Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance.

In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation.

[A Case of Conversion Surgery for Gallbladder Cancer with Para-Aortic Lymph Node Metastasis].

The study presents the case of a 71-year-old woman who visited a nearby hospital for epigastric pain and weight loss. A CT scan showed a mass in the gallbladder, and the CEA level was high, so she was referred to our hospital for further investigation. Abdominal US, CT, and MRI suggested gallbladder cancer with para-aortic metastasis, and the histological findings on the EUS-FNA confirmed the diagnosis. Since surgical resection was not indicated, chemotherapy was performed(gemcitabine plus cisplatin). After 10 courses of chemotherapy, CT and MRI showed downsizing of para-aortic lymph nodes, and no accumulation of FDG was found on FDG-PET. Confirming the downstaging of cancer, conversion surgery, comprising an extended cholecystectomy and a lymph node resection, was performed. The pathological diagnosis showed no lymph node metastasis. No recurrence was observed after 12 months of surgery. Initially, unresectable gallbladder cancer with para-aortic lymph node metastasis was indicated to be compatible with preoperative chemotherapy and conversion surgery.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor.

OBJECTIVE: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). METHODS: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. RESULTS: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. CONCLUSION: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.

Perioperative fluid management influences complication rates and length of hospital stay in the enhanced recovery after surgery (ERAS) protocol for patients with colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of the enhanced recovery after surgery (ERAS) protocol and quantify the impact of each ERAS item on postoperative outcomes. METHODS: We used a generalized linear model to compare 289 colorectal cancer patients treated with the ERAS protocol between June, 2015 and April, 2021, with 99 colorectal cancer patients treated with the conventional colorectal surgery pathway between April, 2014 and June, 2015. RESULTS: The median length of hospital stay (LOHS) was significantly shorter in the ERAS group, at 9 days (range 3-104 days) vs. 14 days (range 4-44 days) (p < 0.001), but the complication rates (Clavien-Dindo grade 2 or more) were similar (16.6% vs. 22.2%; p = 0.227). However, in the ERAS group, the higher the compliance with ERAS items, the lower the complication rate and LOHS (both p < 0.001). Multiple regression analysis demonstrated that "Discontinuation of continuous intravenous infusion on POD1" and "Avoidance of fluid overload" were significantly associated with the LOHS (p < 0.001 and p = 0.008). CONCLUSION: The ERAS protocol is safe and effective for elective colorectal cancer surgery, and compliance with the ERAS protocol contributes to shorter LOHS and fewer complications. Items related to perioperative fluid management had a crucial impact on these outcomes.

[A Case of HER2-Positive Unresectable Advanced Gastric Cancer Showing Long-Term Complete Response Treated by Only Chemotherapy].

A 78-year-old man was diagnosed as HER2-positive unresectable advanced gastric cancer(cT4aN3M1[LYM], Stage Ⅳ). After 2 courses of first-line chemotherapy(S-1 plus oxaliplatin plus trastuzumab), PR was achieved. The treatment could not be continued due to adverse events after 5 courses, thus second-line chemotherapy was conducted. Corresponding to the physical condition. The third-line chemotherapy was also introduced. However, we clinically judged PD because of amount of ascites and chemotherapy was terminated. After that, he has survived for more than 2 years without chemotherapy, and endoscopy and CT showed the disappearance of the tumor, metastatic lymph nodes, and ascites at 41 months after diagnosis. Looking back on the changes in tumor markers, it was possible that he had already achieved CR at the first-line chemotherapy.

[A Case of Lymph Nodes Metastases of Gastric Neuroendocrine Carcinoma Treated with Nivolumab and Showing Complete Response].

A 78-year-old man was diagnosed with lymph node metastasis 2 months after surgery for gastric neuroendocrine carcinoma. He received chemotherapy(CDDP plus CPT-11)and showed partial response(PR)after 3 courses of the regimen. Serum CEA increased 5 months after surgery, thus nab-paclitaxel plus ramucirumab was administered. Although the lymph node kept shrinked after 2 courses of the regimen, the lymph node was detected 12 cm of the size in CT after 5 courses of the regimen. He started to receive nivolumab. The lymph nodes showed PR after 4 courses, and complete response after 6 courses of the regimen for 1 year and 4 months until now.

