YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer.

Tumor-initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial-mesenchymal transition (EMT)-like signature marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis. Mechanistically, ROR1 induces the expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance PDAC proliferation. Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role for ROR1high cells as tumor-initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability.

Prognostic impact of the distance from the root of splenic artery to tumor in the patients with pancreatic body or tail cancer.

BACKGROUND: The impact of the distance from the root of splenic artery to tumor (DST) on the prognosis and optimal surgical procedures in the patients with pancreatic body/tail cancer has been unclear. METHODS: We retrospectively analyzed 94 patients who underwent distal pancreatectomy (DP) and 17 patients who underwent DP with celiac axis resection (DP-CAR) between 2008 and 2018. RESULTS: The 111 patients were assigned by DST length (in mm) as DST = 0: n = 14, 0

Molecular pathology of small cell lung cancer: Overview from studies on neuroendocrine differentiation regulated by ASCL1 and Notch signaling.

Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell-fate decisions, resulting in an NE to non-NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non-SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.

Controlled Release of Lysozyme Using Polyvinyl Alcohol-Based Polymeric Nanofibers Generated by Electrospinning.

Polymeric nanofibers generated via electrospinning offer a promising platform for drug delivery systems. This study examines the application of electrospun polyvinyl alcohol (PVA) nanofibers for controlled lysozyme (LZM) delivery. By using various PVA grades, such as the degree of polymerization/hydrolysis, this study investigates their influence on nanofiber morphology and drug-release characteristics. LZM-loaded PVA monolithic nanofibers having 50% drug content exhibit efficient entrapment, wherein rapid dissolution is achieved within 30 min. The initial burst of LZM from the nanofiber was reduced as the LZM content was lowered. The initial dissolution is greatly influenced by the choice of PVA grade used; fully hydrolyzed PVA nanofibers demonstrate controlled release due to the reduced water solubility of PVA. Furthermore, coaxial electrospinning, which creates core-shell nanofibers with polycaprolactone as a controlled release layer, enables sustained LZM release over an extended period. This study confirms a correlation between PVA characteristics and controlled drug release and provides valuable insights into tailoring nanofiber properties for pharmaceutical applications.

Dose difference between anisotropic analytical algorithm (AAA) and Acuros XB (AXB) caused by target's air content for volumetric modulated arc therapy of head and neck cancer.

Background: We clarified the dose difference between the anisotropic analytical algorithm (AAA) and Acuros XB (AXB) with increasing target's air content using a virtual phantom and clinical cases. Materials and methods: Whole neck volumetric modulated arc therapy (VMAT) plan was transferred into a virtual phantom with a cylindrical air structure at the center. The diameter of the air structure was changed from 0 to 6 cm, and the target's air content defined as the air/planning target volume (PTV) in percent (air/PTV) was varied. VMAT plans were recalculated by AAA and AXB with the same monitor unit (MU) and multi-leaf collimator (MLC) motions. The dose at each air/PTV (5%-30%) was compared between each algorithm with D98%, D95%, D50% and D2% for the PTV. In addition, MUs were also compared with the same MLC motions between the D95% prescription with AAA (AAA_D95%), AXB_D95%, and the prescription to 100% minus air/PTV (AXB_D100%-air/PTV) in clinical cases of head and neck (HNC). Results: When air/PTV increased (5-30%), the dose differences between AAA and AXB for D98%, D95%, D50% and D2% were 3.08-15.72%, 2.35-13.92%, 0.63-4.59%, and 0.14-6.44%, respectively. At clinical cases with air/PTV of 5.61% and 28.19%, compared to AAA_D95%, the MUs differences were, respectively, 2.03% and 6.74% for AXB_D95% and 1.80% and 0.50% for AXB_D100%-air/PTV. Conclusion: The dose difference between AAA and AXB increased as the target's air content increased, and AXB_D95% resulted in a dose escalation over AAA_D95% when the target's air content was ≥ 5%. The D100%-air/PTV of PTV using AXB was comparable to the D95% of PTV using AAA.

Overview and clinical significance of multiple mutations in individual genes in hepatocellular carcinoma.

BACKGROUND: Multiple mutation (MM) within a single gene has recently been reported as a mechanism involved in carcinogenesis. The present study investigated the clinical significance of MMs in hepatocellular carcinoma (HCC). METHODS: Two hundred twenty-three surgically resected HCCs were subjected to gene expression profiling and whole-exome sequencing. RESULTS: MMs in individual genes were detected in 178 samples (MM tumors: 79.8%). The remaining samples all carried a single mutation (SM tumors: 20.2%). Recurrence-free survival in the MM group was significantly worse in comparison to the SM group (P = 0.012). A Cox proportional hazard analysis revealed that MM tumor was an independent predictor for worse a prognosis (hazard ratio, 1.72; 95% confidence interval, 1.01-3.17; P = 0.045). MMs were frequently observed across in various genes, especially MUC16 (15% of samples had at least one mutation in the gene) and CTNNB1 (14%). Although the MUC16 mRNA expression of MUC16 wild-type and MUC16 SM tumors did not differ to a statistically significant extent, the expression in MUC16 MM tumors was significantly enhanced in comparison to MUC16 SM tumors (P < 0.001). In MUC16, MMs were associated with viral hepatitis, higher tumor marker levels and vascular invasion. The MUC16 MMs group showed significantly worse recurrence-free survival in comparison to the MUC16 SM group (P = 0.022), while no significant difference was observed between the MUC16 SM group and the MUC16 wild-type group (P = 0.324). CONCLUSIONS: MM was a relatively common event that may occur selectively in specific oncogenes and is involved in aggressive malignant behavior.

