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Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A.A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe.Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G A, rs2272761) showed a significant association with neutropenia (grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47).Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

Colorectal cancer is the third most common cancer globally, and the poor prognosis of patients with metastatic colorectal cancer (mCRC) warrants urgent attention. We previously obtained 10 candidate serum biomarkers for mCRC. Our aim with this study was to determine the prognostic performance of the pre-treatment serum C-C motif chemokine ligand 7 (CCL7) concentration in patients with mCRC.Protein concentrations of CCL7 were examined using ELISA and immunohistochemistry for serum (n=110) and surgical specimens (n=85), respectively, of patients with mCRC. The relationship between protein concentration and prognosis was examined using Cox regression analysis, receiver operator characteristic curve analysis and the Kaplan-Meier method.The overall survival (OS) of patients with high concentrations of serum CCL7 was significantly poorer than that of patients with low concentrations. Patients with a high CCL7 concentration in the stroma had significantly poorer outcomes than those with a low concentration. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 were significantly higher in the high-CCL7 group, compared to those in the low-CCL7 group. Univariate and multivariate analysis revealed that serum CCL7 concentration was a significant prognostic factor for mCRC. The combination of serum CCL and CEA concentrations was also useful in this regard (area under the curve=0.71).The combined pre-treatment serum levels of CCL7 and CEA are useful prognostic biomarkers for mCRC.

Cancer immunotherapy including immune checkpoint inhibitors(ICIs)have established itself as the fourth cancer therapy. However, the response rate of ICIs is still only about 20%, and tumors resistant to ICIs are often so-called"cold-tumor"with low tumor immunogenicity. Therefore, research and development is being conducted worldwide on how to convert cold- tumors into hot-tumors with high immunogenicity. In this paper, we review the relationship between tumor immunogenicity and ICI, as well as therapeutic methods to enhance tumor immunogenicity, and introduce our research about novel cancer peptide vaccination therapy.

Objective Pancreatic cancer stem-like cells (P-CSLCs) are thought to be associated with poor prognosis. Previously, we used proteomic analysis to identify a chaperone pro-phagocytic protein calreticulin (CALR) as a P-CSLC-specific protein. This study aimed to investigate the association between CALR and P-CSLC. Methods PANC-1-Lm cells were obtained as P-CSLCs from a human pancreatic cancer cell line, PANC-1, using a sphere induction medium followed by long-term cultivation on laminin. To examine the cancer stem cell properties, subcutaneous injection of the cells into immune-deficient mice and sphere formation assay were performed. Cell surface expression analysis was performed using flow cytometry. Results PANC-1-Lm showed an increased proportion of cell surface CALR-positive and side-population fractions compared with parental cells. PANC-1-Lm cells also had higher frequency of xenograft tumor growth and sphere formation than PANC-1 cells. Moreover, sorted CALRhigh cells from PANC-1-Lm had the highest sphere formation frequency among tested cells. Interestingly, the number of programmed death-ligand 1-positive cells among CALRhigh cells was increased as well, whereas that of human leukocyte antigen class I-positive cells decreased. Conclusion In addition to the cancer stem cell properties, the P-CSLC, which showed elevated CALR expression on the cell surface, might be associated with evasion of immune surveillance.

Introduction: Because surgical resection with simultaneous hepatic artery (HA) resection and reconstruction for perihilar cholangiocarcinoma (PHC) is technically demanding, the surgical indication for this challenging procedure is controversial. Thus, this study aimed to evaluate the efficacy of simultaneous HA resection and reconstruction for PHC. Methods: Between January 2002 and January 2018, 13 patients with PHC underwent surgical intervention with simultaneous resection and reconstruction of the HA at Yamaguchi University Hospital (Ube, Japan) and Osaka University Hospital (Suita, Japan). Results: There were 2 cases (15.4%) of 90-day postoperative mortality. Nine patients (69.2%) developed major postoperative complications (Clavien-Dindo classification ≥IIIa). Curative resections (R0) were achieved in 8 cases (61.5%). The median survival time (MST) and 1- and 3-year survival rates after resection (including in-hospital deaths) were 20.9 months and 61.5 and 10.3%, respectively. The MST and 1- and 2-year survival rates of 8 patients who underwent R0 resection were significantly better than those of the other 5 patients (24.2 vs. 10.2 months, 75.0 vs. 40.0%, and 50.0 vs. 0.0%, respectively, p = 0.0228). Conclusions: Simultaneous HA resection and reconstruction is technically possible and may provide long-term survival in selected patients with locally advanced PHC.