Erratum: Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade.

[This corrects the article DOI: 10.1016/j.isci.2020.101584.].

Coexistence of multiple liver metastases from sigmoid colon cancer and a gastrointestinal stromal tumor in the small intestine.

A 60-year-old man was referred to our hospital for the evaluation and treatment of general malaise. Contrast-enhanced computed tomography detected sigmoid colon cancer that had invaded the bladder, multiple liver metastases, and a small intestinal tumor. Hartmann's procedure was performed, with partial bladder and small bowel resection. A pathological examination revealed that the patient had sigmoid colon cancer and a gastrointestinal stromal tumor. The biopsy findings of a tumor in segment 8 of the liver indicated the presence of adenocarcinoma, thereby indicating the origin of multiple liver metastases from sigmoid colon cancer. On chemotherapy, the tumors in liver segments 2/3 and 8 shrank. However, the tumor in segment 6 enlarged. Since radical resection of all metastatic liver tumors was possible, hepatectomy was performed 10 months after the initial surgery. A pathological examination revealed that the tumors in segments 2/3, 4, and 8 were adenocarcinomas and the tumors in segments 4, 6, and 7 had originated from the gastrointestinal stromal tumor. This suggested the coexistence of liver metastases from sigmoid colon cancer and the gastrointestinal stromal tumor. In cases involving multiple primary tumors, it is necessary to consider the possible coexistence of multiple metastases from different primary tumors.

National survey of hepatobiliary and pancreatic surgery in hemophilia patients in Japan.

BACKGROUND: Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan. METHODS: The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications. RESULTS: The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients. CONCLUSIONS: As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS.

[A Case of Cardiac Tamponade during Multimodal Treatment for Mediastinal Lymph Node Metastasis of Gastric Cancer].

A 52-year-old man underwent total gastrectomy for gastric cancer and chemoradiotherapy for thoracic paraaortic lymph node metastasis. He also underwent esophageal stent implantation for stenosis. He was admitted to our hospital with fever and breathing difficulty and was diagnosed with infectious pericarditis. He showed symptoms of shock due to cardiac tamponade. After pericardial drainage, his vital signs improved. When signs of infection are detected in patients with a history of chemoradiotherapy or stent implantation, we should consider infectious pericarditis due to esophageal pericardial fistula and apply immediate drainage of cardiac tamponade.

A case of intraductal papillary mucinous neoplasm developing in the native pancreas after pancreas transplantation treated by total pancreatectomy.

Post-transplant patients reportedly have a higher risk of de novo neoplasms. However, intraductal papillary mucinous neoplasm (IPMN) of the native pancreas after pancreas transplantation (PTx) has not been well investigated. The choice of treatment, especially invasive treatment, for de novo neoplasms in transplant patients should consider their impaired immunity. In this context, we present a case of IPMN developing in the native pancreas of a PTx patient. A 53-year-old man underwent a follow-up abdominal computed tomography scan 6 years after a simultaneous pancreas-kidney transplant for type 1 diabetes mellitus with end-stage diabetic nephropathy requiring hemodialysis. The scan revealed IPMN in the pancreas head; an enhancing internal solid component suggested a high risk of malignancy, indicating surgical resection. Partial pancreatectomy or pancreaticoduodenectomy was anatomically indicated, but considering the insulin-secreting ability of the transplanted pancreas and the potential high risk of postoperative pancreatic fistula due to immune impairment after partial pancreatectomy, total pancreatectomy (TP) was performed. The patient is alive with good pancreas graft function, no signs of indigestion for 18 months after TP, and no evidence of IPMN recurrence. This report should help clinicians characterize de novo IPMN in the native pancreas and determine IPMN therapeutic options for transplant patients.

Randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine and nanoparticle albumin-bound paclitaxel combination therapy as neoadjuvant chemotherapy for resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC-GS/GA-rP2, CSGO-HBP-015).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear. METHODS: A randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100. DISCUSSION: This study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000021484 . This trial began in April 2016.

