Effects of adoptive T-cell immunotherapy on immune cell profiles and prognosis of patients with unresectable or recurrent cholangiocarcinoma.

The identification of immune cell profiles (ICP) involved in anti-tumor immunity is crucial for immunotherapy. Therefore, we herein investigated cholangiocarcinoma patients (CCA) who received adoptive T-cell immunotherapy (ATI). Eighteen unresectable or recurrent CCA received ATI of αß T cells alone or combined with chemotherapy. ICP were evaluated by flow cytometry. There were 14 patients with intrahepatic cholangiocarcinoma (iCCA) and four with distal cholangiocarcinoma (dCCA). After one course of treatment, nine iCCA and four dCCA had progressive disease (PD), while five iCCA had stable disease (SD). Median overall survival (OS) was prolonged to 21.9 months. No significant differences were observed in OS between the PD and SD groups of iCCA. The frequency of helper T cells (HT) in iCCA decreased from 70.3% to 65.5% (P = .008), while that of killer T cells (KT) increased from 27.0% to 30.6% (P = .005). dCCA showed no significant changes of immune cells. OS was prolonged in iCCA with increased frequencies of CD3+ T cells (CD3) (P = .039) and αß T cells (αß) (P = .039). dCCA showed no immune cells associated with OS. The frequencies of CD3+ T cells and αß T cells in the PD group for iCCA decreased from 63.5% to 53% (P = .038) and from 61.6% to 52.2% (P = .028), respectively. In the SD group, the frequency of HT decreased from 65.8% to 56.9% (P = .043), whereas that of KT increased from 30.1% to 38.3% (P = .043). In conclusions, ATI affected ICP and prolonged OS. Immune cells involved in treatment effects differed according to the site of cholangiocarcinoma.

The characteristics of the immune cell profiles in peripheral blood in cholangiocarcinoma patients.

BACKGROUND: Immune related cells are known to be closely related to the therapeutic effects and prognoses of cancer patients. In this study, we analyzed immune cell profiles (ICP) of cholangiocarcinoma patients (CCA). METHODS: To measure the frequency of immune cells, peripheral blood mononuclear cells of 41 CCA and 10 healthy volunteers (HV) were analyzed by FACS. RESULTS: There were significant differences between CCA and HV in ICP, and these differences were a consequence of tumor-bearing status, because many items in ICP before surgery were restored to levels in HV after surgery. Therefore, these changes were specifically attributable to cholangiocarcinoma, and we examined if they can function as biomarkers for therapeutic effects and prognoses. A shorter overall survival was associated with a lower frequency of helper T cells (HT) (p = 0.001), a higher frequency of effector regulatory T cells (eTregs) (p = 0.008), and a lower frequency of CD80 + eTregs (p = 0.024) in the best supportive care group, with a lower frequency of CD25 + naïve Tregs (nTregs) (p = 0.005) in the chemotherapy group, and with a lower frequency of OX40 + HT (p = 0.022), CD25 + CD8 + T cells (p = 0.017), and OX40 + CD8 + T cells (p = 0.032) in the surgery group. The recurrence factors were a higher frequency of CD4 + T cells (p = 0.009), CCR6 + nTregs (p = 0.014), and CXCR3 + nTregs (p = 0.012), and a lower frequency of PD-1 + HT (p = 0.006), OX40 + HT (p = 0.004), CD8 + T cells (p = 0.001), and CTLA-4 + CD8 + T cells (p = 0.036). CONCLUSIONS: The ICP in CCA are specifically attributable to cholangiocarcinoma, and may be biomarkers for therapeutic effects and prognoses.

Usefulness of endoscopic metal stent placement for malignant afferent loop obstruction.

