Contrasting Roles of Programmed Death-Ligand 1 Expression in Tumor and Stroma in Prognosis of Esophageal Squamous Cell Carcinoma.

The assessment of programmed death-ligand 1 (PD-L1) expression in esophageal squamous cell carcinoma (ESCC) has become increasingly important with the rise of immune checkpoint inhibitors (ICIs). However, challenges persist, including subjective interpretation and the unclear significance of staining intensity, as well as contrasting roles in tumoral and stromal regions. Our study enhances the understanding of PD-L1 in ESCCs by analyzing its expression in tumors and stroma with H-scores, highlighting its distinct clinicopathological impacts. In a retrospective cohort of 194 ESCC specimens from surgical resection, we quantified PD-L1 expression in tumoral and stromal compartments using H-scores, analyzing whole slide images with digital pathology analysis software. Kaplan-Meier analysis demonstrated that higher PD-L1 expression is significantly associated with improved postoperative overall survival (OS) and recurrence-free survival (RFS) in both tumoral and stromal areas. Multivariable analysis identified high tumoral PD-L1 expression as an independent prognostic factor for prolonged OS and RFS (HR = 0.47, p = 0.007; HR = 0.54, p = 0.022, respectively). In a separate analysis, high stromal PD-L1 expression was found to correlate with less advanced pathological stages and a prolonged response to cytotoxic chemotherapy, with no similar correlation found for ICI treatment response. This study reveals PD-L1's contrasting role in the ESCC tumor immune microenvironment, impacting prognosis, tumor stage, and treatment response.

Laparoscopic median arcuate ligament section for median arcuate ligament compression syndrome initially detected as splenic infarction: a case report.

BACKGROUND: Median arcuate ligament compression syndrome (MALS) causes upper abdominal pain and at times hemodynamic abnormalities in the pancreaticoduodenal region. Herein, we present a case of a 70 year-old man, initially diagnosed with splenic infarction and was successfully treated laparoscopically. CASE PRESENTATION: A 70-year-old man with abdominal pain admitted to our hospital. Abdominal-enhanced computed tomography revealed a poorly contrasted area in the spleen and stenosis at the root of the celiac artery. Arterial dilatation was observed around the pancreaticoduodenal arcade, however, no obvious aneurysm formation or arterial dissection was observed. Abdominal-enhanced magnetic resonance imaging indicated the disappearance of the flow void at the root of the celiac artery. The patient had no history of atrial fibrillation and was diagnosed with splenic infarction due to median arcuate ligament compression syndrome. We performed a laparoscopic median arcuate ligament section with five ports. Intraoperative ultrasonography showed a retrograde blood flow in the common hepatic artery and the celiac artery. After releasing the compression, the antegrade blood flow from the celiac artery to the splenic artery, and the common hepatic artery were visualized using intraoperative ultrasonography. The postoperative course of the patient was uneventful, and he was discharged on postoperative day 9. Postoperative computed tomography a month after surgery revealed no residual stenosis of the celiac artery or dilation of the pancreaticoduodenal arcade. Furthermore, the poorly contrasted area of the spleen improved. CONCLUSIONS: Reports indicate that hemodynamic changes in the abdominal visceral arteries due to median arcuate ligament compression are related to the formation of pancreaticoduodenal aneurysms. In this case, median arcuate ligament compression syndrome caused splenic infarction by reducing blood flow to the splenic artery.

Tenascin C in pancreatic cancer-associated fibroblasts enhances epithelial mesenchymal transition and is associated with resistance to immune checkpoint inhibitor.