[A Case of Pancreaticoduodenectomy for Vater Papillary Cancer with Celiac Axis Stricture].

During the follow‒up of Vater papillary adenoma, a 74‒year‒old man was admitted to our hospital with a chief complaint of upper abdominal pain and diagnosed as cholangitis with obstructive jaundice. Cholestasis had been considered to be caused by papillary adenoma, however, EUS exam showed continuous bile duct wall irregularity from papilla of Vater. So we diagnosed as papillary carcinoma with extension to the distal bile duct. Preoperative CT showed the stenosis at the root of celiac artery, and hepatic blood flow was considered to be supplied via the pancreatic head arcade from superior mesenteric artery, so an anastomosis of gastroduodenal artery and inferior pancreaticoduodenal artery was performed during pancreaticoduodenectomy( PD). Like this case, when performing PD with celiac artery stricture, it is important to evaluate hepatic blood flow before and during surgery and prepare for the arterial reconstruction.

An optimized protocol for patient-derived xenograft in humanized mice to evaluate the role of IL-34 in immunotherapeutic resistance.

Previously, we identified a therapy-resistant role of IL-34 in an immune checkpoint blockade in murine models. To investigate whether a similar mechanism is applicable in human tumors as well, we used this protocol for the selection of IL-34-neutralizing antibody and transplanting human tumor tissue expressing both IL-34 and PD-L1 as a patient-derived xenograft in immunologically humanized mice. This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors. For complete details on the use and execution of this protocol, please refer to Hama et al. (2020).

Retrograde endoscopic submucosal dissection for early thoracic esophageal carcinoma.

Although the standard treatment for intramucosal esophageal cancer without lymph node metastasis is endoscopic submucosal dissection (ESD), we sometimes encounter patients who are not able to undergo a transoral endoscopic examination. Here, we report a surgical procedure consisting of transgastric retrograde ESD to treat early esophageal cancer (T1a-EP, N0, M0) because of a stricture after hypopharyngeal cancer surgery. This retrograde ESD procedure can be a safe and effective treatment option for early esophageal cancer. This is the first report of a surgical retrograde ESD method for esophageal cancer.

[Analysis of 16 Cases of Primary Duodenal Carcinoma in Our Hospital].

Primary duodenal carcinoma is a rare disease among gastrointestinal malignancies and has little evidence. We evaluated retrospectively the treatment status of 16 cases of primary duodenal carcinoma in our hospital between 2010 and 2019. The median age was 72(58-88)years and 63% of patients were male, and Each stage were Stage 0 in 4 cases, Stage Ⅰ in 1 case, Stage ⅢA in 2 cases, Stage ⅢB in 3 cases, and Stage Ⅳ in 6 cases(UICC 8th edition). Initial treatment was endoscopic therapy in 3 cases, surgery in 10 cases, chemotherapy in 1 case, and best supportive care in 2 case. The 2-year survival rate was 51.3% and the MST was 25.4 months in all cases. The Stage 0, Stage Ⅰ cases had all recurrence-free survival, while the Stage ⅢA or higher cases, 2-year survival rate was 33.8% and the MST was 20.0 months. Also, XELOX was often selected as the first-line treatment for chemotherapy regimens including recurrence treatment.

[A Case of Long-Term Progress Control of Unresectable Progressive Gastric Cancer with Nivolumab Introduced during Effective Duration of Secondary Treatment].

A 65-year-old man with 1 month of general malaise was admitted to our hospital. Thoracoabdominal CT showed that the supra-clavicular, sub-carina, and para-aortic lymph nodes were swelling. Upper gastrointestinal endoscopy revealed 2 type 1 tumors at the esophagogastric junction, and the biopsy showed Group 5, well to moderately differentiated adenocarcinoma. The clinical diagnosis was cardiac gastric cancer and cStage Ⅳ(cT3N3M1[LYM]). We started capecitabine plus oxaliplatin as the first-line chemotherapy, and weekly paclitaxel plus ramucirumab was administered as the second-line treatment. The second-line treatment was successful, and the effect of PR was obtained. However, considering the period of TTF, while the therapeutic effect continued, we switched to third-line treatment with nivolumab after 7 courses of the second treatment. With the third-line treatment, PR was maintained for 1 year and 3 months, and good quality of life and performance status were obtained for a long period without irAE. However, after 32 courses, because the tumor marker was elevated and lymph nodes were enlarged, we judged PD and switched to the fourth-line treatment with nab-paclitaxel plus ramucirumab. The tumor marker levels decreased, the lymph nodes shrank, and PR was achieved again with the fourth-line treatment. The treatment is still ongoing 2 year and 8 months after the diagnosis.

