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.

Endoscopic treatment of bile duct stones with benign choledochojejunal anastomotic stenosis.

BACKGROUND AND AIMS: Endoscopic interventions for bile duct stones (BDSs) with benign choledochojejunal anastomotic stenosis (bCJS) are challenging. Therefore, we investigated endoscopic interventions for BDSs with bCJS. METHODS: Seventeen patients with BDSs with bCJS were retrospectively analyzed. Patient characteristics, technical success, adverse events (AEs), and recurrence were evaluated. RESULTS: In 17 patients, the median diameters of the bile duct and BDSs were both 8 mm. The median number of BDSs was 3. The technical success rate was 94% (16/17). Ten patients underwent balloon dilation at the choledochojejunal anastomotic site (CAS), the median diameter of balloon dilation was 10.5 mm, and waist disappearance was achieved in 2. Six patients had fully covered self-expandable metal stents (FCSEMSs) with a diameter of 10 mm placed at the CAS. BDSs were removed after balloon dilation or FCSEMS removal, and 6 of 16 patients were treated with a combination of lithotripsy and 5 with peroral direct cholangioscopy (PDCS). Regarding AEs, perforation at the CAS by balloon dilation occurred in 1 patient. The median follow-up was 3701 days. Nine of 16 patients (56%) had recurrence. The patients treated with a combination of PDCS at BDS removal (P = .022) and waist disappearance at the CAS by balloon dilation (P = .035) had significantly fewer recurrences. CONCLUSIONS: Endoscopic interventions for BDSs with bCJS are useful and relatively safe; however, long-term follow-up showed frequent recurrences. Recurrence was common in patients not treated with the combination of PDCS at BDS removal and those without waist disappearance at the CAS by balloon dilation.

[Efficacy of nivolumab in combination with chemotherapy after radiotherapy for meningeal carcinomatosis in patients with Epstein-Barr virus-associated gastric cancer:a case report].

A 62-year-old man presented with fever and anorexia since July X. Initial treatments were rendered ineffective, and due to altered consciousness and vomiting, he was referred to our hospital. On admission, he manifested delirium, drowsiness, and disorientation. While blood tests were normal, gastroscopy identified a type 3 tumor in his lower gastric body, later diagnosed as a poorly differentiated adenocarcinoma. Immunohistochemistry demonstrated negative human epidermal growth factor receptor 2 and positive programmed death-ligand 1 expression with a combined positive score ≥5. Furthermore, a positive Epstein-Barr virus-encoded small RNA in situ hybridization result was noted. Abdominal contrast-enhanced CT and PET-CT scans demonstrated multiple lymph node metastases around the stomach and liver, establishing the diagnosis of stage IVB gastric cancer (T4aN2M1). Brain magnetic resonance imaging (MRI) demonstrated enhanced lesions in the brainstem, cerebellar sulci, and right occipital lobe. Although cerebrospinal fluid cytology was negative for malignancy, the clinical symptoms and MRI findings confirmed leptomeningeal carcinomatosis (LMC). The patient underwent radiotherapy for LMC (total of 30Gy in 10 fractions), followed by combination therapy with a nivolumab and SOX regimen. Posttreatment, the LMC symptoms resolved;however, he experienced grade 3 immune-related adverse events related to liver dysfunction. Nivolumab was discontinued, and with steroid administration, the adverse events improved. Imaging evaluations posttreatment showed gastric tumor reduction and the absence of LMC. After 7 cycles, nivolumab was reintroduced, with no liver dysfunction recurrence noted through 15 cycles. Endoscopic examination 1 year postonset demonstrated that the gastric tumor had scarred, and MRI showed no signs of LMC recurrence. In 5-8% of solid tumors, LMC complications are present, resulting in limited treatment options and poor prognosis. Recent reports suggest the potential of immune checkpoint inhibitors in treating intracranial metastasis from solid tumors. In Japan, nivolumab was approved for gastric cancer treatment in 2017 and for first-line therapy in combination with chemotherapy since 2021. We report a case in which radiotherapy and chemotherapy combined with nivolumab provided durable control of LMC originating from gastric cancer for more than 1 year.

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.

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 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.

Biliary stones or ulcers at the choledochojejunal anastomotic site involving the jejunal mucosa at stent removal may be recurrent factors in patients with benign choledochojejunal anastomotic stenosis undergoing endoscopic biliary stenting using fully covered self-expandable metal stents.

BACKGROUND: Temporary fully covered self-expandable metal stent (FCSEMS) placement is performed for benign choledochojejunal anastomotic stenosis (bCJS). However, recurrence may develop after stricture resolution. We investigated endoscopic biliary stenting using FCSEMS for bCJS. METHODS: Sixteen bCJS patients with FCSEMS placement were retrospectively analyzed. FCSEMS was removed endoscopically after 2 months. Technical success, stricture resolution, recurrence, and adverse events were evaluated. RESULTS: The technical success rate for FCSEMS placement was 94% (15/16). Biliary stones were detected and extracted in four patients. FCSEMS removal was successfully performed on 14 patients, excluding one with stent migration. At FCSEMS removal, stricture resolution was noted in 14 patients; however, four had anastomotic ulcers. The median follow-up was 319 days. Three patients with a history of repeated plastic stent placement had no recurrence. Four out of 15 patients (27%) had recurrence, and three had no recurrence after additional interventions. Biliary stones before first FCSEMS placement (P = .003) or anastomotic ulcers at FCSEMS removal (P = .018) were associated with recurrence. CONCLUSIONS: Although FCSEMS placement was useful for stricture resolution, recurrence was detected in patients with biliary stones before first FCSEMS placement or anastomotic ulcers at FCSEMS removal. Anastomotic ulcers are a risk factor for recurrence and only detected by endoscopy.

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.

Long-term outcomes after endoscopic retrograde pancreatic drainage for symptomatic pancreaticojejunal anastomotic stenosis.

There is limited evidence supporting the usefulness of endoscopic retrograde pancreatic drainage (ERPD) for symptomatic pancreaticojejunal anastomotic stenosis (sPJS). We examined the usefulness of ERPD for sPJS. We conducted a retrospective analysis of 10 benign sPJS patients. A forward-viewing endoscope was used in all sessions. Following items were evaluated: technical success, adverse events, and clinical outcome of ERPD. The technical success rate was 100% (10/10) in initial ERPD; 9 patients had a pancreatic stent (no-internal-flap: n = 4, internal-flap: n = 5). The median follow-up was 920 days. Four patients developed recurrence. Among them, 3 had a stent with no-internal-flap in initial ERPD, the stent migrated in 3 at recurrence, and a stent was not placed in 1 patient in initial ERPD. Four follow-up interventions were performed. No recurrence was observed in 6 patients. None of the stents migrated (no-internal-flap: n = 1, internal-flap: n = 5) and no stents were replaced due to stent failure. Stenting with no-internal-flap was associated with recurrence (p = 0.042). Mild adverse events developed in 14.3% (2/14). In conclusions, ERPD was performed safely with high technical success. Recurrence was common after stenting with no-internal-flap. Long-term stenting did not result in stent failure.Clinical trial register and their clinical registration number: Nos. 58-115 and R2-9.

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.