Shin-ichiro Yamada, Yuji Morine, Tetsuya Ikemoto, Yu Saitou, Hiroki Teraoku, Yuhei Waki, Chiharu Nakasu, Takayuki Noma and Mitsuo Shimada : Evaluation of malignancy in gallbladder tumors using the apparent diffusion coefficient obtained by diffusion-weighted MRI., Oncology Letters, Vol.28, No.5, 533, 2024.
(Summary)
The utility of the apparent diffusion coefficient (ADC) of diffusion-weighted image (DWI) magnetic resonance imaging was examined for evaluating malignancy and prognosis in gallbladder tumors. A total of 63 patients (benign tumors, n=33; cancer, n=30) were included after surgical resection for gallbladder tumors, and their mean ADC values by DWI were obtained. Cases of advanced gallbladder cancer (n=25) were divided into ADC and ADC groups, and clinicopathological factors were compared. In 63 cases, ADC values in advanced gallbladder cancer were significantly lower compared with benign tumors and non-advanced gallbladder cancer (P<0.05), and ADC values in early gallbladder cancer were also significantly lower compared with benign tumors (P<0.05). In 25 advanced gallbladder cancer cases, the ADC group tended to have a higher rate of advanced stage disease (P=0.09). Disease-free survival and overall survival (OS) of the ADC group were worse compared with the ADC group (P<0.01). In the multivariate analysis of OS, poor differentiation and low ADC value were independent prognostic factors. ADC values may be useful for evaluating tumor malignancies in gallbladder tumors.
Toshiaki Yoshimoto, Masaaki Nishi, Shohei Okikawa, Kozo Yoshikawa, Takuya Tokunaga, Toshihiro Nakao, Chie Takasu, Hideya Kashihara, Yuuma Wada, Takayuki Noma and Mitsuo Shimada : Blue light irradiation inhibits the M2 polarization of the cancer-associated macrophages in colon cancer., BMC Cancer, Vol.24, No.1, 664, 2024.
(Summary)
Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy. However, the effects of blue light irradiation on cells in the tumor microenvironment, including tumor-associated macrophages (TAMs), are unknown. Here, THP-1 cells were cultured in the conditioned medium (CM) of HCT-116 cells to prepare TAMs. TAMs were divided into LED-irradiated and control groups. Then, the effects of blue LED irradiation on TAM activation were examined. Expression levels of M2 macrophage markers CD163 and CD206 expression were significantly decreased in LED-irradiated TAMs compared with the control group. While control TAM-CM could induce HCT-116 cell migration, these effects were not observed in cells cultured in TAM-CM with LED irradiation. Vascular endothelial growth factor (VEGF) secretion was significantly suppressed in LED-exposed TAMs. PD-L1 expression was upregulated in HCT-116 cells cultured with TAM-CM but attenuated in cells cultured with LED-irradiated TAM-CM. In an in vivo model, protein expression levels of F4/80 and CD163, which are TAM markers, were reduced in the LED-exposed group. These results indicate that blue LED light may have an inhibitory effect on TAMs, as well as anti-tumor effects on colon cancer cells.
Yosuke Iwakawa, Masaaki Nishi, Yuuma Wada, Kozo Yoshikawa, Chie Takasu, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Toshiaki Yoshimoto, Takayuki Noma and Mitsuo Shimada : Feasibility of laparoscopic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumor with tumor diameter of >5 cm., The Journal of Medical Investigation : JMI, Vol.71, No.1.2, 148-153, 2024.
(Summary)
Laparoscopic and endoscopic cooperative surgery (LECS) is an effective treatment for gastric gastrointestinal stromal tumors (GISTs). The utility of LECS for gastric GISTs of > 5 cm remains controversial. This study was performed to investigate the feasibility of LECS for gastric GISTs with a tumor diameter of >5 cm. We analyzed 43 patients with gastric GISTs who underwent LECS or laparoscopic partial gastrectomy (Lap-Partial Gx). We compared the surgical outcomes of LECS versus Lap-Partial Gx and of LECS for a tumor diameter of > 5 versus ≤ 5 cm. In the comparison of LECS versus Lap-Partial Gx, there were no significant intergroup differences in the operative time or blood loss volume. The morbidity rate was similar between the groups. No postoperative mortality occurred in either group. In the comparison of LECS for a tumor diameter of > 5 versus ≤ 5 cm, there were no significant intergroup differences in operative time, or blood loss volume. The morbidity rate was similar between the > 5-cm and ≤ 5-cm groups (0.0% vs. 4.5%, respectively ; p = 0.56). Additionally, no recurrence or death occurred during follow-up in either group. LECS is a feasible option for gastric GISTs with a tumor diameter of > 5 cm. J. Med. Invest. 71 : 148-153, February, 2024.