Background We recently reported the relapse-free survival (RFS) significance of the combination of CD4+ and forkhead box P3+ (FOXP3) T-cell densities identified by immunohistochemistry in patients with stage I, II, and III colorectal cancer (CRC) who underwent curative resections. This study was designed to determine the optimal combination of markers that predict recurrence in patients with T factors of T3/T4a stage II CRC by applying a novel Bayes decision rule. Methods Using 137 cancer tissue specimens from T3/T4a stage II patients, 12 clinicopathologic and immune factors were analysed as predictive candidates for recurrence. Results Our study showed that the combination of low CD4+ and low FOXP3+ T-cell densities resulted in extremely poor RFS. Conclusions Adjuvant chemotherapy may be considered for patients with a combination of low CD4+ and low FOXP3+ T-cell densities. The discovery of this new prognostic indicator is important for the appropriate management of patients undergoing curative resection for T3/T4a stage II CRC.

A proteomic analysis of hepatocellular carcinoma (HCC) has revealed that Heat Shock Protein 70 (HSP70) is among the cancer antigen proteins of HCC. Moreover, we confirmed that HSP70 was highly expressed in HCC by immunohistochemical staining. Based on these results, we developed an HSP70 mRNA-transfected dendritic cell (DC) therapy for treating unresectable or recurrent HCC, and the phase I trial was completed successfully. Thus, we aimed to investigate the safety and efficacy of this therapy as a postoperative adjuvant treatment after curative resection for HCC to prevent recurrence by conducting a phase I/II randomized controlled clinical trial. Patients (n = 45) with resectable HCC of stages II–IVa were registered and randomly assigned into two groups (DC group: 31 patients, control group: 14 patients) before surgery. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were safety and overall survival. The DC therapy was initially administered at approximately 1 week after surgery, and twice every 3–4 weeks thereafter. No adverse events specific to the immunotherapy were observed in the DC group. There was no difference in DFS between the DC and control groups (p = 0.666). However, in the subgroup with HSP70-expressing HCC, DFS of the DC group tended to be better (p = 0.090) and OS of the DC group was significantly longer (p = 0.003) than those of the control group. The HSP70 mRNA-transfected DC therapy was performed safely as an adjuvant therapy. The prognosis of HSP70-expressing HCC cases could be expected to improve with this therapy.

Purpose Anastomotic leakage is one of the most serious postoperative complications associated with surgery for rectal cancer. The present study aimed to identify the protective characteristics and risk factors associated with anastomotic leakage after low anterior resection for rectal cancer. Methods This was a retrospective, single-center study conducted between January 2009 and December 2017 at our institution. In total, 136 rectal cancer patients who underwent low anterior resection were included in the study. We analyzed preoperative and intraoperative factors. In addition, the pelvic dimensions were measured using computed tomography in all cases. Results Among the 136 patients, anastomotic leakage occurred in 21 (15.4%), including 18 males and 3 females. The median body mass index was 21.1 kg/m2. The construction of a covering stoma was found to be a protective factor. In addition, the operation time (≥ 373 min), intraoperative blood loss (≥ 105 ml), and size of the pelvic inlet (≥ 113 mm) were identified as risk factors for anastomotic leakage. Conclusion The construction of a covering stoma was a possible protective factor. However, a longer operation time, higher intraoperative blood loss, and larger pelvic inlet dimensions were possible risk factors for developing anastomotic leakage after low anterior resection in patients with rectal cancer.

Aim To evaluate the efficacy of intraoperative neuromonitoring in identifying recurrent laryngeal nerves and decreasing the incidence of nerve injury in minimally invasive esophagectomies for esophageal cancers. Methods A total of 167 minimally invasive esophagectomy patients were retrospectively reviewed. They were divided into intraoperative neuromonitoring (n = 84) and no intraoperative neuromonitoring (n = 83) groups, based on whether or not intraoperative neuromonitoring was used during surgery. We compared short‐term surgical outcomes and incidence of recurrent laryngeal nerve palsy between the two groups before and after propensity score matching. The association between the loss of signal and recurrent laryngeal nerve palsy was also evaluated. Results The incidence of recurrent laryngeal nerve palsy (grade 2 and higher) was lower in the intraoperative neuromonitoring group than in the no intraoperative neuromonitoring group (6.0% vs 21.2%, P = 0.02). The rate of recurrent laryngeal nerve palsy recovery within 6 months was also significantly higher in the intraoperative neuromonitoring group (87.5% vs 20.0%, P, Intraoperative neuromonitoring was useful in reducing the incidence of laryngeal nerve palsy associated with esophageal surgery.

Background This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. Methods HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose. Results Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. Conclusions This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

To identify preoperative factors, especially other diseases that cause death, that are associated with the prognosis of gastrectomy in elderly patients with gastric cancer.This retrospective study included a total of 211 consecutive patients aged ≥75 years who underwent radical gastrectomy due to gastric cancer. Time-dependent receiver operating characteristic curve analysis was performed to determine the optimal cutoff values for various perioperative factors. Risk factors for the overall survival and death from other diseases were analyzed using the Cox proportional hazards model.Among the all perioperative factors, sex, neutrophil-to-lymphocyte ratio, skeletal muscle mass index, and lymph node dissection in accordance with guidelines or not extracted as independent risk factors for death from other diseases. In an analysis restricted to the preoperative factors, sex, neutrophil-to-lymphocyte ratio, and skeletal muscle mass index of the patients were extracted as independent risk factors for death from other diseases and overall survival. We divided the patients into four groups according to the number of preoperative risk factors for death from other diseases and found that the 5-year non-gastric-cancer-related survival was different among the four groups (risk factor 0, 91.7%; risk factor 1, 83.3%; risk factor 2, 56.3%; risk factor 3, 27.2%;Male sex, low skeletal muscle mass index, and high neutrophil-to-lymphocyte ratio are risk factors for non-gastric-cancer-related death and the overall survival of elderly patients undergoing gastrectomy. Cautious treatment strategies are needed for elderly gastric cancer patients with many risk factors.

