Search

To elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC).We retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models.The MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14-3.78, p = 0.016) than that before NAC (2.14, 1.23-3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26-4.05, p = 0.007); borderline resectability (1.96, 1.04-3.69, p = 0.038); operative blood loss (2.60, 1.38-4.88, p = 0.003); and distant metastasis (3.31, 1.40-7.82, p = 0.006).Sarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.

and purpose: Zinc is an essential element for human health and plays an important role in metabolic, immunological and other biological processes. The present study was conducted to investigate the association between zinc deficiency (ZD) and the perioperative clinical course in patients with pancreatic ductal adenocarcinoma (PDAC).Of 216 patients with PDAC who underwent elective pancreatectomy between 2013 and 2017 at our institution, 206 patients with sufficient clinical data were retrospectively reviewed. The perioperative variables were compared and the risk factors associated with infectious complications were identified.ZD was preoperatively present in 36 (17.5%) of 206 patients with PDAC. In the patients of the ZD group, a higher proportion of males, higher preoperative modified Glasgow prognostic scores, a higher neutrophil-to-lymphocyte ratio, and a higher occurrence of postoperative infectious complications after pancreatectomy were observed, compared to the non-ZD group. By a univariate analysis, three risk factors were significantly associated with infectious complications after pancreatectomy: ZD (vs non-ZD: p = 0.002), serum albumin3.5 g/dl (vs ≥ 3.5 g/dl: p = 0.005), and the procedure of pancreaticoduodenectomy (vs others: p = 0.013). By multivariate logistic regression analysis, the occurrence of infectious complications was significantly associated with ZD (OR 3.430, 95%CI 1.570 to 7.490, p = 0.002) and the procedure of pancreaticoduodenectomy (OR 2.030, 95%CI 1.090 to 3.770, p = 0.025).The current study newly demonstrated that ZD could serve as a preoperative predictor of infectious complications after pancreatectomies in the patients with PDAC.

Metachronous tumors arising in the remnant bile duct after surgical resection for primary biliary tract cancers (BTCs) are rarely treated surgically and have not been well documented. This study aimed to clarify the clinicopathological and genomic features of metachronous tumors arising in the remnant bile duct. Consecutive 12 patients who underwent resection for metachronous BTCs arising in the remnant bile duct after primary surgical resection between 2008 and 2020 were enrolled. Clinicopathological analysis and genomic analysis using targeted amplicon sequencing for 31 biliary tract cancer-related genes, including TP53, APC, ARID1A, ARID2, BAP1, CDKN2A, CTNNB1, ELF3, ERBB2, GNAS, IDH1, KRAS, and SMAD4, and immunohistochemistry for p53, p16, SMAD4, ARID1A, and β-catenin, were performed on 12 matched pair of primary and metachronous BTCs. In the 12 patients, 7 metachronous tumors developed antegradely in the lower portion of the biliary tree, and the remaining 5 metachronous tumors developed retrogradely in the upper portion, with negative bile duct margin at the initial operations. Molecular analysis revealed mutations and copy number alterations in TP53 (87.5%), APC (20.8%), CTNNB1 (20.8%), KRAS (12.5%), GNAS (8.3%), and RNF43 (8.3%). In comparison analysis, the matched primary and metachronous tumors shared identical genomic features in 10 cases, except in 2 cases showing metachronous perihilar and distal bile duct carcinomas after gallbladder cancer resection. Seven patients survived without recurrence, 5 showed postoperative local recurrences, and 2 died. Nine patients achieved 5-year overall survival after primary surgery. In conclusion, among the 12 patients with subsequent metachronous BTCs, 10 originated from neoplastic clones of the primary carcinoma, indicating recurrence due to intramural metastases or intraductal disseminations. Repeated surgical approach for metachronous BTCs may provide definitive local control and potentially prolong survival in these patients.

Activating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants (KRASG12D, KRASG12V, and KRASWT) using a KRASG12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo. We verified that the growth of KRASG12D cells is more aggressive compared to KRASG12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRASG12D and KRASG12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRASG12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRASG12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC.One Sentence SummaryIFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation.

