Yuki Aisu’s research while affiliated with Kyoto University and other places

INTRODUCTION: Experience with the Hugo RAS system in robot-assisted colorectal surgery is limited. This is particularly noticeable when focusing on complex procedures, such as total proctocolectomy (TPC). This study aimed to demonstrate the feasibility and safety of using the Hugo RAS system for TPC. CASE PRESENTATION: A 27-year-old woman with multiple colorectal cancers with a background of familial adenomatous polyposis underwent robot-assisted TPC, including lymph node dissection of the entire colorectal region using the Hugo RAS system. The robotic procedure was divided into 3 steps: 1) Trendelenburg position to perform ascending colon complete mesocolic excision (CME) to the hepatic flexure, 2) descending colon CME and total mesorectal excision with D3 lymph node dissection, and 3) flat position to perform central vessel ligation along the superior mesenteric artery. After undocking, the specimen was extracted transanally, and an ileal pouch was constructed from a small laparotomy at the umbilical incision, followed by ileal pouch-anal anastomosis. The operative time was 632 min, and the estimated blood loss was minimal. The postoperative period was uneventful. CONCLUSIONS: Robot-assisted TPC using the Hugo RAS system is safe and feasible. The flexibility of Hugo, which is carried by a modular-type surgical robot with multiple independent arms, enables safe and effective advanced procedures.

Radical surgery for rectal cancer with bulky lateral pelvic lymph node (LPLN) metastasis involving the sciatic nerve presents both technical and oncological challenges. Preoperative multidisciplinary treatments have recently been anticipated to control the disease as well as to preserve organ function. A 51‐year‐old man, presenting with right buttock pain and impairment of walking, was diagnosed with sciatic nerve impairment due to right LPLN metastasis from rectal cancer. He was initially treated with palliative radiotherapy followed by FOLFOX plus bevacizumab. After 13 cycles of the chemotherapy, his symptoms disappeared and the LPLN shrank. Then, conversion surgery via robot‐assisted low anterior resection with right LPLN dissection was performed. Although he had moderate right leg pain postoperatively, there were no motor deficits or other complications. Pathological examination of the specimen revealed microscopic residual disease at the resection margin, but he is currently surviving recurrence‐free for 1.5 years. Preoperative multidisciplinary treatment enabled the preservation of the sciatic nerve in the robot‐assisted conversion surgery.

Pyruvate is situated at the intersection of oxidative phosphorylation (OXPHOS) and glycolysis, which are the primary energy-producing pathways in cells. Cancer therapies targeting these pathways have been previously documented, indicating that inhibiting one pathway may lead to functional compensation by the other, resulting in an insufficient antitumor effect. Thus, effective cancer treatment necessitates concurrent and comprehensive suppression of both. However, whether a metabolic switch between the metabolic pathways occurs in colorectal and gastric cancer cells and whether blocking it by inhibiting both pathways has an antitumor effect remain to be determined. In the present study, we used two small molecules, namely OXPHOS and glycolysis inhibitors, to target pyruvate metabolic pathways as a cancer treatment in these cancer cells. OXPHOS and glycolysis inhibition each augmented the other metabolic pathway in vitro and in vivo. OXPHOS inhibition alone enhanced glycolysis and showed antitumor effects on colorectal and gastric cancer cells in vitro and in vivo. Moreover, glycolysis inhibition in addition to OXPHOS inhibition blocked the metabolic switch from OXPHOS to glycolysis, causing an energy depletion and deterioration of the tumor microenvironment that synergistically enhanced the antitumor effect of OXPHOS inhibitors. In addition, using hyperpolarized ¹³C-magnetic resonance spectroscopic imaging (HP-MRSI), which enables real-time and in vivo monitoring of molecules containing ¹³C, we visualized how the inhibitors shifted the flux of pyruvate and how this dual inhibition in colorectal and gastric cancer mouse models altered the two pathways. Integrating dual inhibition of OXPHOS and glycolysis with HP-MRSI, this therapeutic model shows promise as a future "cancer theranostics" treatment option.