Tenascin C (TNC) is an extracellular matrix glycoprotein that is highly expressed in cancer stroma and is associated with tumor progression in pancreatic adenocarcinoma (PAAD). In this study, we aimed to investigate the potential involvement of TNC in the response to immune checkpoint inhibitors (ICI) among PAAD patients. Transcriptomic profiles were obtained from public databases and analyzed to compare TNC mRNA levels between tumor and normal tissues. Bioinformatic programs were used to predict paracrine communications between cancer cells and cancer-associated fibroblasts (CAFs), and the Tumor Immune Dysfunction and Exclusion (TIDE) score was calculated to predict response to ICI treatment in PAAD patients. An independent immunotherapeutic cohort was used to validate the clinical impact of the signatures. Results showed that TNC mRNA levels were significantly upregulated in tumors compared to normal tissues in PAAD, and patients with high TNC expression had significantly shorter overall survival than those with low TNC expression (P = 0.0125). TNC was predominantly expressed in CAFs of PAAD patients and was found to potentially enhance the epithelial-mesenchymal transition (EMT) of cancer cells via integrin receptors, contributing to resistance to ICI treatment. Patients with high TNC expression and high ITGαV or ITGB3 expression were associated with poor response to ICI therapy. In conclusion, these findings suggest that TNC-high CAFs play a crucial role in tumor progression and resistance to ICI therapy in PAAD patients, and targeting TNC and its interactions with cancer cells may provide a potential strategy for improving the efficacy of ICI therapy in PAAD.

Prediction of postoperative complications after hepatectomy with dynamic monitoring of central venous oxygen saturation.

BACKGROUND: The usefulness of static monitoring using central venous pressure has been reported for anesthetic management in hepatectomy. It is unclear whether intra-hepatectomy dynamic monitoring can predict the postoperative course. We aimed to investigate the association between intraoperative dynamic monitoring and post-hepatectomy complications. Furthermore, we propose a novel anesthetic management strategy to reduce postoperative complication. METHODS: From 2018 to 2021, 93 patients underwent hepatectomy at our hospital. Fifty-three patients who underwent dynamic monitoring during hepatectomy were enrolled. Flo Trac system was used for dynamic monitoring. The baseline central venous oxygen saturation (ScvO2) was defined as the average ScvO2 for 30 min after anesthesia induction. ScvO2 fluctuation (ΔScvO2) was defined as the difference between the baseline and minimum ScvO2. Postoperative complications were evaluated using the comprehensive complication index (CCI). RESULTS: Patients with ΔScvO2 ≥ 10% had significantly higher CCI scores (0 vs. 20.9: p = 0.043). In univariate analysis, patients with higher CCI scores demonstrated significantly higher preoperative C-reactive protein-to-lymphocyte ratio (7.51 vs. 24.49: p = 0.039), intraoperative bleeding (105 vs. 581 ml: p = 0.008), number of patients with major hepatectomy (4/45 vs. 3/8: p = 0.028), and number of patients with ΔScvO2 ≥ 10% (11/45 vs. 6/8; p = 0.010). Multivariate logistic regression analysis revealed that ΔScvO2 ≥ 10% (odds ratio: 9.53, p = 0.016) was the only independent predictor of elevated CCI. CONCLUSIONS: Central venous oxygen saturation fluctuation during hepatectomy is a predictor of postoperative complications. Anesthetic management based on intraoperative dynamic monitoring and minimizing the change in ScvO2 is a potential strategy for decreasing the risk of post-hepatectomy complications.

Spatial profiling of cancer-associated fibroblasts of sporadic early onset colon cancer microenvironment.