Yuhei Waki, Yuji Morine, Takayuki Noma, Chie Takasu, Hiroki Teraoku, Shin-ichiro Yamada, Yu Saitou, Tetsuya Ikemoto and Mitsuo Shimada : Association between high expression of intratumoral fibroblast activation protein and survival in patients with intrahepatic cholangiocarcinoma., BMC Gastroenterology, Vol.23, No.1, 415, 2023.
(Summary)
Cancer-associated fibroblasts (CAFs) have been reported to exhibit protumorigenic effects. Among the well-known CAF markers such as smooth muscle actin (SMA) and fibroblast activation protein (FAP), high expression of SMA in the peritumoral stroma has been reported to be a prognostic factor in various cancers. However, the effect of high FAP expression in intrahepatic cholangiocarcinoma (IHCC) has not been fully clarified. We evaluated the expression of CAF markers, focusing on FAP expression in the peripheral and intratumoral regions, to clarify the association with survival in patients with IHCC. The study cohort comprised 37 patients who underwent curative resection for IHCC. The FAP expressions were evaluated in the peripheral and intratumoral regions of the resected tissues. Clinicopathological factors and survival outcomes were investigated between patients with high versus low FAP expression. Uni- and multivariate analyses were performed to identify the prognostic factors for overall survival and relapse-free survival. The median area percentages of FAP expression in the peripheral and intratumoral regions were 15.5% and 17.8%, respectively. High FAP expression in the intratumoral region was significantly associated with worse overall survival and disease-free survival than low FAP expression in the intratumoral region. Multivariate analysis identified high intratumoral FAP expression as a risk factor for worse overall survival (hazard ratio, 2.450; p = 0.049) and relapse-free survival (hazard ratio, 2.743; p = 0.034). High intratumoral FAP expression was associated with worse survival, suggesting that intratumoral FAP expression represents malignant progression in patients with IHCC.
(Keyword)
Humans / Neoplasm Recurrence, Local / Cholangiocarcinoma / Cancer-Associated Fibroblasts / Bile Ducts, Intrahepatic / Bile Duct Neoplasms / Prognosis
Yuhei Waki, Yu Saitou, Shuhai Chen, Tetsuya Ikemoto, Takayuki Noma, Hiroki Teraoku, Shin-ichiro Yamada, Yuji Morine and Mitsuo Shimada : Effects of green light-emitting diode irradiation on hepatic differentiation of hepatocyte-like cells generated from human adipose-derived mesenchymal cells., Scientific Reports, Vol.13, No.1, 19954, 2023.
(Summary)
Light-emitting diode (LED) irradiation has been used in the differentiation of mesenchymal stem cells into a variety of cell types. This study investigated the effect of green LED (GLED) irradiation on the differentiation of adipocyte-derived mesenchymal cells into hepatocyte-like cells (HLCs) and the mechanism of its action. HLCs in the hepatocyte maturation phase were irradiated with GLED (520 nm, 21 W/m, 5 min/day for 10 days). The cells were then assessed for expression of hepatocyte maturity genes and opsin 3 (OPN3), hepatocyte function, viability, apoptosis, and levels of reactive oxygen species (ROS), intracellular adenosine triphosphate (ATP) and calcium ions (Ca). GLED irradiation increased Alpha-1 antitrypsin and Ornithine transcarbamylase gene expression, promoted Cytochrome P450 3A4 activity and urea synthesis, and elevated intracellular ROS, ATP and Ca levels. OPN3 expression was significantly more upregulated in GLED-irradiated HLCs than in the non-irradiated HLCs. No significant difference in cell viability or apoptosis was observed between GLED-irradiated and non-irradiated HLCs. GLED irradiation can promote hepatocyte maturation and functions through OPN3. GLED irradiation also stimulated mitochondrial function via Ca/ATP/ROS activation. GLED irradiation has potential to support cell-based transplantation in patients.
