Immature stroma and high infiltration of CD15+ cells are predictive markers of poor prognosis in different subsets of patients with pancreatic cancer.

Preoperative treatment is commonly carried out for borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the relationship between the combination of immune cells in the tumor microenvironment and their intratumoral heterogeneity along with their association with histological findings remains unclear, especially in patients receiving preoperative chemotherapy. We aimed to explore the therapeutic strategies for patients with PDAC with poor prognosis after receiving chemotherapy based on histological and immunological microenvironmental classifications. We investigated the correlation between the prognosis and histological immune microenvironmental factors of patients who initially underwent surgery (n = 100) and were receiving gemcitabine plus nab-paclitaxel (GEM + nabPTX) as preoperative chemotherapy (n = 103). Immune profiles were generated based on immune cell infiltration into the tumor, and their correlation with patient outcomes and histological features was analyzed. Tumor-infiltrating neutrophils (TINs) were identified as independent poor prognostic factors using multivariate analysis in both surgery-first and preoperative chemotherapy groups. The patients were further classified into four groups based on immune cell infiltration into the tumor. Patients with high CD15 infiltration into the tumor and immature stroma at the cancer margins showed the worst prognosis in the preoperative chemotherapy group. The analysis of mRNA expression and immunohistochemical features revealed that CXCR2, the receptor for CXCL8, was correlated with disease-free and overall survival. We inferred that patients with immature stroma at the margins and high infiltration of CD15+ neutrophils within the tumor showed the worst prognosis and they could particularly benefit from treatment with inhibitors targeting CXCR2 or CXCL8.

Interobserver Variability in the International Study Group for Pancreas Surgery (ISGPS)-Defined Complications After Pancreatoduodenectomy: An International Cross-Sectional Multicenter Study.

OBJECTIVE: To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others. SUMMARY BACKGROUND DATA: Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking. METHODS: International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored six standardized case vignettes. This variability and the 'within centers' variability were calculated for twofold scoring (no complication/grade A vs grade B/C) and threefold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula (POPF), post-pancreatoduodenectomy hemorrhage (PPH), chyle leak (CL), bile leak (BL), and delayed gastric emptying (DGE). Interobserver variability is presented with Gwet's AC-1 measure for agreement. RESULTS: Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for twofold scoring was 68% (95%-CI: 55%-81%, AC1 score: moderate agreement) and for threefold scoring 55% (49%-62%, AC1 score: fair agreement). The mean 'within centers' agreement for twofold scoring was 84% (80%-87%, AC1 score; substantial agreement). CONCLUSION: The interobserver variability for the ISGPS defined complications of pancreatoduodenectomy was too high even though the 'within centers' agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability.

A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study).

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). METHODS: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. DISCUSSION: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer.

BACKGROUND: Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME. METHODS: Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients. RESULTS: The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues. The M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues. Among the immunosuppressive cell types assessed, the M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P = 0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3- M-MDSCs and were abundant in treatment-resistant GC patients. CONCLUSIONS: The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.

Higher incidence of cholelithiasis with Roux-en-Y reconstruction compared with Billroth-I after laparoscopic distal gastrectomy for gastric cancer: a retrospective cohort study.

PURPOSE: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer. METHODS: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated. RESULTS: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis. CONCLUSION: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.

Osteosarcopenia: the coexistence of sarcopenia and osteopenia is predictive of prognosis and postoperative complications after curative resection for colorectal cancer.

PURPOSE: To establish if osteosarcopenia is related to postoperative complications, prognosis, and recurrence of colorectal cancer (CRC) after curative surgery. METHODS: The clinical data of 594 patients who underwent curative resection for CRC between January, 2013 and December, 2018 were analyzed retrospectively to examine the relationship between clinicopathological data and osteosarcopenia. The following definitions were used: sarcopenia, low skeletal muscle mass index; osteopenia, low bone mineral density on computed tomography at the level of the 11th thoracic vertebra; and osteosarcopenia, sarcopenia with osteopenia. RESULTS: Osteosarcopenia was identified in 98 patients (16.5%) and found to be a significant risk factor for postoperative complications (odds ratio 2.53; p = 0.011). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the patients with osteosarcopenia were significantly lower than those of the patients without osteosarcopenia (OS: 72.5% and 93.9%, respectively, p < 0.0001; RFS: 70.8% and 92.4%, respectively, p < 0.0001). Multivariate analysis identified osteosarcopenia as an independent prognostic factor associated with OS (hazard ratio 3.31; p < 0.0001) and RFS (hazard ratio 3.67; p < 0.0001). CONCLUSION: Osteosarcopenia may serve as a predictor of postoperative complications and prognosis after curative surgery for CRC.