The incidence of sporadic early-onset colon cancer (EOCC) has increased worldwide. The molecular mechanisms in the tumor and the tumor microenvironment (TME) in EOCC are not fully understood. The aim of this study is to unravel unique spatial transcriptomic and proteomic profiles in tumor epithelial cells and cancer-associated fibroblasts (CAFs). Here, we divide the sporadic colon cancer tissue samples with transcriptomic data into patients diagnosed with EOCC (<50 yrs) and late-onset colon cancer (LOCC, ≥50 yrs) and then, analyze the data using CIBERSORTx deconvolution software. EOCC tumors are more enriched in CAFs with fibroblast associated protein positive expression (FAP(+)) than LOCC tumors. EOCC patients with higher FAP mRNA levels in CAFs have shorter OS (Log-rank test, p < 0.029). Spatial transcriptomic analysis of 112 areas of interest, using NanoString GeoMx digital spatial profiling, demonstrate that FAP(+) CAFs at the EOCC tumor invasive margin show a significant upregulation of WNT signaling and higher mRNA/protein levels of fibroblast growth factor 20 (FGF20). Tumor epithelial cells at tumor invasive margin of EOCC tumors neighboring FAP(+) CAFs show significantly higher mRNA/protein levels of fibroblast growth factor receptor (FGFR2) and PI3K/Akt signaling activation. NichNET analysis show a potential interaction between FGF20 and FGFFR2. The role of FGF20 in activating FGFR2/pFGFR2 and AKT/pAKT was validated in-vitro. In conclusion, we identify a unique FAP(+) CAF population that showed WNT signaling upregulation and increased FGF20 levels; while neighbor tumor cells show the upregulation/activation of FGFR2-PI3K/Akt signaling at the tumor invasive margin of EOCC tumors.

The cholinesterase and C-reactive protein score is a potential predictor of pseudoaneurysm formation after pancreaticoduodenectomy in patients with soft pancreas.

BACKGROUND: Pseudoaneurysm (PA) rupture after pancreaticoduodenectomy (PD) is a life-threatening complication. Most PA cases originate from postoperative pancreatic fistulas (POPFs). Although several risk factors for POPF have been identified, specific risk factors for PA formation remain unclear. Therefore, we retrospectively analyzed PD cases with soft pancreas and proposed a novel strategy for early detection of PA formation. METHODS: Overall, 120 patients underwent PD between 2010 and 2020 at our institution; of these, 65 patients with soft pancreas were enrolled. We evaluated the clinicopathological factors influencing PA formation and developed a risk score to predict PA formation. RESULTS: In total, 11 of the 65 patients developed PAs (PA formation group: PAG), and 8 of these 11 PAs ruptured. The median time to PA formation was 15 days, with a minimum of 5 days. The PAG was significantly older than the non-PA formation group, were predominantly men, and had comorbid diabetes mellitus. Pre- and intra-operative findings were similar between the two groups. Importantly, no significant differences were found in postoperative drain amylase levels and total drain amylase content. Cholinesterase and C-reactive protein (CRP) levels on postoperative day (POD) 3 were significantly different between the two groups. Multivariate analysis showed that cholinesterase ≤ 112 U/L and CRP ≥ 16.0 mg/dl on POD 3 were independent predictors of PA formation. CONCLUSIONS: Decreased cholinesterase and elevated CRP on POD 3 (Cho-C score) are useful predictors of PA formation in cases with soft pancreas. In such cases, periodic computed tomography evaluations and strict drain management are necessary to prevent life-threatening hemorrhage.

Phosphatidylcholine in bile-derived small extracellular vesicles as a novel biomarker of cholangiocarcinoma.

BACKGROUND: Owing to the lack of definite diagnostic modalities, it is challenging to distinguish malignant cases of cholangiocarcinoma (CCA), which often causes biliary tract obstruction, from benign ones. Here, we investigated a novel lipid biomarker of CCA in bile-derived small extracellular vesicles (sEVs) and developed a simple detection method for clinical application. METHODS: Bile samples from seven patients with malignant diseases (hilar CCA = 4, distal CCA = 3) and eight patients with benign diseases (gallstones = 6, primary sclerosing cholangitis = 1, autoimmune pancreatitis = 1) were collected through a nasal biliary drainage tube. sEVs were isolated via serial ultracentrifugation and characterized using nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting (with CD9, CD63, CD81, and TSG101). Comprehensive lipidomic analysis was performed using liquid chromatography-tandem mass spectrometry. Using a measurement kit, we further confirmed whether lipid concentrations could be used as a potential CCA marker. RESULTS: Lipidomic analysis of bile sEVs in the two groups identified 209 significantly increased lipid species in the malignant group. When focusing on lipid class, phosphatidylcholine (PC) level was 4.98-fold higher in the malignant group than in the benign group (P = 0.037). The receiver operating characteristic (ROC) curve showed a sensitivity of 71.4%, a specificity of 100%, and an area under the curve (AUC) of 0.857 (95% confidence interval [CI]:0.643-1.000). Using a PC assay kit, the ROC curve showed a cutoff value of 16.1 µg/mL, a sensitivity of 71.4%, a specificity of 100%, and an AUC of 0.839 (95% CI: 0.620-1.000). CONCLUSION: PC level in sEVs from human bile is a potential diagnostic marker for CCA and can be assessed by a commercially available assay kit.

