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.

MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC. Methods: EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified. Results: We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively. Conclusions: We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.

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.

Diagnostic Performance of a Tumor Marker Gene Test to Personalize Serum CA19-9 Reference Ranges.

PURPOSE: CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test. RESULTS: Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001). CONCLUSIONS: Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy.

Repeated robotic pancreatectomy for recurrent pancreatic metastasis of mesenchymal chondrosarcoma: A case report.

Mesenchymal chondrosarcoma is a rare subset of sarcomas accounting for 3%-10% of all cases of chondrosarcomas. Radical resection is the only curative strategy, even in patients with metastatic tumors. However, data regarding treatment strategies remain limited owing to the small number of cases. Herein, we report a patient who underwent repeated robotic pancreatectomy for recurrent pancreatic metastasis originating from extraskeletal mesenchymal chondrosarcoma of the pelvis. First, robotic pancreaticoduodenectomy with a reconstruction of pancreaticogastrostomy was performed for synchronous pancreatic metastasis 5 months after the primary resection of mesenchymal chondrosarcoma. Ten months after robotic pancreaticoduodenectomy, tumor recurrence was observed at the tail end of the pancreas, which was removed by reperforming robotic distal pancreatectomy. Given the precise tissue manipulation that can be achieved with robotic articulated forceps, the peripheral splenic artery and pancreas were easily isolated and divided in close proximity to the tumor. The central part of the pancreas was preserved. Robotic surgery allowed safe and effective resection of the reconstructed remnant pancreas. The patient survived for 28 months after primary tumor resection. Repeated pancreatectomy with minimally invasive techniques is a feasible and curative treatment for metastatic mesenchymal chondrosarcoma.

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.

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.

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.

Machine learning-based model for prediction and feature analysis of recurrence in pancreatic neuroendocrine tumors G1/G2.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of tumors. Although the prognosis of resected PanNENs is generally considered to be good, a relatively high recurrence rate has been reported. Given the scarcity of large-scale reports about PanNEN recurrence due to their rarity, we aimed to identify the predictors for recurrence in patients with resected PanNENs to improve prognosis. METHODS: We established a multicenter database of 573 patients with PanNENs, who underwent resection between January 1987 and July 2020 at 22 Japanese centers, mainly in the Kyushu region. We evaluated the clinical characteristics of 371 patients with localized non-functioning pancreatic neuroendocrine tumors (G1/G2). We also constructed a machine learning-based prediction model to analyze the important features to determine recurrence. RESULTS: Fifty-two patients experienced recurrence (14.0%) during the follow-up period, with the median time of recurrence being 33.7 months. The random survival forest (RSF) model showed better predictive performance than the Cox proportional hazards regression model in terms of the Harrell's C-index (0.841 vs. 0.820). The Ki-67 index, residual tumor, WHO grade, tumor size, and lymph node metastasis were the top five predictors in the RSF model; tumor size above 20 mm was the watershed with increased recurrence probability, whereas the 5-year disease-free survival rate decreased linearly as the Ki-67 index increased. CONCLUSIONS: Our study revealed the characteristics of resected PanNENs in real-world clinical practice. Machine learning techniques can be powerful analytical tools that provide new insights into the relationship between the Ki-67 index or tumor size and recurrence.

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.

Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front.

PURPOSE: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism. METHODS: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro. RESULTS: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density. CONCLUSION: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.

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.

Clinical significance of postpancreatectomy acute pancreatitis defined by the International Study Group for Pancreatic Surgery.