The clinical benefits of performing staging laparoscopy for pancreatic cancer treatment.

BACKGROUND: The indications and benefits derived from staging laparoscopy (SL) for pancreatic cancer (PC) remain controversial. METHODS: This study involved PC patients in whom resection had been considered possible between 2009 and 2020. We classified the patients into before 2014 (training set) and 2014 and later (validation set) groups, as SL was introduced in 2014, in our institution. In the training set, the predictors of non-curative factors were investigated, and reproducibility was confirmed in the validation set. In addition, the outcomes were compared between the datasets. RESULTS: A total of 802 patients were classified into the training set (n = 241) and validation set (n = 561). In the training set, pancreatic body or tail tumors (odds ratio [OR]: 2.62: P = 0.039), CA19-9 > 88 U/ml (OR: 3.21: P = 0.018) and a tumor diameter >36 mm (OR: 6.07; P < 0.001) were independent predictors of non-curative factors. The increased rate of non-curative factors was confirmed as the number of predictors increased in the validation set. The curative resection (CR) rate was significantly higher in the validation set than in the training set (P = 0.035). Although there was no significant difference in the OS in the not-resected group (P = 0.895), the OS in the CR and non-CR group was significantly better in the validation set than in the training set (CR, P < 0.001; non-CR, P < 0.001). CONCLUSION: The findings suggest potential candidates for SL and revealed improved outcomes by the advent of treatment strategies including SL.

Prognostic Impact of Indicators of Systemic Inflammation and the Nutritional Status of Patients with Resected Carcinoma of the Ampulla of Vater: A Single-Center Retrospective Study.

BACKGROUND: Several indicators of systemic inflammation and nutritional status were recently shown to serve as novel prognostic factors for certain cancers. Here, we aimed to investigate the prognostic impact of preoperative indicators of systemic inflammation and nutritional status associated with the survival of patients with resected ampulla of Vater carcinoma (AC). METHODS: We retrospectively analyzed the records of 91 patients who underwent pancreatoduodenectomy (PD) for AC from January 2002 through December 2018. Indices for systemic inflammation and nutritional status (Systemic immune-inflammation index [SII], Prognostic nutritional index [PNI], modified Glasgow prognostic score [mGPS], and Controlling nutritional status score [CONUT]) were determined using preoperative blood tests. Clinicopathological factors and these indices were analyzed to identify predictors of overall survival (OS). RESULTS: The median preoperative SII and PNI values were 456.7 and 47.5, respectively, and their optimal cut-off values were 670.0 and 50.0, respectively. Univariate analysis revealed that high SII, low PNI, mGPS ≥ 1, and malnutrition, assessed using the CONUT, were significant predictors of shorter OS. Multivariate analysis revealed that high SII (HR = 2.71, p = 0.023) and malnutrition assessed using the CONUT (hazard ratio = 3.98, p = 0.006) were independent predictors of shorter OS. CONCLUSION: SII and the CONUT predicted the survival of patients with AC after radical resection. These indicators are easily calculated using preoperative blood tests and may contribute to the development of improved strategies to treat AC.

Differences in the safety line of the future liver remnant plasma clearance rate of indocyanine green necessary to prevent post-hepatectomy liver failure associated with underlying diseases.

PURPOSE: To evaluate differences in the safety line of the future liver remnant plasma clearance rate of indocyanine green (RemK) necessary to prevent posthepatectomy liver failure (PHLF) associated with liver tumors and comorbidities. METHODS: The subjects of this retrospective study were patients who underwent trisectionectomy, hemihepatectomy, or sectionectomy, other than left lateral sectionectomy, between 2011 and 2018, at the Shizuoka Cancer Center. We analyzed the risk factors for PHLF grades B and C and then evaluated the RemK in these groups, according to various risk factors. RESULTS: A total of 463 patients were selected for the analyses. Among the patients with PHLF grades B and C, those with diabetes mellitus (DM), liver cirrhosis (LC), or hepatocellular carcinoma (HCC) had significantly higher RemK than those without these diseases. Multivariate analysis identified RemK ≤ 0.078, DM, and creatinine clearance rate < 60 mL/min as independent risk factors for PHLF grades B and C. CONCLUSIONS: Hepatectomy for patients with DM, HCC, or LC requires more functional hepatic reserve than that evaluated by RemK.

Dry Powder Inhalers for Proteins Using Cryo-Milled Electrospun Polyvinyl Alcohol Nanofiber Mats.