Anterior superior pancreaticoduodenal artery pseudoaneurysm after distal pancreatectomy with en bloc celiac axis resection successfully treated with balloon-assisted coil embolization.

Bleeding is a fatal complication after pancreatectomy. Although coil embolization is a widely accepted treatment option, ischemia of the remaining organs should be prevented. This study reports the successful treatment of intra-abdominal hemorrhage following distal pancreatectomy with en bloc celiac axis resection (DP-CAR) using balloon-assisted coil embolization (BACE). A 59-year-old man was diagnosed with locally advanced pancreatic cancer. The tumor involves the common hepatic artery, splenic artery, and celiac artery. After four cycles of treatment with gemcitabine/nab-paclitaxel, the soft-density masses, surrounding the artery, shrunk. DP-CAR and R0 resections were performed. A minor postoperative pancreatic fistula occurred. Six months postoperatively, the computed tomography showed delayed asymptomatic bleeding from an anterior superior pancreaticoduodenal artery (ASPDA) pseudoaneurysm located near the gastroduodenal artery confluence. BACE was performed by placing a microballoon catheter in the region of confluence of the ASPDA and posterior superior pancreaticoduodenal artery (PSPDA) to prevent coil migration. After inserting the microballoon catheter, coil embolization was performed in the ASPDA. Hepatic blood flow was maintained from the PSPDA. BACE is a useful technique to preserve blood flow to the remnant organs when performing coil embolization for bleeding following a distal pancreatectomy, especially following a DP-CAR.

Saturated Fatty Acids in Cell Membrane Lipids Induce Resistance to 5-Fluorouracil in Colorectal Cancer Cells.

BACKGROUND/AIM: Resistance to chemotherapy is a major obstacle for patients with unresectable colorectal cancer (CRC); however, the factors that induce chemoresistance have not been elucidated. Lipid composition influences neoplastic behaviour. Therefore, this study examined whether lipid composition affects sensitivity to chemotherapeutic agents in CRC. MATERIALS AND METHODS: We performed a lipidomic analysis of a CRC xenograft-derived spheroid model to identify potential relationships between the lipid profile and chemoresistance to 5-fluorouracil (5-FU). Genetic and pharmacological modulation of lipid synthesis were also used in the HCT-116 and DLD-1 CRC cell lines to further characterize resistance to 5-FU. RESULTS: Our lipidomic profiling revealed that phospholipids with saturated fatty acids (SFAs) were more abundant in 5-FU-resistant spheroids. The importance of phospholipids containing SFA in chemoresistance was confirmed by showing that in HCT-116 and DLD-1 cells, genetic or pharmacological inactivation of stearoyl-CoA desaturase-1, a key enzyme that converts SFAs to monounsaturated fatty acids, increased the proportion of SFAs in membranous phospholipids and reduced cell membrane fluidity, and this ultimately resulted in resistance to 5-FU. CONCLUSION: These data suggest that the saturated to monounsaturated fatty acid ratio in cellular membranous phospholipids affects sensitivity to chemotherapeutic agents.

Comparison of operative outcomes between monopolar and bipolar coagulation in hepatectomy: a propensity score-matched analysis in a single center.