Background Probiotics have been reported to be beneficial for the prevention of postoperative complications and are often used during the perioperative period. Among the probiotic-related adverse events, bacteremia is rare. Here, we report two cases of probiotic-related bacteremia after major hepatectomy for biliary cancer. Case presentation 1 A 74-year-old man was referred to our hospital to be treated for gallbladder cancer. Neoadjuvant chemotherapy, two courses of gemcitabine plus S-1 combination therapy, was administered. Extended right hepatectomy with caudate lobectomy, extrahepatic bile duct resection and biliary reconstruction were performed 3 weeks after chemotherapy. Probiotics, Clostridium butyricum (C. butyricum) MIYAIRI 588, were administered 6 days before surgery and continued after surgery. Sepsis of unknown origin occurred 17 days after surgery and developed into septic shock. C. butyricum was detected in blood cultures at postoperative day 26 and 45. After stopping the probiotic agent, C. butyricum was undetectable in the blood cultures. The patient died due to an uncontrollable sepsis 66 days after surgery. Case presentation 2 A 63-year-old man with diabetes mellitus whose past history included total colectomy, papillectomy, and Frey’s operation at the age of 19, 34 and 48, respectively, was referred to our hospital to be treated for perihilar cholangiocarcinoma. Extended left hepatectomy with caudate lobectomy, extrahepatic bile duct resection and reconstruction of bile duct were performed. Probiotics were administered during the perioperative period. Combined probiotics that included lactomin, amylolytic bacillus and C. butyricum, were given before surgery. C. butyricum MIYAIRI 588 was given after surgery. Sepsis occurred 16 days after surgery and developed to respiratory failure 8 days later. Blood culture at postoperative day 25 revealed Enterococcus faecalis and C. butyricum. After the probiotics were stopped at postoperative day 27, C. butyricum was not detected in the blood culture. The general condition improved with intensive care. The patient was transferred to another hospital for rehabilitation at postoperative day 156. Conclusion It should be noted that the administration of probiotics in severe postoperative complications can lead to probiotic-related bacteremia.

The significance of surgical resection in pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal cytology (PPC) is controversial. This study aimed to evaluate whether preceding chemotherapy could be beneficial for patients with PDAC with PPC. Between 2017 and 2019, 34 consecutive PDAC patients diagnosed with PPC without distant metastasis were retrospectively reviewed. Twenty-three patients did not receive neoadjuvant treatment (NAT) and 11 received NAT. All patients received systemic chemotherapy after PPC was confirmed, and they underwent surgical resection if PPC turned negative. The treatment course, ratio of conversion surgery (CS), and prognosis were evaluated. Moreover, the prognosis of PPC patients who underwent up-front surgery without NAT between 2003 and 2016 was analyzed as a comparative cohort. The median survival time (MST) of the patients without NAT was 31.4 months. CS was performed in 52.2% of the patients. Patients who underwent CS had better prognoses than those who did not undergo CS (p = 0.005). The CS rate was significantly higher in resectable PDAC (78.5%) than in borderline/unresectable PDAC (11.1%) (p = 0.002). The prognosis of patients with resectable PDAC was improved with preceding chemotherapy compared with up-front surgery (MST 13.0 months; p = 0.016). After NAT, the CS rate was low (27.3%), and the MST was only 14.1 months. As an initial treatment for PDAC patients with PPC, chemotherapy may lead to a favorable prognosis. Especially, resectable PDAC is associated with a greater chance of improved prognosis. Future studies are required to ascertain whether up-front surgery or preceding chemotherapy should be performed for these patients.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

ObjectiveIntrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression.DesignWe evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems.ResultsPlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.ConclusionPlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

This study proposes improvements to 22.2 multichannel (22.2 ch) sound broadcasting service. 22.2 ch sound is currently used in the 8K satellite broadcasting in Japan. In this study, the audio system is migrated from channel-based audio to object-based audio. The object-based audio equips 22.2 ch sound with alternative and adaptive functionalities: the alternative functionality is related to dialogue controls such as multilingual services, while the adaptive functionality enables 22.2 ch sound to be adapted to the audio format of the playback equipment. Moving Picture Experts Group (MPEG)-H 3D Audio (3DA), which is the latest audio coding standard, is used as the audio coding scheme. A real-time encoder and decoder based on 3DA was developed to verify the practicability of the proposed system. The encoded audio data is packetized and transmitted by MPEG-H MPEG Media Transport (MMT) to be multiplexed with video data. A transmission experiment with 8K video was carried out in which the proposed system was proved to operate as designed in this study.