Aim: The International Study Group for Pancreatic Surgery (ISGPS) developed a structured definition of postpancreatectomy acute pancreatitis (PPAP) in 2021. This study aimed to evaluate the clinical significance of PPAP as defined by the ISGPS criteria. Methods: We evaluated the medical records and postoperative computed tomography (CT) findings of 247 patients who underwent pancreaticoduodenectomy. Postoperative hyperamylasemia (POH) was defined as an elevation in serum amylase levels over the upper baseline limit (≥133 U/L) on postoperative days 1 and 3. PPAP was defined as acute pancreatitis satisfying the following three requirements: POH, clinically relevant deterioration, and radiologic features consistent with acute pancreatitis. Results: Postoperative hyperamylasemia and PPAP were prevalent in 9.7% (24/247) and 3.6% (9/247) of the patients, respectively. PPAP grade B occurred in eight patients, seven of whom experienced Clavien-Dindo grade IIIA complications, including postoperative pancreatic fistula (POPF) and extended periods of postoperative hospitalization. PPAP grade C occurred in one patient, who died from the exacerbation of underlying interstitial pneumonia following the POPF occurrence. Acute pancreatitis determined by CT was observed in 15.3% (38/247) of the patients who underwent pancreaticoduodenectomy and was strongly associated with severe morbidity (P < .0001) and longer postoperative hospitalization (P < .0001). POH preceded acute pancreatitis on CT in only 23.7% (9/38) of those cases, resulting in a low incidence rate of PPAP. Conclusion: Post-pancreatectomy acute pancreatitis is a major postoperative complication of pancreatic resection; however, based on the current ISGPS criteria, its prevalence is low. Defining PPAP promotes universal evaluation and understanding of this new concept.

Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study.

BACKGROUND/AIMS: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases. METHODS: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed. RESULTS: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week < 8 (p = 0.0285), radiological response, stable disease or progression disease (p = 0.0212), and pathological stage > IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion. CONCLUSIONS: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.

Alterations in the Duodenal Fluid Microbiome of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: The tumor microbiome of patients with pancreas ductal adenocarcinoma (PDAC) includes bacteria normally present in the upper gastrointestinal tract. If the predominant source of intratumoral bacteria in patients with PDAC is retrograde migration from the duodenum, duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC. METHODS: We performed a case-control study comparing bacterial and fungal (16S and 18S rRNA) profiles of secretin-stimulated duodenal fluid collections from 308 patients undergoing duodenal endoscopy including 134 normal pancreas control subjects, 98 patients with pancreatic cyst(s) and 74 patients with PDAC. RESULTS: Alterations in duodenal fluid microbiomes with diminished alpha diversity were significantly associated with age >70 and proton pump inhibitor use. Patients with PDAC had significantly decreased duodenal microbial alpha diversity compared with age-matched control subjects with normal pancreata and those with pancreatic cyst(s). There was evidence of enrichment of Bifidobacterium genera in the duodenal fluid of patients with PDAC compared with control subjects and those with pancreatic cyst(s). There were also enrichment of duodenal fluid Fusobacteria and Rothia bacteria among patients with PDAC with short-term survival. Duodenal fluid microbiome profiles were not significantly different between control subjects and patients with pancreatic cyst(s). CONCLUSION: Patients with PDAC have alterations in their duodenal fluid microbiome profiles compared with patients with pancreatic cysts and those with normal pancreata. ClinicalTrials.gov, Number: NCT02000089.

Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer.

BACKGROUND AND AIMS: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer. METHODS: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated. RESULTS: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%. CONCLUSION: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.

Gallbladder Ciliated Foregut Cyst Suspected of Malignancy Preoperatively.

BACKGROUND: Gallbladder ciliated foregut cysts (CFCs) of the lower diaphragm are extremely rare. Furthermore, they are rarely suspected of malignancy preoperatively. Case Presentation. A 50-year-old woman was referred to our hospital for further examination and treatment of a gallbladder tumor that was detected using abdominal ultrasonography (US). After a close inspection, she was diagnosed with a gallbladder tumor that was possibly malignant. Accordingly, open whole layer cholecystectomy was performed because intraoperative US revealed a tumor located on the intraperitoneal side of the gallbladder, and a rapid intraoperative pathological diagnosis identified no malignancy. A postoperative pathological examination revealed a cystic lesion with thin walls covered with ciliated epithelium, which laid on a connective tissue with smooth muscle fibers. Based on the above results, the final pathological diagnosis was CFC of the gallbladder without malignancy. CONCLUSIONS: Cases of gallbladder CFC can be considered as cysts requiring treatment owing to CFCs' potential for malignant transformation and high-frequency symptoms.