BACKGROUND: Various hemostatic devices have been utilized to reduce blood loss during hepatectomy. Nonetheless, a comparison between monopolar and bipolar coagulation, particularly their usefulness or inferiority, has been poorly documented. The aim of this study is to reveal the characteristics of these hemostatic devices. METHODS: A total of 264 patients who underwent open hepatectomy at our institution from January 2009 to December 2018 were included. Monopolar and bipolar hemostatic devices were used in 160 (monopolar group) and 104 (bipolar group) cases, respectively. Operative outcomes and thermal damage to the resected specimens were compared between these groups using propensity score matching according to background factors. Multivariate logistic regression analysis was performed to identify predictive factors for postoperative complications. RESULTS: After propensity score matching, 73 patients per group were enrolled. The monopolar group had significantly lower total operative time (239 vs. 275 min; P = 0.013) and intraoperative blood loss (487 vs. 790 mL; P < 0.001). However, the incidence rates of ascites (27.4% vs. 8.2%; P = 0.002) and grade ≥ 3 intra-abdominal infection (12.3% vs. 2.7%; P = 0.028) were significantly higher in the monopolar group. Thermal damage to the resected specimens was significantly longer in the monopolar group (4.6 vs. 1.2 mm; P < 0.001). Use of monopolar hemostatic device was an independent risk factor for ascites (odds ratio, 5.626, 95% confidence interval 1.881-16.827; P = 0.002) and severe intra-abdominal infection (odds ratio, 5.905, 95% confidence interval 1.096-31.825; P = 0.039). CONCLUSIONS: Although monopolar devices have an excellent hemostatic ability, they might damage the remnant liver. The use of monopolar devices can be one of the factors that increase the frequency of complications.

Current status of gastrointestinal tract cancer brain metastasis and the use of blood-based cancer biomarker biopsy.

Brain metastasis (BM) frequently occurs in patients with cutaneous melanoma, lung, and breast cancer; although, BM rarely arises from cancers of the gastrointestinal tract (GIT). The reported incidence of GIT cancer BM is less than 4%. In the last few years, effective systemic therapy has prolonged the survival of GIT patients and consequently, the incidence of developing BM is rising. Therefore, the epidemiology and biology of BM arising from GIT cancer requires a more comprehensive understanding. In spite of the development of new therapeutic agents for patients with metastatic GIT cancers, survival for patients with BM still remains poor, with a median survival after diagnosis of less than 4 months. Limited evidence suggests that early detection of isolated intra-cranial lesions will enable surgical resection plus systemic and/or radiation therapy, which may lead to an increase in overall survival. Novel diagnostic methods such as blood-based biomarker biopsies may play a crucial role in the early detection of BM. Circulating tumor cells and circulating cell-free nucleic acids are known to serve as blood biomarkers for early detection and treatment response monitoring of multiple cancers. Blood biopsy may improve early diagnosis and treatment monitoring of GIT cancers BM, thus prolonging patients' survivals.

A comprehensive strategy for perioperative care of pancreaticoduodenectomy according to the risk stratification by pancreatic fistula and delayed gastric emptying.

BACKGROUND/OBJECTIVE: Pancreaticoduodenectomy (PD) is highly invasive with unsatisfactory postoperative complication rates. Nutritional and fluid management after major surgery attracts much attention with regard to the reduction in severe postoperative complications. We retrospectively analyzed PD cases and proposed a novel strategy for perioperative fluid and nutritional therapy according to the risk stratification by pancreatic fistula (PF) and delayed gastric emptying (DGE). METHODS: Between 2003 and 2018, 140 patients underwent PD at our institute of which 134 patients were enrolled. We evaluated the clinicopathological factors affecting severe (≥10%) body weight loss (BWL), factors affecting the incidence of PF and intraabdominal complications (IAC), and factors related to DGE. RESULTS: Multivariate analysis indicated that male sex, severe PF, and DGE are significant risk factors for BWL ≥10%. PF and IAC were predominantly observed in male patients and those with non-pancreatic cancer. A fluid balance ≥6000 ml on postoperative day 2 was the sole risk factor for primary DGE. Secondary DGE significantly correlated with stomach preserving PD. Importantly, the average BWL was around 15% in grade B or C secondary DGE. CONCLUSION: Severe postoperative complications resulted in significant BWL. Enteral feeding is unnecessary in cases with a hard pancreas and dilated pancreatic duct if appropriate perioperative fluid management is performed. Secondary DGE followed by PF or IAC is unavoidable to some extent, especially in the case of soft pancreas with a fine pancreatic duct. In such cases, enteral feeding with tube ileostomy should be considered, and stomach preserving PD is likely to be harmful.