A 49-year-old man came to our department for the purpose of scrutinizing liver tumor. CA19-9 and CA125 increased, and AFP and PIVKA-Ⅱ were within the normal range. CT showed a large number of early ring enhanced tumor, and a tumor thrombus in the left branch of the portal vein. Tumor biopsy revealed adenocarcinoma. Chemotherapy(gemcitabine, cisplatin plus S-1: GCS)was performed for intrahepatic cholangiocarcinoma(r/o combined hepatocellular carcinoma and cholangiocarcinoma). Lenvatinib was administered because portal vein tumor thrombus and PIVKA-Ⅱ increased after GCS therapy. Two months later, CA19-9 and PIVKA-Ⅱ were decreased and portal vein tumor thrombus was shrunk. Extended left hepatectomy was performed for the purpose of disease control. Histopathological examination revealed some hepatocellular carcinoma components in intrahepatic cholangiocarcinoma. Tumor thrombus was vitrified and necrotic. After hepatectomy, administration of lenvatinib was continued for the residual lesion, and no significant tumor growth was observed.

This study reports a case of a 61-year-old man with a chief complaint of anemia. The patient was diagnosed with esophageal cancer(Stage Ⅰ). Preoperative examination revealed alcoholic liver cirrhosis(Child-Pugh A, liver damage B). After a period of abstinence to improve liver function, minimally invasive esophagectomy, retrosternal reconstruction with a gastric tube, and two-field lymph node dissection were performed. The thoracic duct was preserved during the operation. Post- surgery, the bill pleural effusion was increased. Drainage was initiated using thoracentesis with frosemide, spironolactone, and tolvaptan. On post-operating day(POD)35, the patient was discharged; however, right pleural effusion continued to increase. Therefore, cell-free and concentrated reinfusion therapy for right pleural effusion was performed on POD 56. After the treatment, the pleural effusion was well-controlled with 20 mg of frosemide. This case suggested that cell-free and concentrated pleural effusion reinfusion therapy contributed to the management of refractory pleural effusion in patients with esophageal cancer accompanied by cirrhosis.

This case pertains to a female patient in her 60s who was diagnosed with carcinoma in the cecum with lung, ovarian, and peritoneal metastases. She complained of abdominal distension and poor feeding because her ascites and ovarian metastasis worsened 18 months after chemotherapy initiation. Repeated cytologic examination of the ascitic fluid revealed no malignant cells. Therefore, Pseudo-Meigs' syndrome was suspected. Bilateral salpingo-oophorectomy was performed as palliative surgery because of the patient's reduced capacity to perform activities of daily living(ADL)due to ascites. After palliative surgery, her ascites disappeared, and she was able to better perform ADL. Further, chemotherapy was resumed. The patient remains well 10 months after surgery. This case highlights the importance of considering Pseudo-Meigs' syndrome in patients with massive ascites and ovarian metastasis, because surgical resection can improve their quality of life.

An 80 year-old woman with anorexia and jaundice was diagnosed with mass-forming intrahepatic cholangiocarcinoma, lymph node metastasis, common hepatic duct strictures, and obstructive jaundice. PET-CT showed FDG accumulation in the primary lesion(SUVmax 19.0)and swollen lymph nodes. Her ADL and major organ functions were judged to be sufficient for treatment. After treatment for jaundice, she received a total of 6 courses of gemcitabine, cisplatin plus S-1(GCS)therapy as neoadjuvant chemotherapy(NAC). Her first treatment was an 80% dose of GCS, but she was subsequently diagnosed with Grade 4 thrombocytopenia(CTCAE v5.0). The dose of gemcitabine was further reduced, and no adverse events of Grade 3 or higher were observed thereafter. After NAC, PET-CT showed decreased FDG accumulation in the primary lesion(SUVmax 3.3)and normalization of FDG accumulation in the lymph nodes. Extended right hepatectomy and biliary reconstruction were performed as radical resection(R0). The final diagnosis was pT2, N0, M0, Stage Ⅱ. After hepatectomy, her anorexia and poor ADL persisted. She was discharged to her home 151 days after her surgery.