BACKGROUND: Malignant afferent loop obstruction (mALO) can cause cholangitis, pancreatitis, and perforation due to blind loop dilatation. However, peritoneal dissemination, lymph node metastasis, and recurrence of the tumor are the main causes of mALO, and most cases are in the advanced stage with thoracicoabdominal fluid retention, for which surgery and percutaneous transhepatic treatment are challenging. At our hospital, endoscopic metal stent placement (EMSP) has been applied for such mALO. We retrospectively investigated the usefulness of EMSP for mALO. METHODS: We conducted a retrospective analysis of 11 mALO patients with EMSP between January 2008 and December 2018. The following items were evaluated: the characteristics of patients, technical success and adverse events of EMSP, clinical efficacy, and outcome after EMSP. RESULTS: The surgical procedures and reconstruction methods were distal gastrectomy with Billroth II reconstruction for 3 patients, pancreaticoduodenectomy with modified-Child reconstruction for 7, choledochojejunostomy with Roux-en-Y reconstruction for 1. The cause of mALO was peritoneal dissemination for 6 patients, local recurrence for 3, lymph node metastasis for 1, and afferent loop invasion for 1. EMSP was attempted in 13 sessions for 11 patients, and successful in 12 of 13 sessions. There were no adverse events. The clinical efficacy was high in successful EMSP. The median survival time after EMSP was 118 days. Ten patients died of primary disease and one patient died of uncontrollable cholangitis after the failure of EMSP. mALO recurred and EMSP was repeated for 2 of 10 patients who died of primary disease. CONCLUSIONS: The success rate of EMSP for mALO was high in patients with poor general conditions due to advanced-stage malignant tumors and it was able to be safely performed, suggesting its high clinical efficacy. The incidence of mALO recurrence after EMSP was low.

Successful biliary self-expandable metallic stenting using an ultra-slim endoscope for cholangitis caused by pancreatic cancer.

Highlight Kida and colleagues described their method for successfully performing biliary self-expandable metallic stenting with the through-the-scope technique using an ultra-slim endoscope for malignant biliary obstruction with duodenal stenosis. This procedure may be useful in cases of duodenal stenosis in which it is difficult to reach the major duodenal papilla.

Phase II clinical trial of second-line weekly paclitaxel plus trastuzumab for patients with HER2-positive metastatic gastric cancer.

BACKGROUND: Combination therapy with fluorouracil, platinum, and trastuzumab (Tmab) is the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, and there is currently no established second-line therapy. We evaluated the efficacy and safety of weekly paclitaxel plus Tmab as second-line chemotherapy for HER2-positive gastric cancer patients. PATIENTS AND METHODS: Eligible patients were older than or equal to 20 years, had histologically confirmed gastric adenocarcinoma that was HER2 positive (immunohistochemistry 3+ or immunohistochemistry 2+ and fluorescence in-situ hybridization positive or dual color in-situ hybridization positive), and had been treated previously with chemotherapy (pretreated or not with Tmab). Patients received weekly paclitaxel plus Tmab as the second-line chemotherapy. The primary endpoint was the overall response rate (ORR; threshold ORR=20% and expected ORR=35%). RESULTS: Twenty-eight patients were enrolled. ORR was 21.4%. The median progression-free survival (PFS) was 4.6 months. The median overall survival (OS) was 9.6 months. No significant differences were observed in ORR, PFS, or OS between the Tmab beyond progression (TBP) group (n=20) and the non-TBP group (n=8). However, in the TBP group, a therapeutic effect was associated with the duration of PFS in the first-line Tmab treatment [≥6 months PFS in the first-line Tmab treatment (n=10) vs. <6 months (n=10); ORR: 40 and 10%, P=0.303, PFS: 6.2 and 2.8 months, P=0.005, OS: 15.8 and 6.5 months, P=0.006, respectively]. CONCLUSION: Weekly paclitaxel plus Tmab was not superior as second-line chemotherapy for HER2-positive gastric cancer patients, but may be effective for patients who showed better responses to Tmab-combined chemotherapy in the first-line treatment.

Immune responses against tumour-associated antigen-derived cytotoxic T lymphocyte epitopes in cholangiocarcinoma patients.