Ephrin Receptor A4 Expression Enhances Migration, Invasion and Neurotropism in Pancreatic Ductal Adenocarcinoma Cells.

BACKGROUND/AIM: We sought to identify the mechanisms of perineural invasion in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We utilized in vitro cancer cell-nerve co-culture models comprising human PDAC cell lines (MIA Paca2 and PANC-1) and a dorsal root ganglion (DRG) isolated from neonatal mice. We compared gene expression profiles between cell lines with/without DRG conditioned medium (DRG-CM) using RNA-sequencing (RNA-seq). RESULTS: Migration, invasion, and neurotropism were significantly enhanced in MIA Paca2 but not in PANC-1 cells co-cultured with DRGs. Among 285 genes which showed significant differences in expression levels between cell lines in RNA-seq, we focused on Ephrin receptor A4 (EPHA4), which was upregulated in MIA Paca2 cells treated with DRG-CM. The abilities of migration, invasion, and neurotropism enhanced by DRG co-culture were abolished when EPHA4 was knocked down by siRNA in MIA Paca2 cells. CONCLUSION: EPHA4 can be a potential target gene to regulate perineural invasion in PDAC cells.

Risk Factors for Totally Implantable Central Venous Access Port-related Infection in Patients With Malignancy.

BACKGROUND: We sought to identify the risk factors of totally implantable central venous access port (TICVAP)-related infections in patients with malignant disease. PATIENTS AND METHODS: Overall, 324 consecutive patients who received a TICVAP at our institution were retrospectively analysed. We further analysed cases of TICVAP-related complications. The risk factors for TICVAP-related infection were investigated using Cox regression hazard models. RESULTS: With a median TICVAP duration of 268 days (range=1-1,859 days), TICVAP-related complications were observed in 36 cases and infectious complications in late phase were the most common, seen in 19 cases (9.26%). A multivariate analysis showed that patients with head and neck malignancy (p<0.001) and patients who received TICVAP insertion in the upper arm (p<0.001) were independently at a higher risk for TICVAP-related infections. CONCLUSION: Patients with head and neck malignancy or TICVAP insertion in the upper arm have potentially increased risk for late-phase TICVAP-related infections.

Aggressive Recurrent Pancreatic Cancer Producing Granulocyte Colony-Stimulating Factor.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein which stimulates the proliferation, differentiation, and functional activation of myeloid hematopoietic cells. G-CSF-producing pancreatic cancer is rare and its prognosis is strikingly poor. A 69-year-old woman with well-to-moderately differentiated ductal adenocarcinoma (pT3N0M0, stage IIA) underwent distal pancreatectomy and splenectomy. Postoperative adjuvant chemotherapy with S-1 was administered for 6 months. Eleven months after surgery, periodic blood examination revealed remarkable leukocytosis (19,120/µL) without fever, which worsened 3 weeks later (36,160/µL). Furthermore, laboratory data showed elevation of the fibrin degradation product-D dimer and that the G-CSF level was high (406 pg/mL), as well as thrombopenia. Multiple liver and lung metastases were detected by contrast-enhanced computed tomography (CT). The patient was treated with gemcitabine plus nab-paclitaxel, and heparin, thrombomodulin alfa, and platelet transfusion were administered concurrently. Leukocytosis and thrombopenia were alleviated after 1 course of chemotherapy. However, remarkable leukocytosis (53,480/µL) recurred on day 1 of the third course of chemotherapy. Contrast-enhanced CT showed a significantly increased number of liver metastases and lung metastases. The patient chose not to receive second-line chemotherapy and died 1 month later at the affiliated hospital. Pancreatic cancer producing G-CSF shows very aggressive behavior. Leukocytosis without infection during routine observation should be considered as a warning of a rapidly growing recurrence.