Although the current standard of care for patients with lower rectal cancer in Japan includes total mesorectal resection with lateral lymph node dissection, postoperative local and distant recurrence rates are high. Multidisciplinary treatment is important to improve the prognosis. A man in his 30s was diagnosed with lower rectal cancer due to bloody stool and referred to our department. He was diagnosed as cT3N3M0, cStage Ⅲc with right obturator lymph node metastasis. Four courses of neoadjuvant chemotherapy(NAC)with FOLFOXIRI plus cetuximab were performed. Because Grade 3 neutropenia was observed in the first cycle(CTCAE v5.0), pegfilgrastim was administered in the second and subsequent cycles, and NAC was completed without dose reduction. The patient underwent laparoscopy-assisted intersphincteric rectal resection and D3+rtLD2 dissection. Histopathological resection margins were negative, and the resection was R0. Lymph node metastasis was found only in No. 263d-rt, and the pathological diagnosis was ypT3N3M0, pStage Ⅲc. Histological evaluation of response to treatment was Grade 2. The postoperative course was good and the patient was discharged on postoperative day 15. The patient received 8 courses of adjuvant chemotherapy with mFOLFOX6 from the 7th postoperative week and is alive and recurrence-free 6 months after surgery.

Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated.Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing.The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells.Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.

Background Cancer stem cells (CSCs) are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) which possess enhanced chemoresistance and metastatic potential. To enable the development of targeted therapy against CSLCs, we identified a gene responsible for this phenotype in CSLC. Methods Human hepatoma cell line SK-HEP-1 was used for CSLC induction with a unique sphere inducing medium, and HuH-7 cells were used as non-sphere forming cells in the same condition. RNA-sequencing was performed followed by validation with quantitative RT-PCR and western blotting. Knockdown experiments were done by using CRISPR-Cas9 genome-editing, and the rescue experiments were performed using the expressing plasmid vector. Chemoresistance and liver metastasis of the cells, was studied following the splenic injection of cells to severely immune deficient mice and evaluated using the MTS assay. Quantification of exosomes in the medium was done using ELISA. Results RAB3B was identified as an up-regulated gene in both CSLCs and prognostically poor hepatocellular carcinoma (HCC) by RNA-sequencing. RAB3B-KD cells showed altered CSLC phenotypes such as sphere formation, chemoresistance, and metastatic potentials, and those were rescued by RAB3B complementation. Increased exosome secretion was observed in CSLCs, and it was not observed in the RAB3B-KD cells. In addition, the RAB3B expression correlated with the expression of ABCG2, APOE, LEPR, LXN, and TSPAN13. Conclusion The up regulation of RAB3B may play an important role in the chemoresistance and metastatic potential of CSLCs.

Background CD3 + and CD8 + T-cell infiltration were reported as positive predictive markers of survival in colorectal cancer (CRC) patients. Here, we demonstrate the prognostic significance of CD4 + and FOXP3 + T-cell densities in CRC. Methods We quantified the intratumoural densities of CD3 + , CD8 + , CD4 + and FOXP3 + T cells by immunohistochemistry and digital pathology in 342 CRC patients who underwent curative resection. Microsatellite instability was also assessed in 322 specimens. Patient demographics, clinicopathological features and survival rates were analysed. Results High CD3 + , CD4 + and FOXP3 + T-cell densities were associated with improved relapse-free survival (RFS); high CD8 + , CD4 + and FOXP3 + T-cell densities were associated with improved disease-specific survival (DSS). Patients with low CD4 + and low FOXP3 + T-cell densities exhibited extremely poor prognoses. T stage, vascular/lymphatic invasion and CD4 + T-cell density were independent prognostic indicators for DSS. The distributions of CD4 + and FOXP3 + T-cell densities were not significantly different between the high microsatellite instability group and other groups, in contrast to those of CD3 + and CD8 + T-cell densities. Conclusions Intratumoural CD4 + T-cell density and combined CD4 + and FOXP3 + T-cell densities were stronger prognostic indicators than other clinicopathological features. These results may facilitate the establishment of novel prognostic factors and therapeutic strategies for CRC.

Objective Malnutrition is common in patients with esophageal cancer, resulting in increased postoperative complications and mortality. Although preoperative immunonutrition can significantly reduce the incidence of postoperative infectious complications, its effect in patietns with esophageal cancer undergoing esophagectomy remains unclear. The aim of this study was to investigate the effects of perioperative immunonutritional support on the postoperative course and long-term survival of this group of patients. Methods This prospective, randomized study enrolled 40 patients with thoracic esophageal carcinoma undergoing esophagectomy. The patients were divided into two groups and received either immunomodulating enteral nutrition (IMPACT group; IG) or standard enteral nutrition (Ensure group; EG) continuously for 7 d before and 7 d after surgery. Nutritional status, such as rapid turnover protein, postoperative intensive care unit (ICU) length of stay (LOS), postoperative hospital LOS, morbidity, and mortality were investigated prospectively. Results There were no significant differences in patient demographic characteristics between the two groups. Levels of retinol-binding protein, as a rapid-turnover protein, were significantly higher on postoperative day (POD) −1, 7, and 14 in the IG compared with the EG group (P = 0.009, P = 0.004, and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics were significantly lower in the IG group than in the EG group (P = 0.048 and P = 0.012, respectively). There was no significant difference in postoperative ICU or postoperative hospital LOS between the two groups. The 5-y progression-free survival rates in the IG and EG groups were 75% and 64%, respectively (P = 0.188), and the overall survival rates were 68% and 55%, respectively (P = 0.187). Conclusions Perioperative immunonutrition may improve early postoperative nutritional status and reduce postoperative infectious complications in patients with esophageal cancer undergoing esophagectomy.