[A Case of Hepatocellular Carcinoma with Extrahepatic Growth-A Difficult Preoperative Diagnosis].

A 75-year-old man was admitted to our hospital for breathing difficulty. CT showed a 20 cm mass with clear boundaries and internal non-uniformity, which we suspected to be a gastrointestinal stromal tumor(GIST). Surgical resection was been considered to be risky because the mass was close to surrounding organs, such as the stomach, liver and diaphragm. Thus, we chose imatinib therapy. After 2 months, he was admitted to our hospital for anemia. CT showed the size of mass to be smaller, but the area of low density with internal non-uniformity had increased. We diagnosed intratumoral bleeding, and chose surgical resection. The mass was under the omentum, and had infiltrated the extrahepatic area and lesser curvature of the stomach. We diagnosed the mass derived from the stomach, and performed partial gastrectomy with partial liver resection. Pathological diagnosis was extrahepatically growing hepatocellular carcinoma(HCC, pT3N0M0, pStage Ⅲ).

[Two Cases of Resectable Gastric Cancer with Extensive Nodal Metastasis That Received Preoperative DOS Therapy].

Case 1: A 67-year-old male had a type 1 tumor in the stomach with a lymph node metastasis 50 mm in size. He was diagnosed with cT4aN(+)M0, cStage Ⅲ and received preoperative docetaxel plus oxaliplatin plus S-1(DOS)therapy. After 3 courses of the regimen, the patient underwent laparoscopic total gastrectomy. The final stage was ypT3N1(1/38) M0, ypStage ⅡB, R0, and the pathological response was Grade 2b. Case 2: A 64-year-old male had a type 3 tumor in the abdominal esophagus and a lymph node metastasis 15 mm in size. He was diagnosed with cT3N(+)M0, cStage Ⅲ and received preoperative DOS therapy. After 3 courses, he underwent laparoscopic esophagectomy. The final stage was ypT0N0M0, ypStage 0, R0, and the pathological response was Grade 3. DOS therapy may be effective as a neoadjuvant chemotherapy.

[Two Cases of Large Gastrointestinal Stromal Tumors Safely and Completely Resected by Laparoscopic Surgery Followed by Neoadjuvant Imatinib Therapy].

Case 1, the patient was a 51-year-old man. Upper gastrointestinal endoscopy revealed a submucosal tumor with delle at the posterior wall of the gastric body, and the biopsy demonstrated a diagnosis of GIST. Abdominal CT scan showed a tumor at the size of 130×110×90 mm. Six months after administration of 400 mg/day of imatinib, the maximum diameter was reduced to 55 mm, then partial gastrectomy was performed by laparoscopic surgery. He continued to take imatinib after the surgery for 3 years, and he is alive without recurrence 4 years postoperatively. Case 2, the patient was a 68-year-old man. An abdominal CT scan showed a tumor at the size of 160×120×85 mm on the posterior outside of the stomach, but no submucosal tumor could be identified by upper gastrointestinal endoscopy. Gastric GIST was suspected and he started taking imatinib 400 mg/day. Because the Grade 3 generalized eruption was appeared, imatinib was discontinued, and then the dose was reduced. Nine months after the initiation of the treatment, the maximum diameter was reduced to 90 mm, and laparoscopic partial gastrectomy was performed. The patient is followed up without administration of imatinib after the surgery, and is alive without recurrence for 1 year and 6 months postoperatively. We report 2 cases that the large gastric GIST was able to be resected safely and completely due to tumor shrinkage by neoadjuvant imatinib therapy.