Multimodal therapy with surgery and adjuvant nivolumab for late-onset multiple liver metastases of choroidal malignant melanoma: a case report.

BACKGROUND: Choroidal malignant melanoma is the most common primary malignant tumor of the eye in adults. Prognosis after recurrence of this disease has been dismal because of the absence of an effective therapy. However, resection of recurrent foci and a subsequent treatment with immune-checkpoint inhibitor may improve the prognosis after recurrence of this disease. This study presents a case of late-onset liver metastases of choroidal malignant melanoma, successfully treated with hepatectomy and postoperative adjuvant nivolumab. CASE PRESENTATION: A 53-year-old woman had undergone left ocular enucleation because of choroidal malignant melanoma 13 years prior to admission. She visited a nearby clinic with complaints of epigastric pain. She was referred to our hospital because a giant liver tumor was observed on abdominal ultrasonography. Enhanced computed tomography revealed multiple liver tumors in the right lobe, 49 mm in diameter with ring enhancement in subsegment (S) 5/6, and 14 and 8 mm without any enhancement in S7 and S5, respectively. On magnetic resonance imaging, the main tumor showed high intensity on T1-weighted with fat suppression, suggesting melanin deposition. Based on the diagnosis of multiple liver metastases of choroidal malignant melanoma, right hepatectomy and regional lymphadenectomy were performed. She was discharged without postoperative complications. Histological examination revealed that all tumors were metastatic malignant melanoma. She was treated with nivolumab postoperatively, and no recurrences were observed during 22 months of follow-up. CONCLUSIONS: Aggressive surgery plus adjuvant nivolumab appears to be a promising treatment for choroidal malignant melanoma with late-onset liver metastases.

Tenascin C in the Tumor-Nerve Microenvironment Enhances Perineural Invasion and Correlates With Locoregional Recurrence in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Perineural invasion is common in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. Tenascin C (TNC), an extracellular matrix glycoprotein, modulates tumor progression. We evaluated the functional roles of TNC, especially in perineural invasion of PDAC. METHODS: We examined immunohistochemical TNC expression in 78 resected PDAC specimens. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Interactions between cancer cells and nerves with TNC supplementation were investigated using an in vitro coculture model with PDAC cell line and mouse dorsal root ganglion (DRG). RESULTS: Tenascin C expression was predominant in perineural sites at the invasive tumor front. High perineural TNC expression in 30 patients (38%) was associated with perineural invasion, pathological T stage ≥3, and postoperative locoregional recurrence. High TNC expression was independently associated with postoperative, poor recurrence-free survival by multivariate analysis. In the in vitro coculture model, a TNC-rich matrix enhanced both PDAC cell colony extensions toward nerves and DRG axonal outgrowth toward cancer cell colonies, whereas TNC did not affect axonal outgrowth or cancer cell proliferation in separately cultured DRG and PDAC cells. CONCLUSIONS: Strong perineural TNC expression indicated poor prognosis with locoregional recurrence. The neurotropism of TNC-induced PDAC suggests that TNC is a potential PDAC therapeutic target.

[Simultaneous occurrence of an ampullary neuroendocrine tumor and multiple duodenal/jejunal gastrointestinal stromal tumors in a patient with neurofibromatosis type 1].

A 60-year-old female visited our hospital because of the identification of two duodenal tumors on upper gastrointestinal endoscopy performed for the investigation of anemia. The oral ampullary tumor was proven to be a neuroendocrine tumor (NET) on endoscopic biopsy. However, biopsy was not performed for the anal submucosal tumor (SMT) in the third duodenal portion because the tumor was included in the planned resection area. Multiple dermal soft tumors and café-au-lait spots were noted;her mother and daughter showed the same symptoms. The patient was diagnosed with neurofibromatosis type 1 (NF1). Laparotomy revealed more than 10 nodules at the serosal surface of the duodenum and proximal jejunum. Pancreaticoduodenectomy was performed with an additional 30-cm length of the jejunum that included most of the protruding tumors. Pathologically, the ampullary tumor and the other duodenal/jejunal SMTs were NET G2 and gastrointestinal stromal tumors (GISTs), respectively. Here, we report the rare case of simultaneous occurrence of an ampullary NET and multiple duodenal/jejunal GISTs in a patient with NF1.