A 67-year-old woman was admitted with melena. A colonoscopy detected a 50 mm submucosal tumor close to the dentate line. We diagnosed the rectal gastrointestinal stromal tumor by EUS-FNA. With the expectation of tumor shrinkage and strong hope of the patient, we started imatinib mesylate as neoadjuvant chemotherapy. A CT scan after 3 months after administration of imatinib mesylate showed the reduction of the size to 35 mm. We operated transanal endoscopic surgery considering the localization of the tumor. From histopathological findings, the tumor was low risk in the modified-Fletcher classification, and low risk in the Miettinen classification. Eight months after the operation, no recurrence was observed without further adjuvant chemotherapy. In this case, we were able to resect the tumor without injuring the film of tumor by operating transanal endoscopic surgery, because of tumor shrinkage with imatinib mesylate as neoadjuvant chemotherapy. I considered that using imatinib mesylate preoperatively was contributed to minimally invasive surgery.

Patient is 69-year-old man, who underwent a high anterior resection with laparoscopic support for rectal cancer. The patient was diagnosed with anastomotic recurrent rectal cancer after 14 months after surgery. The pelvic MRI scan showed invasion of the prostate and seminal vesicles, so NACRT was performed. Tumors were found to have decreased in size, although there was still some residual invasion of the prostate and seminal vesicle. Laparoscopic total pelvic exenteration (Lap-TPE), and combined excision of the anal elevator muscle and bladder were performed. Preoperative diagnosis was ycT4b, N0, M0, ycStage Ⅱ, and pathological diagnosis was pT4b (prostate and seminal vesicles), INF b, Ly2, v2, Pn1b, pPM0, pDM0, pRM0, and pN0. Laparoscopic surgery allowed to operate safely, with minimal blood loss and a good field of vision. After postoperative adjuvant chemotherapy, lung and liver metastasis appeared after 6 months after surgery, but there was no local recurrence. The patient is treated with chemotherapy, and the metastases are under control. The patient is survive 17 months after Lap-TPE.

Case 1: The patient was a 74-year-old man with a performance status(PS)of 0. He was referred to our department for pyloric gastric cancer with multiple liver, lung, and lymph node metastases. We started chemotherapy after making the diagnosis of an unresectable gastric cancer. During chemotherapy, the hemoglobin level dropped due to bleeding from the tumor. We attempted endoscopic hemostasis, which was not successful; therefore, we attempted a palliative radiotherapy. The total dose was 30 Gy in 10 Fr and hemostasis was achieved on the 10th day from the start of the radiotherapy. There were no adverse events due to the radiation, and the chemotherapy could be restarted 5 days after the end of the radiotherapy. Case 2: The patient was a 78-year-old man with a PS of 2. He was referred to our department because of vomiting and anemia. As a result of a close inspection, we made the diagnosis of an unresectable gastric body cancer with para-aortic lymph node metastasis and peritoneal dissemination, for which chemotherapy was initiated. Anemia was observed at the first visit, and we started radiotherapy to stop the tumor bleeding. The total dose was 30 Gy in 10 Fr, and hemostasis was achieved on the 12th day. There were no adverse events during the radiotherapy, and chemotherapy could be continued. Palliative radiotherapy is an available method of hemostasis that is less invasive than surgery or transcatheter arterial embolization and can be expected to have a certain effect for gastric cancer bleeding, although it takes several days to obtain a therapeutic effect.

A 60-year-old man underwent thoracoscopic subtotal esophagectomy and posterior mediastinal gastric tube reconstruction after neoadjuvant chemotherapy. One year and 8 months postoperatively, recurrence was observed in the abdominal lymph nodes around the celiac artery and abdominal aorta. Chemoradiotherapy was initiated, followed by chemotherapy. Two months after the completion of chemoradiotherapy, the patient developed epigastric pain and anorexia because of the necrotic lymph node penetrating the gastric tube with cavity formation. Upper gastrointestinal endoscopy revealed a 25- mm-sized ulcer with central necrotic slough on the posterior wall of the stomach. Abdominal symptoms alleviated after conservative treatment with fasting and administration of antibiotics, and the inflammatory reaction improved. Oral nutritional supplements were started on hospitalization day 7, and abdominal symptoms or inflammatory reactions did not recur after resuming diet. The patient was discharged on hospitalization day 39 when the general condition stabilized. Subsequently, chemotherapy was restarted, and no regrowth of metastatic lesions was observed on endoscopy or CT examination 4 months later. Three years and 8 months after the recurrence, the recurrent disease has been controlled.