Simple pelvimetry predicts the pelvic manipulation time in robot-assisted low and ultra-low anterior resection for rectal cancer.

PURPOSE: This study explored the difficulty factors in robot-assisted low and ultra-low anterior resection, focusing on simple measurements of the pelvic anatomy. METHODS: This was a retrospective analysis of the clinical data of 61 patients who underwent robot-assisted low and ultra-low anterior resection for rectal cancer between October 2018 and April 2023. The relationship between the operative time in the pelvic phase and clinicopathological data, especially pelvic anatomical parameters measured on X-ray and computed tomography (CT), was evaluated. The operative time in the pelvic phase was defined as the time between mobilization from the sacral promontory and rectal resection. RESULTS: Robot-assisted low and ultra-low anterior resections were performed in 32 and 29 patients, respectively. The median operative time in the pelvic phase was 126 (range, 31-332) min. A multiple linear regression analysis showed that a short distance from the anal verge to the lower edge of the cancer, a narrow area comprising the iliopectineal line, short anteroposterior and transverse pelvic diameters, and a small angle of the pelvic mesorectum were associated with a prolonged operative time in the pelvic phase. CONCLUSION: Simple pelvic anatomical measurements using abdominal radiography and CT may predict the pelvic manipulation time in robot-assisted surgery for rectal cancer.

Computed tomographic characteristics of testicular teratoma in a cat.

A 5-year-old intact male mixed-breed cat weighing 4.5 kg was referred to our hospital with a left testicular mass. CT revealed mild heterogeneous contrast enhancement and calcification in the testicular mass. A well-defined, contrast-enhancing, multiloculated mass with fluid-filled areas was extended from the testicular mass in the scrotum to the caudal aspect of the left kidney. The abdominal mass extended to the right crus of the diaphragm, and the gastrointestinal tract was compressed dorsally. Histopathology was consistent with teratoma. Characteristic CT findings in a feline testicular teratoma may include calcification and cystic areas.

[Microbiome in the Therapy for the Pancreatic Cancer].

An association between periodontal disease and the development of pancreatic cancer has been pointed out since before. Advances in genome analysis technology have revealed that a pancreatic cancer-specific microbiome is formed in the intestines and tumors of pancreatic cancer patients and modifies the progression of pancreatic cancer. Disturbance of microbiome( dysbiosis)suppresses anti-tumor immunity against pancreatic cancer, promoting cancer progression. Therefore, attempts are being made to correct dysbiosis by administration of probiotics or transplantation of microbiome, which is especially activating immune checkpoint inhibitors against cancer. In addition, specific intratumor bacteria has been identified that create an immunosuppressive microenvironment through crosstalk with pancreatic cancer cells. In the future, analysis of the microbiome distribution in pancreatic cancers may determine the following treatment strategy as an individualized treatment. We hope that innovations in omics technology will reveal more detailed functions of microbiome and lead to the development of effective treatments for pancreatic cancer.

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.

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.

Prognostic Impact of Preoperative Osteosarcopenia for Patients with Pancreatic Ductal Adenocarcinoma After Curative Resection.