BACKGROUND & AIMS: Immunotherapy is a promising treatment option for cholangiocarcinoma. We compared cytotoxic T lymphocyte (CTL) responses against several tumour-associated antigen (TAA)-derived epitopes in cholangiocarcinoma patients to identify candidate epitopes for immunotherapy. METHODS: Twenty-six TAAs were selected, and the expression of TAAs in 6 cholangiocarcinoma cell lines and 9 specimens were measured using real-time polymerase chain reaction (PCR). CTL responses against 38 TAA-derived epitopes were measured using samples from 26 cholangiocarcinoma patients by interferon-γ enzyme linked immunospot (ELISPOT)-assay. RESULTS: Most TAAs were expressed in cholangiocarcinoma cell lines and specimens in PCR. Epitopes that stimulated a specific immune response were defined as those that elicited a CTL response in more than 3 patients and little response in healthy volunteers, as measured by ELISPOT-assay. Based on these criteria, there were 18 epitopes that stimulated specific immune responses: squamous cell carcinoma antigen recognized by T cells (SART)1690 , P53161 , multidrug resistance-associated protein (MRP)3503 , Survivin2B80 , melanoma-associated antigen (MAGE)-A4143 , receptor tyrosine kinase ErbB-2/neu (Her2/neu)63 , Wilms tumour (WT1)235 , WT1417 , ß-catenin29 , carcinoembryonic antigen (CEA)268 , CEA652 , epithelial cell adhesion molecule (EpCAM)173 , enhancer of zeste homolog (EZH)2291 , mucin 5AC (MUC5AC)716 , glypican-3 (GPC3)298 and kinesin family member 20A (KIF20A)66 . Furthermore, the absolute number of lymphocytes in peripheral blood was significantly correlated with the TAA-specific response. Lastly, the overall survival was significantly prolonged in patients with 2 or more TAA-specific CTL responses compared with none to one. CONCLUSIONS: These results demonstrated several TAAs may be promising for immunotherapy for cholangiocarcinoma, and patients with high lymphocyte counts may benefit more from immunotherapy.

A case of macrocystic-type serous cystic neoplasm with repeated pancreatitis within a short period of time.

The patient was a 39-year-old woman in whom computed tomography (CT) in 201X had revealed a pancreatic cystic neoplasm (PCN) of 4.3 cm in diameter in the pancreatic body. In June 201X + 3, the patient consulted our hospital regarding severe acute pancreatitis. The condition improved through treatment with large-volume fluid replacement and continuous regional arterial infusion therapy. Thereafter, acute pancreatitis recurred twice, in November 201X + 3 and in January 201X + 4. During an 8-month period, acute pancreatitis occurred three times. The PCN was examined by endoscopic ultrasound, thin-slice contrast-enhanced CT, and T2-weighted magnetic resonance imaging, which led to the diagnosis of macrocystic-type serous cystic neoplasm (SCN). The SCN was found to be 5.8 cm in diameter with dilatation of the main pancreatic duct (MPD) caudal to the SCN for 3 years. We suspected that the repeated pancreatitis had been obstructive pancreatitis resulting from displacement of the MPD caused by the SCN, and therefore recommended that the patient undergo surgery for the SCN. In March 201X + 4, distal pancreatectomy was performed. In the resected specimen, a macrocystic-type SCN was diagnosed. No recurrence of acute pancreatitis has been observed postoperatively. A macrocystic-type SCN with repeated pancreatitis within a short period of time is rare.

Pancreatic acinar cell carcinoma with extensive tumor embolism at the trunk of portal vein and pancreatic intraductal infiltration.