The patient was a woman in her 80s. Operative treatment was performed for papillary thyroid cancer(pT3N0M0)13 years ago. A follow-up CT scan 1 year ago revealed a skin, lung, and lymph node metastasis. At the same time, a tumor with a size of 24 mm was initially observed in the tail of the pancreas, which was considered to be pancreatic metastasis of thyroid papillary cancer and was followed up. Only the pancreatic lesions tended to gradually increase, although other lesions did not increase. Therefore, the patient was referred to our department. It was difficult to diagnose preoperatively. Thus, diagnostic and therapeutic laparoscopic distal pancreatectomy with splenectomy was performed. The pathological diagnosis was dedifferentiated liposarcoma. Postoperatively, a Grade B pancreatic fistula was observed, but the patient recovered conservatively and was discharged on postoperative day 55. Primary liposarcoma of the pancreas is extremely rare, and few cases have been reported. Primary liposarcoma of the pancreas is very difficult to diagnose preoperatively by only diagnostic imaging.

In recent years, breast reconstruction has been increasingly performed in breast cancer surgery with improving the appearance of the breast. We report a case of local breast cancer recurrence after artificial breast reconstruction. The patient was a 52-year-old woman. She had undergone total mastectomy for left breast cancer 11 years ago, and reconstruction with breast implant 3 years ago. She presented to our hospital with the chief complaint of skin redness and induration of the reconstructed breast. A core needle biopsy was performed, and its results showed in the invasive ductal carcinoma. She had an operation of resection of tumor and reconstruction implant. As a result of histopathological diagnosis, it was a local recurrence of breast cancer 11 years ago. After the surgery, she underwent endocrine therapy and there is no recurrence. As the increase in the number of cases of breast reconstruction, the number of recurrences in the reconstructed breast is expected to increase the future. The treatment strategy for cases of local recurrence after breast reconstruction is currently under review, the accumulation of evidence is necessary.

Background: Complete rectal prolapse (CRP) commonly affects the daily life of older people and has no established operative treatment approach. We describe our simple method of laparoscopic, sutureless rectopexy, involving rectal mobilization (along with its peritoneum bilaterally) and fixation to the sacral promontory using a fixation device. We also present an analysis of short-term outcomes in patients treated using this procedure. Materials and Methods: We retrospectively evaluated 62 patients with CRP, who underwent a laparoscopic rectopexy via tack fixation, between 2004 and 2017. The peritoneum was widely attached near the site of peritoneal reflection, as in rectal cancer surgery. The hypogastric nerve was carefully detached from the front of the sacrum. Keeping the nerve intact, we lifted and mobilized the dissected rectum cranially towards the promontory, and the rectal peritoneum was affixed to the sacrum by applying 2 to 3 fixed tacks bilaterally, using a fixation device. Results: The median age of the study group was 80 (10 to 91) years. All procedures were successful without serious intraoperative complications; only 1 patient required conversion to open surgery. Median values for operative duration, intraoperative blood loss, and postoperative period of hospitalization were 177 (125 to 441) minutes, 5 (0 to 275) mL, and 7 (3 to 17) days, respectively. Only 6 (9.7%) patients experienced recurrence during the follow-up period. Conclusion: Laparoscopic tacking rectopexy performed using a fixation device for repairing CRP is a simple, safe, and sutureless procedure with no severe complications or mortality.

Surgical resection is the only curative treatment for pancreatic cancer. Arterial resection and reconstruction during pancreaticoduodenectomy for advanced pancreatic cancer remain controversial due to a high rate of complications. We report two cases of pancreatic cancer with hepatic artery resection and reconstruction using the right gastroepiploic artery during pancreaticoduodenectomy after neoadjuvant therapy. The patients underwent pancreaticoduodenectomy with resection of the right hepatic and common hepatic arteries. Achieving direct anastomosis was difficult; therefore, we planned hepatic artery reconstruction using the right gastroepiploic artery. We performed the reconstruction using an interrupted suture with end-to-end anastomosis. The first patient developed a postoperative pancreatic fistula, while the postoperative course of the second patient was uneventful. However, there were no adverse events related to the arterial reconstruction. R0 resection was achieved, and postoperative computed tomography revealed good patency of the reconstructed artery. Hepatic artery reconstruction using the right gastroepiploic artery in pancreatic cancer might be technically safe and might become one of the alternative options.