(Keyword)
Humans / Reactive Oxygen Species / Hepatocytes / Cell Differentiation / Adipocytes / Adenosine Triphosphate / Rod Opsins
Takayuki Noma, Masaaki Nishi, Chie Takasu, Yuuma Wada, Kozo Yoshikawa, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Toshiaki Yoshimoto, Yuko Miyakami, Kengo Atsumi, Hisanori Uehara and Mitsuo Shimada : Conversion surgery after successful response to chemotherapy (S-1 + oxaliplatin + nivolumab) in a patient with stage IV gastric cancer with peritoneal metastasis (P1, CY1): a case report., International Cancer Conference Journal, Vol.13, No.1, 11-16, 2023.
(Summary)
We here present a case report of a patient with Stage IV gastric cancer with peritoneal metastasis (P1, CY1) who underwent conversion surgery after a successful response to chemotherapy (S-1 + oxaliplatin + nivolumab). The patient was a woman in her 60 s. Her chief complaint was epigastric pain. Upper gastrointestinal endoscopy showed Type 4 advanced carcinoma on the lesser curvature of the gastric body. Biopsy showed Group 5 (poorly differentiated adenocarcinoma) and HER2 was negative. Staging laparoscopy revealed seeding in the round ligament of the liver (P1) and adenocarcinoma cells in ascites (CY1). Ten courses of chemotherapy (S-1 + oxaliplatin + nivolumab) were administered, after which contrast-enhanced computed tomography showed that the primary tumor had shrunk and seeding was no longer detectable. Upper gastrointestinal endoscopy revealed scar-like changes. A second staging laparoscopy revealed that ascites cytology was negative and a biopsy of the round ligament of the liver showed no malignant cells (P0, CY0). Conversion surgery comprising laparoscopic total gastrectomy with D2 lymph node dissection and resection of the round ligament of the liver was performed. The postoperative course was uneventful. Histopathological examination of the resected specimen revealed no tumor cells in the gastric mesentery or the round ligament of the liver. The pathological diagnosis was gastric cancer [M, U, L, Less, Ant, Post, type4, T3(SS), N0, M0 (H0, P0, CY0), ypStage IIA]. Adjuvant chemotherapy (S-1) was commenced. The patient is still alive 7 months later with no evidence of recurrence.
Takayuki Noma, Masaaki Nishi, Chie Takasu, Yuuma Wada, Kozo Yoshikawa, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Toshiaki Yoshimoto, Yuko Miyakami, Kengo Atsumi, Hisanori Uehara and Mitsuo Shimada : Conversion surgery after successful response to chemotherapy (S-1 + oxaliplatin + nivolumab) in a patient with stage IV gastric cancer with peritoneal metastasis (P1, CY1): a case report., International Cancer Conference Journal, Vol.13, No.1, 11-16, 2023.
(Summary)
We here present a case report of a patient with Stage IV gastric cancer with peritoneal metastasis (P1, CY1) who underwent conversion surgery after a successful response to chemotherapy (S-1 + oxaliplatin + nivolumab). The patient was a woman in her 60 s. Her chief complaint was epigastric pain. Upper gastrointestinal endoscopy showed Type 4 advanced carcinoma on the lesser curvature of the gastric body. Biopsy showed Group 5 (poorly differentiated adenocarcinoma) and HER2 was negative. Staging laparoscopy revealed seeding in the round ligament of the liver (P1) and adenocarcinoma cells in ascites (CY1). Ten courses of chemotherapy (S-1 + oxaliplatin + nivolumab) were administered, after which contrast-enhanced computed tomography showed that the primary tumor had shrunk and seeding was no longer detectable. Upper gastrointestinal endoscopy revealed scar-like changes. A second staging laparoscopy revealed that ascites cytology was negative and a biopsy of the round ligament of the liver showed no malignant cells (P0, CY0). Conversion surgery comprising laparoscopic total gastrectomy with D2 lymph node dissection and resection of the round ligament of the liver was performed. The postoperative course was uneventful. Histopathological examination of the resected specimen revealed no tumor cells in the gastric mesentery or the round ligament of the liver. The pathological diagnosis was gastric cancer [M, U, L, Less, Ant, Post, type4, T3(SS), N0, M0 (H0, P0, CY0), ypStage IIA]. Adjuvant chemotherapy (S-1) was commenced. The patient is still alive 7 months later with no evidence of recurrence.