The combination therapy of lenvatinib plus pembrolizumab (LP) is increasingly recognized as an important second-line regimen for advanced or recurrent endometrial cancer (EC). However, the safety and efficacy of conversion surgery with low anterior rectal resection for unresectable EC following LP therapy is unknown. A 37-year-old woman was referred with unresectable EC with pleural fluid, peritoneal dissemination, and ascites. After the failure of first-line platinum-based chemotherapy, she was administered LP as second-line treatment. After 10 treatment cycles, uterine and peritoneal tumors significantly reduced in size, except the left ovarian metastatic tumor which became slightly larger. Cytoreductive surgery, including low anterior resection of the rectum and colorectal anastomosis, achieved complete resection. However, on postoperative day 11, the patient experienced an anastomotic leakage around the colorectal anastomosis site, necessitating a double-barreled colostomy and percutaneous drainage. She was discharged 15 days after the second surgery and resumed LP therapy after 44 days following the second surgery. We report a case in which conversion surgery after LP therapy was conducted for unresectable advanced endometrial cancer. Our findings indicate that if bowel resection is required, a longer preoperative withdrawal period may be necessary to prevent postoperative anastomotic leakage.

Low‐grade appendiceal mucinous neoplasm (LAMN) is principally characterized by low‐grade cytology without evidence of invasion to other organs. We report a LAMN surgical case whose appendiceal tumor penetrated the sigmoid colon wall. An 87‐year‐old man was referred for endoscopic resection (ER) of a colon polyp. Despite four ERs over 5 years, the polyp recurred at the same site. Laparoscopic surgery revealed a dilated appendix firmly attached to the sigmoid colon. We performed en bloc resection of both the sigmoid colon and appendix without tumor exposure. The histopathological evaluation showed that the LAMN had penetrated the sigmoid colon wall, forming two polyps on the colonic mucosa. In cases where the appendiceal‐colonic fistula is suspected, en bloc resection of the appendix and colon wall should be considered.

Introduction: Pyruvate(Pyr) metabolism is a keystone in cancer metabolism, as well as normal cells, and has two major metabolic fluxes; Glycolysis and Oxidative Phosphorylation (OXPHOS). Especially in cancer cells, increased Pyr metabolism meets the demand of higher energy consumption during rapid cell growing state. Therefore, monitoring tumor Pyr metabolic flux in vitro and in vivo should be necessary to develop a therapeutic strategy using small molecules which can inhibit the fluxes.Aim: We performed in vitro metabolic analysis on pancreatic cancer cells (MiaPaCa2) and applied a novel in vivo imaging technology “hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging (HP-MRSI)” to dynamic monitoring of the impact of Glycolysis and OXPHOS inhibitors on the MiaPaCa2 xenografts. Methods: We used a novel LDH inhibitor “NCI-006” for Glycolysis inhibition and Mitochondrial Complex 1(MC1) Inhibitor "Metformin(Met)", which is already clinically available, and “IACS-010759(IACS)” for OXPHOS inhibition, in vitro and in vivo. Extracellular flux (EXF) analysis and HP-MRSI were performed before and after administration of each or both to assess inhibitor impact on metabolic flux in vitro and in vivo, respectively. Results: HP-MRSI confirmed that LDH activity in the tumor was suppressed by NCI-006 (83.3±4.4% decrease) and accelerated by Met (69.9±6.6% increase) and IACS (88.6±25.1% increase). We confirmed these in vivo observations are fully consistent with the effect of those inhibitors in vitro on the energy profile of MiaPaCa2, and also the close correlation of these data with the results of the ex vivo LDH activity assay, suggesting HP-MRSI can reliably monitor in vivo on target effects of the inhibitors without need for tissue sampling. In addition, combined treatment with the NCI-006 and MC1 inhibitor significantly suppressed in vitro cell growth and tumor growth in an efficacy study of MiaPaCa2 xenografts, compared to each single administration. Apoptosis assay showed the combined treatment induced apoptosis in MIA Paca2 cells. Conclusion: Using EXF analyzer and HP-MRSI revealed that Glycolysis inhibition redirects tumor Pyr toward OXPHOS and also MC1 inhibition redirects tumor Pyr toward Glycolysis. Combination therapy suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo. HP-MRSI is thought to be useful for pancreatic cancer patients to establish the current treatment model because of no need to obtain clinical samples, such as patients-derived cancer cells or spheroid from the patients. The current proof of concept can be of great value in developing new therapeutic strategies using metabolic inhibitors to treat cancers. Citation Format: Nobu Oshima, Yuki Aisu, Shigeo Hisamori, Shigeru Tsunoda, Hiroki Hashida, Kenji Uryuhara, Hiroyuki Kobayashi, Masato Kondo, koji Kitamura, Satoshi Kaihara, Kazutaka Obama, Krishna Murali, Len Neckers. Comprehensive monitoring of pyruvate metabolism in cancer cells and tumors reveals vulnerability to metabolic inhibition therapy with small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6222.