Laparoscopic liver resection is beneficial compared to open liver resection. This study aimed to evaluate whether laparoscopic liver resection could reduce postoperative infections. This study included 125 and 115 patients with liver tumors who underwent open and pure laparoscopic partial resections or left lateral sectionectomies, respectively. Propensity score matching and stabilized inverse probability of treatment weighting were carried out to compare the postoperative infectious complication rates between the two groups. Patients with tumors located in Couinaud segment 1, 7, or 8; with tumors adjacent to major vessels; or who underwent repeated resections were more likely to receive open resection. After propensity score matching, the superficial incisional surgical site infection rate tended to be lower in the laparoscopic liver resection group than in the open liver resection group. Moreover, overall infectious complication rate and superficial incisional surgical site infection rate were lower in the laparoscopic group (the cohort formed by the stabilized inverse probability of treatment weighting). Using the laparoscopic approach for partial resections and left lateral sectionectomies for liver tumors, the superficial incisional surgical site infection rate could be reduced.

Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC.

A 67-year-old man was admitted with melena. A colonoscopy detected advanced rectal cancer, and a CT scan revealed invasion of the seminal vesicle and prostate. Given the wild-type RAS status of the tumor, we administered 6 courses of XELOX plus cetuximab as neoadjuvant chemotherapy. After treatment, the tumor had shrunk, and the rectum had narrowed. Later, following a diagnosis of coronary artery disease, colostomy was performed. The patient was treated for the coronary artery disease for 2 months. Following treatment, tumor progression was detected, and hence, the patient was treated with the same chemotherapy regimen for 4 more courses. We performed a laparoscopic assisted abdominoperineal resection of the rectum with combined resection of the seminal vesicle and prostate. Pathological examination revealed a complete response to treatment. Six months after the operation, no recurrence was observed without further adjuvant chemotherapy.

The patient was a 17-year-old woman. An abnormal urinalysis was observed, and abdominal echography showed a pancreatic cystic mass. At the first examination, computed tomography(CT)and endoscopic ultrasound(EUS)showed a unilocular cystic mass of 60mm in size in the pancreatic body and tail, and no malignant findings were observed. After 14 months, CT and positron emission tomography-computed tomography(PET-CT)showed that the cystic mass had a mural nodule with FDG accumulation, and presence of a tumor in hepatic S8 with FDG accumulation. Laparoscopic distal pancreatectomy and hepatic subsegmentectomy of S8 were performed for diagnostic and therapeutic purposes. The pathological diagnosis was mucinous cystadenocarcinoma(MCC)and metastatic liver cancer in the form of MCC. S-1 was administered after surgery. Nine months after resection, multiple metastatic liver tumors were found, and GEM plus nab-PTX was administered. After 2 courses of treatment, the patient is still alive without new lesions.

A 64-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a submucosal tumor of 52mm in size at the lower thoracic esophagus. Biopsy yielded a pathological diagnosis of c-kit-positive esophageal gastrointestinal stromal tumor(GIST). We started neoadjuvant therapy with imatinib to avoid excessive surgical invasion. After 6 months of treatment, CT revealed a reduction in tumor size to 27 mm. We performed laparoscopic lower esophagectomy, proximal gastrectomy, double-tract reconstruction, and complete tumor resection. Neoadjuvant imatinib therapy was effective for the esophageal GIST.

The patient was a 66-year-old man presenting with epigastric pain and jaundice. PET-CT demonstrated limited-accumulation on the tumor at the head of the pancreas, diagnosed as borderline resectable adenosquamous carcinoma. The patient was treated with preoperative chemoradiation therapy with 2 courses of gemcitabine followed by administration of S-1 and gemcitabine for 13 months, which reduced the tumor size. After preoperative therapy, pancreaticoduodenectomy was performed. Histopathological examination revealed that no viable tumor cells were detected in the pancreas or lymph nodes, and the patient had achieved a pathological complete response. Postoperative adjuvant chemotherapy was not performed, and the patient is still alive without recurrence for 66 months after surgery.

Background Colorectal cancer is the third most common cancer worldwide. If biomarkers can be identified in liquid biopsy, diagnosis and treatment can be optimized even when cancerous tissues are not available. The purpose of this study was to identify proteins from liquid biopsy that would be useful as markers of poor prognosis. Methods First, we comprehensively analyzed serum proteins to identify potential biomarkers and focused on serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). The relationship between LOX-1 and the prognosis of patients with colorectal cancer has not been reported. Next, we validated this marker using serum samples from 238 patients with colorectal cancer by ELISA and 100 tissue samples by immunohistochemical staining. Results The optimal cut-off value of serum LOX-1 was 538.7 pg/mL according to time-dependent receiver operating characteristics curve analysis. The overall survival of patients with high levels of serum LOX-1 was significantly poorer than that of individuals with low levels of LOX-1 in the training and test datasets. In multivariate analysis for overall survival, serum LOX-1 was an independent prognostic factor identified in liquid biopsy (hazard ratio = 1.729, p = 0.027). The prognosis of patients with high LOX-1 expression in tumor tissues was significantly poorer than that of individuals with low expression (p =0.047 ). Additionally, inflammatory factors such as white blood cell count, C-reactive protein level, neutrophil/lymphocyte ratio, and monocyte/lymphocyte ratio were significantly higher in the group with high serum LOX-1 levels. Conclusions Serum LOX-1 might be a useful biomarker of poor prognosis in colorectal cancer.