BACKGROUNDS: The clinical significance of preoperative osteosarcopenia in pancreatic ductal adenocarcinoma (PDAC) has not been fully studied. The purpose of this study was to evaluate the role of preoperative osteosarcopenia in predicting the survival of patients with PDAC. METHODS: We retrospectively analyzed 265 patients who underwent curative surgical resection for PDAC between 2012 and 2018 in two Japanese institutes. The skeletal muscle index at the L3 vertebrae and the bone mineral density at the Th11 vertebra were calculated for the evaluation of osteosarcopenia before surgery. The relationship between perioperative osteosarcopenia and clinicopathological factors and prognosis was analyzed. RESULTS: The median overall survival (OS) and disease-free survival (DFS) of patients with osteosarcopenia were significantly shorter than those of patients without osteosarcopenia (OS: 23 and 48 months, respectively, P < 0.001; DFS: 13.4 and 21.2 months, respectively, P = 0.004). On multivariate analysis, osteosarcopenia was found to be an independent factor associated with OS (hazard ratio [HR] 1.98; 95% confidence interval [CI] 1.40-2.80; P < 0.001) and DFS (HR 1.53; 95% CI 1.11-2.10; P = 0.009). CONCLUSIONS: Preoperative osteosarcopenia may be a useful prognostic factor in patients with PDAC who undergo surgical resection. Further studies are needed to assess whether perioperative, nutritional interventions and rehabilitation contribute to improving the prognosis of these patients.

A Prospective Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement.

BACKGROUND: Only two clinical trials have shown the effects of neoadjuvant treatment for borderline resectable pancreatic cancer with arterial involvement (BRPC-A). Here, we aimed to analyze the efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel (GnP) for BRPC-A. PATIENTS AND METHODS: A prospective, single-arm, multicenter phase II trial was conducted. Patients who were radiologically and histologically diagnosed with BRPC-A were enrolled. A central review was conducted to confirm the presence of BRPC-A. Patients received two to four cycles of GnP before surgery. The primary endpoint of the study was the R0 resection rate. Overall survival (OS) was evaluated in an ancillary study. RESULTS: Thirty-five patients were enrolled, of whom 33 were subjected to central review and 28 were confirmed to have BRPC-A. All eligible patients with BRPC-A received neoadjuvant GnP. Nineteen patients underwent pancreatic resections. Postoperative complications of Clavien-Dindo IIIa or lower were observed in 11 patients. No treatment-related mortalities were observed. R0 resection was achieved in 17 patients (89%); the R0 resection rate was 61% in eligible patients. One patient underwent curative resection after termination of the treatment protocol, resulting in an overall R0 resection rate of 64%. The median overall survival (OS) and 2-year OS rate were 24.9 months [95% confidence interval (CI) 19.0 months to not estimatable] and 53.6%, respectively. OS in patients with BRPC-A who achieved overall R0 resection was significantly longer than that in the other patients (p = 0.0255). CONCLUSIONS: Neoadjuvant GnP is a safe and effective strategy for BRPC-A, providing a chance for curative resection and improved survival.

Ampullary Neuroendocrine Neoplasm: Clinicopathological Characteristics and Novel Endoscopic Entity.

BACKGROUND: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN. METHODS: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN). RESULTS: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (<10 mm) with endoscopic papillectomy and large NET G1 with pancreaticoduodenectomy. There were no cases of recurrence after resection. All ampullary NECs presented with the characteristic endoscopic finding of a "crater sign" similar to deep-mining ulcers seen in gastric malignant lymphoma. Four cases underwent surgical resection, and 1 case was unresectable. Two patients who underwent multidisciplinary treatment were maintained without recurrence for over 2 years. CONCLUSIONS: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.

A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament (with video).

BACKGROUND: In recent years, the number of minimally invasive pancreatoduodenectomy (MIPD) has been increasing; however, the procedure has not been widely accepted due to its complexity and difficulty. We have developed a technique to mobilize the pancreas head using a left-sided approach with a focus on the complete dissection of the Treitz ligament. METHODS: This technique focuses on the secure mobilization of the pancreas head using a left-sided approach. First, the transverse mesocolon is flipped upward and the anterior side of the mesojejunum is excised to expose the first jejunal artery (1st JA) from the distal side to its origin. During the procedure, the left sides of the SMA and Treitz ligament are exposed. The Treitz ligament is retracted to the left side and dissected anteriorly. Thereafter, the jejunum is flipped to the right side and the retroperitoneum around the origin of the jejunum and duodenum is dissected to identify the inferior vena cava (IVC). The rest of the Treitz ligament is dissected posteriorly and complete resection of the Treitz ligament releases the limitation of duodenal immobility. Thereafter, dissection proceeds along the anterior wall of the IVC, and mobilization of the pancreas head is completed from the left side. RESULTS: A total of 75 consecutive patients underwent MIPD from April 2016 to July 2022. The median operation times of laparoscopic and robotic procedures were 528 min (356-757 min) and 739 min (492-998 min), respectively. The volume of blood loss during laparoscopic and robotic procedures was 415 g (60-4360 g) and 211 g (17-1950 g), respectively. There was no mortality in any of the cases. CONCLUSION: Mobilization of the pancreas head and left-sided approach using a caudal view will be a safe and useful technique for MIPD.

Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video).

BACKGROUND: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach. METHODS: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches. RESULTS: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903). CONCLUSIONS: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.

Relationship between prognostic impact of N3 lymph node metastasis at the root of the feeding artery and location of colon cancer.

PURPOSE: To determine whether N3 nodal involvement predicts outcomes and whether its prognostic implications vary with tumor location in patients with Stage III colon cancer (CC). METHODS: We defined N3 as lymph node metastases near the bases of the major feeding arteries. We retrospectively examined recurrence rates and patterns by tumor location and sites of lymph node metastases in 57 patients with N3 CC who had undergone curative resections between January 2000 and March 2019. Survival analysis was performed to compare the prognoses of patients with and without N3 lymph node metastasis. RESULTS: Most N3 patients had large tumors (T ≥ 3); five had T2 disease. Recurrence occurred quickly in one patient with T2N3M0 disease. Multivariate survival analysis demonstrated that N3 lymph node metastasis is an independent predictor of poor prognosis in Stage III CC patients (P < 0.001). Categorizing N3 patients according to UICC-TNM staging system does not stratify risk of recurrence (P = 0.970). To investigate the impact of tumor location on recurrence risk, we classified N3 CC into two subtypes according to tumor location: metastasis at the base of the superior mesenteric artery in right-sided CC and inferior mesenteric artery in left-sided CC. The former was found to have a statistically significant poorer prognosis than the latter (P = 0.091). CONCLUSION: N3 is a robust prognostic marker in CC patients. Recurrence risk varies by tumor location. N3 right-sided CCs with lymph node metastasis at the base of the superior mesenteric artery have poorer prognoses than do N3 left-sided CCs.

Risks and benefits of pancreaticoduodenectomy in patients aged 80 years and over.

PURPOSE: The frequency of pancreaticoduodenectomy is increasing in oldest old patients owing to population aging. We aimed to clarify the clinical significance of pancreaticoduodenectomy in patients aged ≥ 80 years with multiple underlying diseases. METHODS: A total of 649 consecutive patients who underwent pancreaticoduodenectomy from April 2010 to March 2021 in our institute were divided into two groups according to their age: ≥ 80 years (51) and ≤ 79 years (598). We compared mortality and morbidity between the groups. The age-related prognosis was analyzed in 302 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma treatment. RESULTS: There were no significant differences in morbidity (Clavien-Dindo classification grade III or higher; P = 0.1300), mortality (P = 0.0786), or postoperative hospital stay (P = 0.5763) between the groups. Patients aged ≥ 80 years, who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, had shorter overall survival than those aged ≤ 79 years (median survival time, 16.7 months vs. 32.7 months; P = 0.0206). However, the overall survival of patients aged ≥ 80 years who received perioperative chemotherapy was comparable to that of patients aged ≤ 79 years (P = 0.9795). In the multivariate analysis, the absence of perioperative chemotherapy was identified as an independent prognostic factor, while age ≥ 80 years was not. Perioperative chemotherapy was the sole independent prognostic factor in patients aged ≥ 80 years who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. CONCLUSIONS: Pancreaticoduodenectomy is safe for patients aged ≥ 80 years. The survival benefits of pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma aged ≥ 80 years might be limited to those who can receive perioperative chemotherapy.

Circulating CD8+CD122+ T cells as a prognostic indicator of pancreatic cancer.

PURPOSE: The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer. METHODS: Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed. RESULTS: Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (< 90 days). After chemotherapy, CD8+CD122+ T cells decreased in patients who had a partial response or stable disease. Moreover, by analyzing resected specimens, we first proved that the existence of CD8+CD122+ T cells in a tumor microenvironment (TME) depends on their proportion in peripheral blood. CONCLUSION: Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.

ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. METHODS: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. RESULTS: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. CONCLUSIONS: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.