Introduction In median arcuate ligament syndrome (MALS), a hyperplastic MAL causes compression and stenosis of the celiac artery (CA). The treatment involves releasing the external pressure on this artery by dissecting the ligament. However, it is difficult to identify the artery because of its deep anatomical location. Stereotactic navigation provides real-time information regarding the surgical instrument's location on computed tomography (CT) images. We utilized this system to overcome the difficulty of anatomical identification. Materials and Surgical Technique We present a case of aneurysm rupture caused by MALS, which was treated with laparoscopic MAL dissection with real-time stereotactic navigation. Surgery was performed in a hybrid operating room with three-dimensional C-arm CT (Artis Zeego, Siemens) and an installed Curve navigation system (BrainLab). Preoperative CT images were aligned with intraoperative C-arm CT-like images and the surgical instrument position was projected onto preoperative CT images. After the left gastric artery isolation, the fibrous tissue surrounding the left gastric artery was dissected toward the CA while confirming the location of the CA and aortic wall using the navigation system. The CA's diameter was dilated from 1.8 to 2.6 mm with intraoperative angiography. Discussion This is the first report of laparoscopic MAL dissection using real-time stereotactic navigation. Although navigation setting was time-intensive, this system helped us understand the anatomical structures and in safely and precisely dissecting the MAL.

Groin hernias include indirect inguinal, direct inguinal, and femoral hernias. Obturator and supravesical hernias appear very close to the groin. High-quality repairs are required for groin hernias. The concept of "tension-free repair" is generally accepted, and surgical repairs with mesh are categorized as "hernioplasties". Surgeons should have good knowledge of the relevant anatomy. Physicians generally focus on the preperitoneal space, myopectineal orifice, topographic nerves, and regional vessels. Currently, laparoscopic surgery has therapeutic potential in the surgical setting for hernioplasty, with laparoscopic transabdominal preperitoneal (TAPP) repair appearing to be a powerful tool for use in adult hernia patients. TAPP offers the advantages of accurate diagnoses, repair of bilateral and recurrent hernias, less postoperative pain, early recovery allowing work and activities, tension-free repair of the preperitoneal (posterior) space, ability to cover obturator hernias, and avoidance of potential injury to the spermatic cord. The disadvantages of TAPP are the need for general anesthesia, adhering to a learning curve, higher cost, unexpected complications related to abdominal organs, adhesion to the mesh, unexpected injuries to vessels, prolonged operative time, and as-yet-unknown long-term outcomes. Both technical skill and anatomical familiarity are important for safe, reliable surgery. With increasing awareness of the importance of anatomy during TAPP repair, we address the skills and pitfalls during laparoscopic TAPP repair in adult patients using illustrations and schemas. We also address debatable points on this subject.