Significance Immune checkpoint blockade (ICB) has been efficacious in several cancer types. However, mismatch repair–proficient (pMMR) metastatic colorectal cancer (CRC), ∼95% of total metastatic CRC cases, typically does not respond to ICB. Here, we show that orthotopic liver metastasis mouse models of pMMR CRC cell lines are unresponsive to ICB and recapitulate the resistance of human disease, unlike subcutaneous tumors of the same cell lines. We also show that just like the human disease, orthotopic pMMR CRC liver metastases have a paucity of T cells and dendritic cells, and that treatment with Flt3L sensitizes the liver metastases to ICB. Our findings highlight that orthotopic tumor models, and not subcutaneous models, should be used for preclinical studies of cancer immunotherapy., Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

Background The fractional abundance of tumor-derived DNA in body fluids depends on the metastatic sites and the degree of expansion. We aimed to assess the clinical significance of tumor-derived DNA testing in the peritoneal lavage of patients with pancreatic cancer. Methods The prevalence and abundance of tumor-derived DNA was assessed in 204 subjects with ascites by peritoneal lavage (AS) and the evaluable paired plasma (PL) from 149 pancreatic cancer patients undergoing abdominal exploration. Genetic profiles were evaluated by next-generation sequencing, and prognostic impact was assessed using Cox proportional hazard models. Results Of 204 subjects, AS samples from patients with peritoneal dissemination (PER+) and positive cytology (CY+) showed significantly higher prevalence and abundance of tumor-derived DNA than those with negative counterparts. Tumor-derived DNA prevalence and abundance in AS were more likely to be higher than in paired PL in a subgroup of patients with PER+ and CY+, respectively. Next-generation sequencing revealed concordant or discrepant mutational patterns between the AS and PL samples. Multivariate analysis showed that both tumor-derived DNA in AS (hazard ratio [HR] 3.940, p = 0.009) and PL (HR 2.936, p = 0.026) were independently associated with poor survival in treatment-naive patients. In patients who underwent resection, tumor-derived DNA positivity in the AS was more predictive of early recurrence than in PL. Conclusions Tumor-derived DNA in AS can serve as characterizing the genetic profiles of tumor cells attributable to the development of PER+ and predicting the minimal residual disease and early recurrence in patients with pancreatic cancer.

Background and aims Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and results We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8+ ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody. Conclusions We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.

A 64-year-old woman was referred to our hospital for treatment of pancreatic head cancer with acute pancreatitis due to iatrogenic injury of the pancreatic duct during endoscopic retrograde cholangiopancreatography. In addition to a 28 mm pancreatic head tumor, soft tissue shadow and fluid collection surrounding the superior mesenteric artery(SMA)due to pancreatitis were observed in the abdominal CT scan. The tumor was histologically diagnosed as adenocarcinoma by endoscopic ultrasound-guided fine needle aspiration. Neoadjuvant chemotherapy with gemcitabine and S-1 was performed to control the progression of the pancreatic cancer and improve the inflammatory changes for reduction of the operative risk. After 2 courses of neoadjuvant chemotherapy, abdominal CT scan revealed stable disease according to the Response Evaluation Criteria in Solid Tumors and attenuation of the inflammatory changes surrounding the SMA. Then, subtotal stomach- preserving pancreaticoduodenectomy was performed without the difficulty of peeling around the SMA in spite of the old inflammatory changes. Histological examination of the resected specimen showed R0 resection. The patient was discharged 18 days after surgery without any complications and is surviving 9 months postoperatively without any recurrence. Neoadjuvant chemotherapy was helpful for disease control and improvement of the inflammatory changes.