A 59-year-old man was admitted to the hospital with acute pancreatitis. The cause was suggested to be a pancreatic tumor based on computed tomography (CT). The pancreatic tumor was 45 mm with an extensive tumor embolism at the trunk of the portal vein and intraductal infiltration of the main pancreatic duct (MPD). The pancreatic tumor was diagnosed as acinar cell carcinoma (ACC) by endoscopic ultrasound guided fine needle aspiration. Therefore, the cause of acute pancreatitis was diagnosed to be intraductal infiltration of ACC in the MPD. Chemotherapy was initially performed because it was difficult to perform surgery due to extensive tumor embolism at the trunk of the portal vein. Degeneration and reduction of ACC and tumor embolism of the portal vein was noted on CT after chemotherapy, and extended distal pancreatectomy with portal vein reconstruction was performed. There has been no relapse for 5 years postoperative follow-up. This is an interesting and rare case because ACC with intraductal infiltration of MPD is low in frequency; most ACCs are asymptomatic when they are found, and many cases tend to have poor prognosis in spite of surgical cases.

A unique case of massive gastrointestinal bleeding.

OBJECTIVES: Lipomas are the second most common benign tumors of the small bowel, and most lipomas are asymptomatic. However, lipomas with diameters of >20 mm tend to be symptomatic, for example, to cause bleeding, obstructive jaundice, abdominal pain, intestinal obstruction, intussusception, and/or perforation. METHODS/RESULTS: We report a case of massive gastrointestinal bleeding from a jejunal lipoma combined with intussusception. A preoperative diagnosis of gastrointestinal bleeding derived from a jejunal lipoma combined with intussusception was made based on double-balloon enteroscopy and contrast-enhanced computed tomography, and partial resection of the small intestine was performed. After surgery, there was no additional gastrointestinal bleeding. CONCLUSION: There have only been a few reports about cases of jejunal lipoma involving simultaneous bleeding and intussusception. Double-balloon enteroscopy is useful for preoperatively diagnosing bleeding from a lipoma. Our case highlights that jejunal lipoma can cause massive unexplained gastrointestinal bleeding.

A pedunculated polyp-shaped small-bowel lymphangioma causing gastrointestinal bleeding and treated by double-balloon enteroscopy.

We report a rare case of a small-bowel lymphangioma causing massive gastrointestinal (GI) bleeding that we successfully diagnosed and treated using double-balloon enteroscopy (DBE). An 81-year-old woman suffering from repeated GI bleeding of unknown origin underwent a capsule endoscopy at a previous hospital. She was suspected of having bleeding from the jejunum, and was referred to our department for diagnosis and treatment. An oral DBE revealed a 20 mm × 10 mm, regularly surfaced, white to yellowish, elongated, pedunculated jejunal polyp with small erosions at 10 cm distal to the ligament of Treiz. Since no other source of bleeding was identified by endoscopy in the deep jejunum, an endoscopic polypectomy (EP) was performed for this lesion. A subsequent histopathological examination of the resected polyp showed clusters of lymphatic vessels with marked cystic dilatation in the submucosa and the deep layer of the lamina propria mucosae. These characteristics are consistent with the typical features of small-bowel lymphangioma with erosions. Although clipping hemostasis was performed during EP, re-bleeding occurred. Finally, a complete hemostasis was achieved by performing an additional argon plasma coagulation.

[A case of hepatocellular carcinoma showed the usefulness of endoscopic ultrasound-guided fine needle aspiration cytology using the cell block technique for differential diagnosis of gastric submucosal tumor].

A mass lesion presenting difficulty in differential diagnosis between a tumor in the lateral segment of the liver and a gastric submucosal tumor (SMT) was found in a 59-year-old man with chronic hepatitis B. For differential diagnosis between the 2 lesions, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed. EUS showed a tumor exhibiting a mosaic pattern with a halo derived from the lateral segment of the hepatic left lobe in contact with the stomach. FNA using the cell block technique revealed findings consistent with HCC. No examination-associated complications developed. In patients with HCC that is in contact with the stomach and shows extrahepatically protruding growth, which is difficult to differentiate from gastric SMT, EUS-FNA is a method worthy of trying.