Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells.

BACKGROUND: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. METHODS: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. RESULTS: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. CONCLUSIONS: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

Tertiary lymphoid structures correlate with enhancement of antitumor immunity in esophageal squamous cell carcinoma.

BACKGROUND: Tertiary lymphoid structures (TLSs) are associated with a favorable prognosis in several cancers. However, the correlation between TLSs and outcomes of esophageal squamous cell carcinoma (ESCC) and the impact of TLSs on the tumor immune microenvironment (TIME) remain unknown. METHODS: We pathologically evaluated the significance of TLSs in ESCC focusing on TLS maturation using 180 ESCC specimens and performed single-cell RNA sequencing (scRNA-seq) using 14 ESCC tissues to investigate functional differences of immune cells according to TLS presence. RESULTS: TLS+ cases had better recurrence-free-survival (RFS) (p < 0.0001) and overall survival (OS) (p = 0.0016) compared with TLS- cases. Additionally, mature TLS+ cases had better RFS and OS compared with immature TLS+ cases (p = 0.019 and p = 0.015) and TLS- cases (p < 0.0001 and p = 0.0002). The scRNA-seq showed that CD8+ T cells in TLS+ tumors expressed high levels of cytotoxic signatures and antigen-presentation of dendritic cells (DCs) was enhanced in TLS+ tumors. Immunohistochemistry showed that the densities of tumor-infiltrating CD8+ T cells and DCs were significantly higher in TLS+ tumors than those in TLS- tumors. CONCLUSIONS: These data suggest the prognostic and functional significance of TLSs in ESCC and provides new insights into TLSs on the TIME.

Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis.

Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.

Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy.

PURPOSE: To evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy. METHODS: Among 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery. RESULTS: Nineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level. CONCLUSIONS: Post-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.

Endovascular treatment after the fenestrated frozen elephant trunk technique.

Recently, several centers have performed total arch replacement using the fenestrated frozen elephant trunk technique for acute Stanford type-A aortic dissection. However, the long-term results and need for additional treatment following this procedure are unclear. We report a case of a 54-year-old man who underwent endovascular therapy for endoleaks after total arch replacement using the fenestrated frozen elephant trunk technique for acute type-A aortic dissection with an isolated left vertebral artery. After the surgery, the endoleak was resolved, and the patient was asymptomatic with no neurological deficits. This strategy might be effective in similar cases.

Recurrent intraductal papillary mucinous neoplasms of the pancreas mimicking ampullary cancer.

Although several studies have reported that some patients developed metachronous/recurrent intraductal papillary mucinous neoplasms (IPMNs) after partial pancreatectomy, recurrence of IPMN mimicking ampullary cancer is extremely rare. We report the case of a 62-year-old man who developed recurrent IPMN mimicking ampullary cancer. Every 3-6 months, the patient had received surveillance with computed tomography after distal pancreatectomy for IPMN, high-grade, pancreatobiliary type. However, a villous tumor at the major duodenal papilla was found incidentally by upper gastrointestinal endoscopy 2 years and 3 months after initial surgery, and the biopsy result was adenocarcinoma. Endoscopic ultrasonography showed a tumor at the periampullary lesion; however, the origin of the tumor could not be determined definitively. Remnant total pancreatectomy was performed, and the histological diagnosis revealed IPMN, high-grade, pancreatobiliary type. Some patients develop recurrent IPMN mimicking ampullary cancer; thus, careful surveillance for periampullary lesions as well as remnant pancreas should be performed.

Correction to: Intramural metastasis to the appendix from ascending colon cancer: a case report.

In the original publication of this article [1], an author's name should be changed from Shin Takasue to Shin Takesue.

Intramural metastasis to the appendix from ascending colon cancer: a case report.

BACKGROUND: Intramural metastasis is rare in colorectal cancer, especially metastasis of ascending colon cancer to the appendix. CASE PRESENTATION: A 64-year-old man was admitted to our hospital for surgery for ascending colon cancer detected by medical examination. Colonoscopy identified a type-2 tumor in the ascending colon, which was diagnosed as adenocarcinoma. Abdominal computed tomography revealed focal thickening of the ascending colon and middle of the appendix and swelling of the lymph nodes around the ileocolic artery. The patient underwent laparoscopic right hemi-colectomy with D3 lymph node dissection. Histopathological findings revealed that the ascending colon cancer was moderately differentiated adenocarcinoma with lymphatic and vascular invasion (stage IIIB; pT3N2M0). Additionally, moderately differentiated adenocarcinoma was observed mainly in the submucosa and muscularis propria of the appendix, which was approximately 10 cm proximal to the ascending colon cancer. These findings indicated intramural metastasis to the appendix from the ascending colon cancer. The patient experienced recurrence with lung metastasis 2.5 years after the first surgery. CONCLUSIONS: Intramural metastasis of ascending colon cancer to the appendix is extremely rare. Because the risk of recurrence and the prognosis for intramural metastasis has not been clarified, careful follow-up is recommended.