Background The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the recurrence predictive ability of such markers after curative resection in patients with these neoplasms.Methods Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan–Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals.Results Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR=3.49 95% CI 1.05-11.7; P=0.042) and 2017 World Health Organization classification (HR=8.81, 95% CI 1.46-168.2; P=0.015) were independent recurrence predictors.Conclusions The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

Background The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms. Methods Circulating/systemic neutrophil–lymphocyte, monocyte–lymphocyte, platelet–lymphocyte, and platelet–white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan–Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals. Results Univariate analysis demonstrated that preoperative neutrophil–lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil–lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil–lymphocyte ratio (HR = 3.49 95% CI 1.05–11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46–168.2; P = 0.015) were independent recurrence predictors. Conclusions The circulating/systemic neutrophil–lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

The aims of this study were to compare the perioperative outcomes after hepatectomy with prior bilioenteric anastomosis to those without prior anastomosis, and to elucidate the mechanisms and preventative measures of its characteristic complications. The demographic data and perioperative outcomes of 525 hepatectomies performed between January 2007 and December 2018, including 40 hepatectomies with prior bilioenteric anastomosis, were retrospectively analyzed. A propensity score matching analysis demonstrated that hepatectomies with prior bilioenteric anastomosis were associated with a higher frequency of major complications (p = 0.015), surgical site infection (p = 0.005), organ/space surgical site infection (p = 0.003), and bile leakage (p = 0.007) compared to those without. A multivariate analysis also elucidated that prior bilioenteric anastomosis was one of the independent risk factors of organ/space surgical site infection. In the patients with prior bilioenteric anastomosis, bile leakage was associated with organ/space surgical site infection at a significantly higher rate than those without prior bilioenteric anastomosis (p

Background Neoadjuvant therapy (NAT) is considered a potential approach to improve survival for patients with pancreatic adenocarcinoma (PA). The objective of this study was to identify the clinical implications of washing peritoneal cytology (CY) status after NAT. Methods Between 2005 and 2016, 151 consecutive patients with resectable (R)/borderline resectable (BR) PA underwent NAT with intention of subsequent resection at our institution. Of them, 13 and 123 patients underwent pancreatectomies with positive (CY+) and negative (CY-) cytology, respectively, while the remaining 15 patients did not undergo resection due to gross metastases at laparotomy. The clinicopathological factors influencing overall survival were clarified by the uni- and multivariate analyses. Results The postoperative overall survival (OS) and disease-free survival (DFS) were markedly worse in patients who underwent resection with CY+, compared with those who were CY- (median OS, 14.8 m vs 30.8 m, p = 0.026, and median DFS 6.0 m vs 15.1 m, p = 0.008). According to the resectability by NCCN guidelines, CY+ indicates worse prognosis than CY- in R-PA patients (mOS: 30.1 m vs 71.1 m: p = 0.080). Similarly, in BR-PA patients, CY+ showed the significantly worse prognosis than CY- (mOS: 13.8 m vs 24.5 m: p = 0.048), which prognosis is comparable with patients who did not undergo resection. The multivariate analysis revealed that resectability, CY status and the induction of adjuvant therapy were significant predictors of postoperative OS (p = 0.007: Hazard ratio 2.264, 0.040:2.094 and 0.002:3.246, respectively). Conclusions CY+ is a significant predictor of poorer prognosis in PA patients after NAT. The subsequent pancreatectomies with CY+ after NAT do not contribute to prolonged survival.

Staging laparoscopy is considered useful for determining treatment plans for advanced pancreatic cancer. However, the indications for staging laparoscopy are not clear. This study aimed to evaluate the safety of staging laparoscopy and its usefulness for detecting distant metastases in patients with pancreatic cancer. A total of 146 patients with pancreatic cancer who underwent staging laparoscopy between 2013 and 2019 were analyzed. Staging laparoscopy was performed in all pancreatic cancer patients in whom surgery was considered possible. In this cohort, 42 patients (29%) were diagnosed with malignant cells on peritoneal lavage cytology, 9 (6%) had peritoneal dissemination, and 11 (8%) had liver metastases. A total of 48 (33%) had radiologically negative metastases. On a multivariate analysis, body and tail cancer [odds ratio (OR) 5.00, 95% confidence interval (CI) 2.15–11.6, p

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared to their subcutaneous tumor counterparts. Furthermore, treatment with FMS-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC. Citation Format: William W. Ho, Igor L. Gomes-Santos, Shuichi Aoki, Meenal Datta, Kosuke Kawaguchi, Nilesh P Talele, Sylvie Roberge, Jun Ren, Hao Liu, Ivy X Chen, Patrik Andersson, Sampurna Chatterjee, Ashwin S. Kumar, Zohreh Amoozgar, Qixian Zhang, Peigen Huang, Mei Rosa Ng, Vikash P Chauhan, Lei Xu, Dan G. Duda, Jeffrey W. Clark, Mikael J. Pittet, Dai Fukumura, Rakesh K Jain. Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits the efficacy of immune checkpoint blockade [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P061.

