenetic modification. Moreover, carbon ion beam radiotherapy is a promising treatment for CSCs. Evidence indicates that the carbon ion beam is more effective against CSCs than the conventional X-ray beam. Combination therapies of radiosensitizing microRNAs and carbon ion beam radiotherapy may be a promising cancer strategy. This review focuses on the identification and treatment resistance of CSCs and the potential of microRNAs as new radiosensitizers and carbon ion beam radiotherapy as a promising therapeutic strategy against CSCs.

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.

The combination of the expression of hexokinase 2 and pyruvate kinase M2 is a prognostic marker in patients with pancreatic cancer.

Metabolism may determine the biologically malignant behavior of pancreatic cancer. To investigate the significance and prognostic value of cancer metabolism in cancer patients, we investigated the expression of two key enzymes in anaerobic glycolysis, hexokinase 2 (HK2) and pyruvate kinase isoenzyme type M2 (PKM2), in surgical specimens obtained from 36 patients who underwent curative resection of pancreatic ductal carcinoma. The hk2-glycolysis axis is a key system in the clinical imaging of tumors via positron emission tomography. Immunohistochemical staining for hk2 and pkm2 was performed and the data were statistically analyzed to evaluate their prognostic power. The expression of hk2 and pkm2 was associated with clinicopathological variables and patient prognosis, including overall survival, local recurrence-free survival and distant metastasis-free survival. Staining for hk2 was negative and positive in 42 and 58% of the patients, respectively, whereas staining for pkm2 was negative and positive in 56 and 44%, respectively; hk2-positive staining was correlated with progressive pathological tumor stage (pT3 vs. pT1 and pT2; P=0.017). In the univariate analysis, the positive expression of hk2 and pkm2, pathological stage (pT3 vs. pT1 and pT2) and nodal metastasis were significantly correlated with poor prognosis (P<0.03). In the multivariate analysis, pathological nodal metastasis was an independent prognostic factor for overall survival, whereas the positive expression of hk2 and pkm2 exhibited borderline significance (P=0.08 and 0.12, hazard ratio = 2.57 and 2.16, respectively). In addition, the combination of high expression of hk2 as well as pkm2 was found to be significant (P<0.05). These results suggested that the expression of hk2 and pkm2, particularly their combination, in surgical specimens obtained during curative resection, may predict an unfavorable clinical outcome in patients with pancreatic cancer.

MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

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 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 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.