Pyogenic liver abscesses concomitant with advanced gastric cancer: a case report.

It has been reported that gastric cancer rarely causes pyogenic liver abscesses because of its mucosal acid barrier. Herein, we describe a rare case of pyogenic liver abscesses concomitant with advanced gastric cancer. A 61-year-old man was transferred to our hospital with persistent nausea and fever. Computed tomography showed a lobulated lesion in the caudate lobe of the liver, slightly rim-enhanced lesions in the right lobe, enhanced mass on the lesser curvature of the upper gastric body, and enlarged regional lymph nodes. Subsequent upper gastrointestinal endoscopy revealed a type 3 tumor on the lesser curvature of the upper gastric body; pathological examination of a biopsy showed adenocarcinoma. After treatment with antibiotics, the lesion in the caudate lobe decreased in size and the enhanced lesions in the right lobe resolved. The patient underwent curative gastrectomy; the pathological diagnosis was gastric cancer, T4aN3aM0 stage IIIB, according to the Japanese classification of gastric carcinoma (Third English edition). The patient was discharged without complications and underwent adjuvant chemotherapy. Gastric cancer can cause pyogenic liver abscesses. Although differentiating between liver abscesses and hepatic metastases can be difficult, multidisciplinary and appropriate treatment strategies are needed.

Temporal and spatial changes of peroxiredoxin 2 levels in aortic media at very early stages of atherosclerotic lesion formation in apoE-knockout mice.

The events that trigger early onset of atherosclerotic lesion formation are poorly understood. Initially, microscopic atherosclerotic lesions appear in the aortic root in 10-week-old apoE-knockout mice that are fed normal chow. Using proteome and immunohistochemical analyses, we investigated proteins in aortic media whose expression changes in athero-prone regions at the beginning of lesion formation. Protein profiles of the root/arch and thoracic/abdominal regions of aortas in 10-week-old apoE-knockout mice were analyzed using 2D-gel electrophoresis. Proteins in 81 spots with different abundance were identified. Among them, we focused on proteins related to oxidative stress and smooth muscle cells (SMCs). The level of peroxiredoxin 2 (Prx2), a major cellular antioxidant enzyme that reduces hydrogen peroxide, was lower in aortic root/arch compared with thoracic/abdominal aorta. Immunohistochemical staining demonstrated that Prx2 expression in SMCs in the aortic root was high at 4 weeks and decreased at 10 weeks in apoE-knockout mice, while Prx2 expression in the aorta was unchanged in wild-type mice. The level of Prx2 expression correlated positively with the SMC differentiation markers, α-smooth muscle actin and transgelin, suggesting that a decline in Prx2 expression accompanies SMC dedifferentiation. Accumulated acrolein-modified proteins and the infiltration of macrophages in aortic media were observed in areas with low Prx2 expression. These results showed that Prx2 expression declines in athero-prone aortic root before lesion formation, and this reduction in Prx2 expression correlates with lipid peroxidation, SMC dedifferentiation, and macrophage recruitment.

Hemodynamics and changes after STA-MCA anastomosis in moyamoya disease and atherosclerotic cerebrovascular disease measured by micro-Doppler ultrasonography.

Moyamoya disease (MMD) and atherosclerotic cerebrovascular disease (ACVD) differ in angiographic appearance and probably hemodynamics. Pediatric MMD (PMMD) usually presents with cerebral ischemia, while intracranial hemorrhage is more common in adult MMD (AMMD), suggesting differences in cerebral hemodynamics. We analyzed the cortical flow velocity and direction of recipient arteries using micro-Doppler ultrasonography to evaluate the cortical circulation before and after anastomosis in MMD and ACVD. Twenty-eight patients with adult MMD (AMMD), 7 with pediatric MMD (PMMD), 16 with ACVD, and 12 control patients were studied. A micro-Doppler probe was applied on the cortical recipient artery (A4 or M4) before and after anastomosis. Systolic maximum flow velocity (V max) and blood flow direction were investigated at proximal and distal parts of anastomosed sites in recipient arteries. Pre- and postoperative regional cerebral blood flow was measured by cold xenon-computed tomography (Xe-CT). Before anastomosis, retrograde cortical flow was significantly more common in PMMD patients, and V max in cortical artery was significantly lower in AMMD patients. Bypass surgery changed the direction of blood flow from the anastomosis site to proximal and distal sites of the recipient artery in most patients, but pre-anastomosis flow direction was preserved more frequently in PMMD patients. The rate of V max increase after anastomosis was significantly higher in AMMD than in PMMD (11.6 ± 9.8 vs. 3.9 ± 1.8; P = 0.01). Micro-Doppler ultrasonography identified differences in cortical circulation among AMMD, PMMD, and ACVD. In AMMD, significantly low velocity in the cortical artery was observed before anastomosis, and bypass surgery reversed the flow and significantly increased flow velocity. The data of PMMD showed unique hemodynamics of the cortical artery before anastomosis, characterized by a higher frequency of retrograde flow and preserved velocity. The V max increase rate was significantly higher in patients with postoperative cerebral hyperperfusion on Xe-CT, and further study is warranted to validate the clinical use of intraoperative micro-Doppler monitoring to predict postoperative hyperperfusion.