Body weight loss after surgery affects the continuity of adjuvant chemotherapy for pancreatic cancer.

BACKGROUND: Postoperative chemotherapy is beneficial for many pancreatic cancer patients. However, some patients require dose reduction or the discontinuation of adjuvant chemotherapy because of adverse treatment-related effects. In this study, we aimed to evaluate two main outcomes. First, we evaluated the clinicopathological factors affecting patient disease-free survival (DFS) and overall survival (OS) following upfront surgery. Second, we evaluated the factors that influence the continuity of adjuvant chemotherapy. METHODS: Fifty-four patients with resected pancreatic cancer were enrolled. First, we evaluated the clinicopathological factors affecting postoperative survival using the Kaplan-Meier method and Cox regression method. Next, factors affecting the continuity of adjuvant chemotherapy were analyzed using multiple logistic regression analysis. RESULTS: Univariate and multivariate analyses revealed that positive LN metastasis (HR (95% CI) 6.329 (2.381-16.95); p < 0.001) and relative dose intensity (RDI) < 80% for adjuvant chemotherapy (HR (95% CI) 5.154 (1.761-15.15); p = 0.003) were independent predictive factors for DFS. Regarding OS, extended dissection of the nerve plexus around the superior mesenteric artery (SMA) (HR (95% CI) 4.504 (1.721-11.76); p = 0.002), positive microscopic surgical margin (HR (95% CI) 5.565 (1.724-17.96); p = 0.004), and adjuvant chemotherapy of RDI < 80% (HR (95% CI) 3.534 (1.135-2.667); p = 0.029) were also independent predictive factors. Moreover, the level of RDI significantly correlated with DFS and OS. Multiple logistic regression analysis revealed that low RDI was significantly associated with postoperative body weight loss (BWL) ≥ 10%. CONCLUSIONS: The following factors were significantly associated with poor survival: extended dissection of the nerve plexus around the SMA, lymph node metastasis, residual tumor, and RDI of the adjuvant chemotherapy. Patient's prognosis with adjuvant chemotherapy of RDI < 80% was worse. BWL ≥10% was the most important factor affecting the continuity of adjuvant chemotherapy. Perioperative nutritional intervention is necessary for patients who receive adjuvant chemotherapy for advanced pancreatic cancer.

Hepatic angiomyolipoma with early drainage veins into the hepatic and portal vein.

Hepatic angiomyolipoma (AML) is a rare stromal tumor composed of variable admixtures of thick-walled vessels, smooth muscles and adipose tissue. One of the specific radiological findings of hepatic AML is an early drainage vein noted via enhanced computed tomography (CT). We report a case of hepatic AML showing early drainage veins into both the hepatic and portal vein. The case involved a 46-year-old woman who was referred to our hospital because of a giant hepatic tumor. CT revealed well-enhanced 14 cm and 1 cm tumors in the left and right lobes, respectively. Magnetic resonance imaging demonstrated the existence of adipose tissues in the larger tumor. Hepatic arteriography revealed early drainage veins draining into both the hepatic and portal vein. Based on a diagnosis of hepatic AML, left hepatectomy and partial hepatectomy were performed. Pathology revealed both tumors as hepatic AML based on human melanoma black-45 immuno-positivity. Hepatic AML with early drainage veins into both the hepatic and portal vein is rare. The dilated and retrogressive vein drains the abundant arterial blood flow of the tumor. The finding of early drainage veins into not only the hepatic vein but also the portal vein should be helpful for diagnosing hepatic AMLs.