Takayuki Noma, Masaaki Nishi, Chie Takasu, Yuuma Wada, Kozo Yoshikawa, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Toshiaki Yoshimoto, Yuko Miyakami, Kengo Atsumi, Hisanori Uehara and Mitsuo Shimada : Conversion surgery after successful response to chemotherapy (S-1 + oxaliplatin + nivolumab) in a patient with stage IV gastric cancer with peritoneal metastasis (P1, CY1): a case report., International Cancer Conference Journal, Vol.13, No.1, 11-16, 2023.
(Summary)
We here present a case report of a patient with Stage IV gastric cancer with peritoneal metastasis (P1, CY1) who underwent conversion surgery after a successful response to chemotherapy (S-1 + oxaliplatin + nivolumab). The patient was a woman in her 60 s. Her chief complaint was epigastric pain. Upper gastrointestinal endoscopy showed Type 4 advanced carcinoma on the lesser curvature of the gastric body. Biopsy showed Group 5 (poorly differentiated adenocarcinoma) and HER2 was negative. Staging laparoscopy revealed seeding in the round ligament of the liver (P1) and adenocarcinoma cells in ascites (CY1). Ten courses of chemotherapy (S-1 + oxaliplatin + nivolumab) were administered, after which contrast-enhanced computed tomography showed that the primary tumor had shrunk and seeding was no longer detectable. Upper gastrointestinal endoscopy revealed scar-like changes. A second staging laparoscopy revealed that ascites cytology was negative and a biopsy of the round ligament of the liver showed no malignant cells (P0, CY0). Conversion surgery comprising laparoscopic total gastrectomy with D2 lymph node dissection and resection of the round ligament of the liver was performed. The postoperative course was uneventful. Histopathological examination of the resected specimen revealed no tumor cells in the gastric mesentery or the round ligament of the liver. The pathological diagnosis was gastric cancer [M, U, L, Less, Ant, Post, type4, T3(SS), N0, M0 (H0, P0, CY0), ypStage IIA]. Adjuvant chemotherapy (S-1) was commenced. The patient is still alive 7 months later with no evidence of recurrence.
In Japan, the standard treatment for stage II/III advanced low rectal cancer is total mesorectal excision plus lateral lymph node dissection (LLND). There are also recent reports on the use of transanal LLND. However, the transanal anatomy is difficult to understand, and additional support tools are required to improve the surgical safety. The present study examined the utility of holograms with mixed reality as an intraoperative support tool for assessing the complex pelvic anatomy. Polygon (stereolithography) files of patients' pelvic organs were created and exported from the SYNAPSE VINCENT imaging system and uploaded into the Holoeyes MD virtual reality software. Three-dimensional images were automatically converted into patient-specific holograms. Each hologram was then installed into a head mount display (HoloLens2), and the surgeons and assistants wore the HoloLens2 when they performed transanal LLND. Twelve digestive surgeons with prior practice in hologram manipulation evaluated the utility of the intraoperative hologram support by means of a questionnaire. Intraoperative hologram support improved the surgical understanding of the lateral lymph node region anatomy. In the questionnaire, 75% of the surgeons answered that the hologram accurately reflected the anatomy, and 92% of the surgeons answered that the anatomy was better understood by simulating the hologram intraoperatively than preoperatively. Moreover, 92% of the surgeons agreed that intraoperative holograms were a useful support tool for improving the surgical safety. Intraoperative hologram support improved the surgical understanding of the pelvic anatomy for transanal LLND. Intraoperative holograms may represent a next-generation surgical tool for transanal LLND.
Hiroki Mori, Takayuki Noma, Yuji Morine, Hiroki Ishibashi and Mitsuo Shimada : Carcinogenic risk in the biliary epithelium of children with congenital biliary dilatation via the DNA damage repair pathway., Surgery Today, Vol.53, No.10, 1126-1131, 2023.