Clinical presentation of intracranial epidermoids: a surgical series of 20 initial and four recurred cases.

Epidermoids are generally recognized as benign tumors; however, total resection is often difficult. The recurrence from the residual capsule, dissemination of the tumor, and aseptic meningitis are common problems. The aim of the present study was to analyze and report on the clinical characteristics of intracranial epidermoids, particularly complications and cases with a poor clinical outcome. 24 patients with intracranial epidermoids who were treated surgically at Tokyo Women's Medical University Hospital between 1997 and 2007 were examined. The location and size of the tumor, pre-and postoperative symptoms, adherence of the tumor to cranial nerves, and proliferative capacity were determined. The most frequent site of the tumor was the cerebello-pontine (C-P) angle (16/24); eight of these patients presented with hearing loss and six presented with trigeminal neuralgia. In many cases, hearing loss and diplopia persisted after surgery. All epidermoids located in the C-P angle were attached to and/or compressed the trigeminal nerves, therefore, the origin is suggested to be the dura mafer of petrous bone around the trigeminal nerve. Of all 24 patients, the tumor recurred in four (after 3, 5, 10 and 20 years). One patient had a poor prognosis, with dissemination and brain stem infarction. Epidermoids can recur from residual capsule adhering to the brain stem or cranial nerves up to 10-20 years after the initial surgery. Long-term follow-up imaging studies are required when complete resection of the tumor capsule is not possible. In rare cases, spontaneous cyst rupture, dissemination, and brain stem infarction result in a poor prognosis.

Determination of the period for establishment of a liver network echogenic pattern in Schistosoma japonicum infection.

Schistosomiasis is caused by infection with Schistosoma haematobium, S. mansoni, S. japonicum, or S. mekongi. S. japonicum infection results in liver cirrhosis at the final stage. A "network" (NW) echogenic pattern on hepatic ultrasonography appears to be specific to S. japonicum infection. The principal aim of the present study was to determine the exact year(s) or even month(s) required for the establishment of the liver NW echogenic pattern from the initial infection in young patients with schistosomiasis japonica since there are few data on this important point. We conducted yearly ultrasonographic, serologic, coprologic, and physical examinations of schistosomiasis patients in the Philippines from 1996 up to the present. During that period, the total number of patients examined was approximately 2,000, among whom we selected 2 patients for determination of the duration required for NW establishment, when they were 10 years old. Although the exact time of initial exposure to schistosomes cannot be determined, the duration for the establishment of NW was definitively confirmed in patient no. 1 to be between 19-24 months based on the results of serologic and coprologic examinations. For patient no. 2, the circumstantial evidence suggested that the establishment of a NW might require 5 to 6 years at maximum. To the best of our knowledge, this is the first evidence-based report on the determination of the period required for the establishment of a liver NW echogenic pattern in S. japonicum infection in the Philippines.

Supernumerary phantom limbs associated with left hemispheric stroke: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Supernumerary phantom limb (SPL) is extremely rare. Literature reports noted 17 cases that occurred after right cerebral hemispheric stroke and 2 cases that occurred after left cerebral hemispheric stroke, but without imaging diagnoses. CLINICAL PRESENTATION: A 45-year-old male patient complained of SPLs on the right side after recurrent left thalamic hemorrhage. Computed tomography and magnetic resonance imaging demonstrated the lesion causing the left hemispheric stroke. INTERVENTION: The patient was treated conservatively. Computed tomographic scans demonstrated that the lesion had disappeared by 15 days after admission. The sensation of SPLs disappeared after 28 days. CONCLUSION: SPL may occur among patients with left hemispheric stroke, especially those with lesions in the thalamus, spastic paresis on the right side immediately after stroke, and psychiatric disorders such as alcohol and tobacco intoxication.