Survival after surgery for pancreatic adenocarcinoma (PA) is poor and heterogeneous, even for curative (R0) resection. Serum carbohydrate antigen (CA) 19-9 levels are important prognostic markers for resected PA. However, sustained elevation of CA19-9 in association with the patterns of recurrence has been rarely investigated. Patients who underwent R0 resection (n = 539) were grouped according to postoperative serum CA19-9 levels (Group E: sustained elevation; Group N: no elevation). Clinicopathological factors, patterns of recurrence, and survival were compared between the groups. Group E (n = 159) had significantly shorter median overall survival (17.1 vs. 35.4 months, p

// Mitsuhiro Shimura 1 , Masamichi Mizuma 1 , Tatsuyuki Takadate 1 , Yasutake Katoh 2, 3 , Takashi Suzuki 4 , Masahiro Iseki 1 , Tatsuo Hata 1 , Shuichi Aoki 1 , Yukie Suzuki 1 , Naoaki Sakata 1 , Hideo Ohtsuka 1 , Hiroki Hayashi 1 , Takanori Morikawa 1 , Kei Nakagawa 1 , Fuyuhiko Motoi 1 , Takeshi Naitoh 1 , Kazuhiko Igarashi 2, 3 , Hironobu Sasano 5 and Michiaki Unno 1 1 Department of Surgery, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan 2 Department of Biochemistry, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan 3 Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan 4 Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan 5 Department of Pathology, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan Correspondence to: Masamichi Mizuma, email: masamichi@surg.med.tohoku.ac.jp Keywords: PanNEN; liver metastasis; CNPY2; ANXA6; proteomics Received: October 11, 2017 Accepted: March 17, 2018 Published: May 11, 2018 ABSTRACT The aim of this study was to identify novel liver metastasis-correlated proteins of PanNEN by proteomics to compare pancreatic tumor (PT) with paired metastatic liver tumor (LT). Of 118 surgical cases with PanNEN, 7 cases with formalin-fixed paraffin-embedded (FFPE) tissues of both PT and paired LT were evaluated by proteomics. Tumor cells were selectively collected from FFPE tissues by laser capture microdissection. A total of 3,722 proteins were detected from extracted peptides by mass spectrometry-based shotgun analysis. Selection of the candidate proteins expressed differently between PT and LT were performed by semi-quantitative comparison in silico and confirmation with immunohistochemistry. We focused on ANXA6, CNPY2, RAB11B and TUBB3, all of which had higher expressions in LT. In all surgical cases with FFPE samples, liver recurrence-free survival (RFS) was evaluated in correlation to the expression of the candidate proteins in PT by immunohistochemistry. Liver RFS was significantly poorer in CNPY2 positive patients than in negative patients (10-year liver RFS; 39.8% vs. 92.3%, p = 0.012). Also, liver RFS tended to be poorer in ANXA6 positive patients than in those who were negative (10-year liver RFS; 51.4% vs. 95.0%, p = 0.099). In the multivariate analysis, the independent predictors of liver RFS were CNPY2 positivity (HR: 6.19, 95 % CI: 1.47–42.79, p = 0.011) and tumor size ≥ 42 mm (HR: 4.63, 95 % CI: 1.03–23.23, p = 0.045). In conclusion, CNPY2 is a novel liver metastasis-correlated protein of PanNEN.

Background The morbidity rate after pancreaticoduodenectomy remains high. The objectives of this retrospective cohort study were to clarify the risk factors associated with serious morbidity (Clavien–Dindo classification grades IV–V), and create complication risk calculators using the Japanese National Clinical Database. Methods Between 2011 and 2012, data from 17,564 patients who underwent pancreaticoduodenectomy at 1,311 institutions in Japan were recorded in this database. The morbidity rate and associated risk factors were analyzed. Results The overall and serious morbidity rates were 41.6% and 4.5%, respectively. A pancreatic fistula (PF) with an International Study Group of Pancreatic Fistula (ISGPF) grade C was significantly associated with serious morbidity (P

Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8+ T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.