(Summary)
Congenital biliary dilatation (CBD) is a high-risk factor for biliary tract cancer (BTC). We previously reported the potential for carcinogenesis in the biliary epithelium of patients with CBD. In this study, we investigated potential carcinogenetic pathways, focusing on the DNA damage repair response, in children with CBD and compared the findings with those in adults. We enrolled 6 children with CBD and 10 adults with CBD without BTC who underwent extrahepatic bile duct resections, plus 4 control patients who underwent pancreaticoduodenectomy for non-biliary cancer. Levels of phosphorylated histone H2AX (γH2AX), MRE11, and Ku-70 in the biliary tract epithelium were evaluated by immunohistochemistry. The levels of γH2AX, MRE11, and Ku-70 were significantly higher in the gallbladder epithelium and bile duct epithelium of both children and adults than in controls. Children and adults with CBD might develop BTC via the DNA damage repair pathway, as evidenced by increased γH2AX, MRE11, and Ku-70 expression.
Yuji Morine, Yu Saitou, Shin-ichiro Yamada, Hiroki Teraoku, Yuhei Waki, Takayuki Noma, Tetsuya Ikemoto and Mitsuo Shimada : Multiplication of tumor maximum diameter and number as a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma., Hepatology Research, Vol.53, No.6, 531-539, 2023.
(Summary)
Recent advances in treatment modalities have been made, limiting the indication of hepatic resection in the treatment strategy for hepatocellular carcinoma (HCC) patients. This retrospective study investigated the significance of multiplication of tumor maximum diameter and number (MDN) as a surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC. A total of 49 patients with Barcelona Clinic Liver Cancer intermediate-stage HCC who underwent curative hepatic resection between 2000 and 2020 were enrolled in this study. Prognostic factors of overall survival and disease-free survival, including the product of MDN, were analyzed. Patients with MDN >12 experienced significantly worse prognosis compared with those with MDN ≤12 (p = 0.0395), and 5-year overall survival rates after hepatic resection were 60.0% and 23.4%, respectively. Furthermore, the disease-free survival rate of patients with MDN >12 was significantly worse compared with those with MDN ≤12 (p = 0.0049), and all patients with MDN >12 experienced recurrence within 3 years after hepatic resection. In the multivariate analysis, MDN >12 was identified as the only independent prognostic factor of both overall survival and disease-free survival. In addition, patients with MDN >12 suffered from uncontrollable recurrence by locoregional treatment, such as more than four intrahepatic and extrahepatic recurrences, after hepatic resection. MDN index might be a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC, and influence clinical decision-making for individual treatment strategies.
Hiroki Teraoku, Yuji Morine, Tetsuya Ikemoto, Yu Saitou, Shin-ichiro Yamada, Yuhei Waki, Shohei Okikawa, Katsuki Miyazaki, Chiharu Nakasu, Takayuki Noma, Akira Takahashi and Mitsuo Shimada : Impact of pancreatic resection in patients with liver cirrhosis., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 189-194, 2023.
(Summary)
Several reports have shown a high mortality rate in patients with liver cirrhosis (LC) who undergo pancreaticoduodenectomy, however, there are few reports on its long-term prognosis. Twelve patients with LC who had undergone pancreatic resection were enrolled. To compare clinicopathological variables, 159 non-LC patients who had undergone resection for pancreatic cancer were enrolled. Pancreaticoduodenectomy (PD) was performed in 5 LC patients and distal pancreatectomy (DP) was performed in 7 LC patients. Patients in the LC group had more co-morbidities, lower platelet counts and higher Fib4 index than the non-LC group. The postoperative complication rate was higher in the LC group (83.3% vs 47.8%). While the postoperative hospital stay and 30-day mortality rate were not different, the 90-day mortality rate was higher in the LC group (25.0% vs 2.5% ; p<0.01). Comparison by operative procedure showed no significant differences of postoperative outcomes in DP cases. However, in PD cases, postoperative complications were more frequent (100% vs 42.3%) and 90-day mortality was higher (40.0% vs 2.9% ; p<0.01) in the LC group. PD resulted in higher postoperative morbidity and mortality rates in patients with LC compared with non-LC patients. DP could be tolerated in the LC patients. J. Med. Invest. 70 : 189-194, February, 2023.
Mitsuo Shimada, Yuuma Wada, Takayuki Noma, Yu Saitou and Yuji Morine : The combination of CD8 and TIM3 expression to predict survival outcomes in hepatocellular carcinoma., ASCO-GI 2024, San Francisco, Jan. 2024.