Co/Ti-substituted Sr-based M-type hexagonal ferrite containing composite sheets are used for the demonstration of electromagnetic noise suppression at and above 6 GHz. Three different compositions (SrCoxTixFe12 − 2xO19 with x = 1.0, 1.2, and 1.4) and two different size groups with the average diameter of ∼10 µm and ∼1 µm have been studied to understand the effect of Co-Ti substitution level and size on the high frequency magnetic characteristics of SrM hexaferrites. A drop in coercivity from 285 Oe to 40 Oe and 710 Oe to 90 Oe was observed as the Co/Ti substitution level, x, increases from 1.0 to 1.4 in the case of 10-µm and 1-µm particles respectively. Complex permeability was measured by two methods – by microstrip probe, and by all-shielded and shorted microstrip line. Ferromagnetic resonance frequency drops from ∼20 GHz to ∼3 GHz as x increases from 1.0 to 1.4, while it decreases a little as the particle size decreases. Electromagnetic noise suppression was demonstrated by measuring the ratio of power loss in the magnetic element to the input power by placing it on top of a microstrip line. With a 500-µm thick composite sheet, electromagnetic noise suppression up to 20% was achieved.

High-frequency permeability spectra of magnetic films were measured over a wideband frequency range of 0.1–30 GHz using a shielded and short-circuited microstrip line jig. In this measurement, spurious resonances had to be suppressed up to the highest frequency. To suppress these resonances, characteristic impedance of the microstrip line should approach 50 Ω at the junction between connector and microstrip line. The main factors dominating these resonances were structures of the jig and the sample. The dimensions were optimized in various experiments, and results demonstrated that the frequency could be raised to at least 20 GHz. For the transverse electromagnetic mode to transmit stably along the microstrip line, the preferred sample was rectangular, with the shorter side parallel to the line and the longer side perpendicular to it, and characteristic impedance strongly depended on the signal line width of the jig. However, too small a jig and sample led to a lower S/N ratio.

For their use as flexible frameworks in high-frequency electromagnetic devices, soft magnetic thin films must have a high relative permeability μ up to frequencies of the order of 10 GHz and must overcome directional limitations. In this study, we demonstrate full in-plane, high-frequency, soft magnetic performance of Co $_{x}$ -(SiO2) $_{1-x}$ nanogranular films with large out-of-plane anisotropy. For a film with Co concentration $x = 0.52$ , we obtained a high value μ = 4 up to the resonance frequency of 13 GHz for every direction in the film plane. The fine magnetic-maze-domain structure that we observed using magnetic force microscopy was unaffected by the application of an external magnetic field. Both the large out-of-plane anisotropy fields of a few thousand oersteds and the negligibly small remanent magnetization contribute to produce a resonance frequency greater than 10 GHz and to enable magnetically isotropic conditions in the film plane, with high reversibility in external magnetic fields. This film with the large out-of-plane anisotropy promises to be a useful material for applications in fully directional and flexible designs of electromagnetic devices.

Summary Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of this study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we performed microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were administered. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently we performed reverse transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis revealed that the expression of miR-378a in stromal cells showed the best performance among the 3 predictors (HR, 2.730; 95% CI, 1.027-7.585; P = 0.044). In conclusion, miR-125b-1 and miR-378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer. This article is protected by copyright. All rights reserved.

Few reports exist regarding surgical resection of metachronous lung metastases (MLM) from pancreatic ductal adenocarcinoma (PDA) after curative resection. To elucidate the indications for surgical resection of MLM and long-term survival, we analyzed Japanese case reports of MLM from PDA. Between 1983 and 2014, 17 Japanese case reports concerning surgical resection of MLM from PDA were published. We determined long-term survival in 16 patients (considering the published data of 15 patients and 1 of our own) by using a questionnaire survey and analyzing the relationships between background factors and long-term survival. In 16 patients with long-term survival, 4 patients were still alive without recurrence. The remaining 12 patients died of disease after recurrence. The median survival after the initial lobectomy was 37 months and the 3- and 5-year survival for all patients after lobectomy was 50% and 41%, respectively. Fourteen patients had a disease-free interval after initial resection of the primary pancreatic tumor of20 months. These patients had a longer median survival period after lobectomy (46 vs. 25.5 mo, P=0.19). Seven patients had MLM of16 mm. These patients had a statistically longer overall survival after lobectomy (83 vs. 16 mo, P=0.04). Three of 4 patients with primary stage I tumors were still alive without recurrence. We found that the conventional criteria for surgical resection of MLM from PDA (first disease-free interval of20 mo with no other metastatic lesions) were appropriate. In addition, it is possible that MLM of16 mm or primary stage I tumors are novel criteria.