To enable the efficient delivery of drugs to the lungs, the drug particle design for most dry powder inhalers (DPIs) involves reducing the aerodynamic particle size to a few microns using methods such as spray-drying or jet-milling. Stresses, including heat and the shear forces generated by the preparation processes, may result in the degradation and denaturation of drugs such as those based on peptides and proteins. Here, we showed that cryo-milled polyvinyl alcohol nanofiber mats loaded with α-chymotrypsin by electrospinning exhibited suitable inhalation properties for use in DPIs, while maintaining enzymatic activity. The cryo-milled nanofiber mats were porous to fine particles, and the particle size and drug stability depended on the freezing and milling times. The median diameter of the milled fiber mats was 12.6 µm, whereas the mass median aerodynamic diameter was 5.9 µm. The milled nanofiber mats were successfully prepared, while retaining the enzymatic activity of α-chymotrypsin; furthermore, the activity of milled fiber mats that had been stored for 6 months was comparable to the activity of those that were freshly prepared. This novel method may be suitable for the DPI preparation of various drugs because it avoids the heating step during the DPI preparation process.

Histological pancreatic findings correlate with computed tomography attenuation and predict postoperative pancreatic fistula following pancreatoduodenectomy.

BACKGROUND: Although a soft pancreas is a widely-accepted reliable risk factor for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD), there is no established preoperative evaluation of pancreatic texture. METHODS: Two hundred thirty-seven patients who underwent PD with histological pancreatic assessment were retrospectively enrolled. The degree of fibrosis and fatty infiltration was scored histologically as seven grades and five grades, respectively. Computed tomography (CT) attenuation of the pancreas was measured on preoperative unenhanced CT images. Correlations between the CT attenuation of the pancreas and the histological pancreatic findings, and the development of POPF were analyzed. RESULTS: The fibrosis grade was significantly higher for hard pancreas than for soft pancreas (p < 0.001), whereas the fatty infiltration grade was similar between the two types (p = 0.161). CT attenuation of the pancreas was inversely correlated with both fibrosis grade (Spearman's rank correlation coefficient ([r] = -0.609, p < 0.001) and fatty infiltration grade (r = -0.382, p < 0.001). Multivariate analysis showed that body mass index ≥25 kg/m2 (odds ratio [OR]: 5.64, p < 0.001) and fibrosis grade ≤2 (OR: 18.0, p < 0.001) were independent risk factors for clinically significant POPF. CONCLUSION: Histological pancreatic texture can be evaluated with CT attenuation and might be helpful in preoperatively predicting the development of POPF after PD.

Portal vein thrombosis after right hepatectomy: impact of portal vein resection and morphological changes of the portal vein.

BACKGROUND: Right hepatectomy occasionally requires portal vein resection (PVR) and causes postoperative portal vein thrombosis (PVT). METHODS: A total of 247 patients who underwent right hepatectomy were evaluated using a three-dimensional analyzer to identify the morphologic changes in the portal vein (PV). The patients' characteristics were compared between the PVR group (n = 73) and non-PVR group (n = 174), and risk factors for PVT were investigated. The PVR group were subdivided into the wedge resection (WR) group (n = 38) and segmental resection (SR) group (n= 35). RESULTS: Postoperative PVT occurred in 20 patients (8.1%). Multivariate analyses in all patients revealed that postoperative left PV diameter/main PV diameter (L/M ratio) <0.56 (odds ratio [OR] 4.00, p = 0.009) and PVR (OR 3.31, p = 0.031) were significant risk factors for PVT. In 73 patients who underwent PVR, PVT occurred in 14 (19%) and WR (OR 11.5, p = 0.005) and L/M ratio <0.56 (OR 5.51, p = 0.016) were significant risk factors for PVT. CONCLUSION: PVR was one of the significant risk factors for PVT after right hepatectomy. SR rather than WR may be recommended for preventing PVT.

Reconsidering the Optimal Regional Lymph Node Station According to Tumor Location for Pancreatic Cancer.

BACKGROUND: A consensus regarding the optimal extent of lymph node dissection for pancreatic cancer has not yet been achieved. The purpose of this study was to evaluate the efficacy of lymph node dissection according to the location for pancreatic cancer. METHODS: A total of 495 patients diagnosed with invasive ductal carcinoma of the pancreas who had undergone a pancreatectomy between October 2002 and December 2015 were analyzed. The efficacy index (EI) was calculated for each lymph node station via multiplication of the frequency of metastasis to the station and the 5-year survival rate of the patients with metastasis to that station. RESULTS: For pancreatic head (Ph) tumors, mesocolon lymph nodes had a high EI, although not regional. For pancreatic body (Pb) tumors, peri-Ph lymph nodes had a high EI, although not regional. For pancreatic tail (Pt) tumors, lymph nodes along the celiac axis and common hepatic artery had a zero EI, although regional. When the Ph was segmented into the pancreatic neck (Ph-neck), uncinate process (Ph-up), and periampullary regions, hepatoduodenal ligament lymph nodes had a zero EI for Ph-up, although regional; the mesojejunum lymph node also had a zero EI, even for Ph-up, regardless of a high incidence of metastasis. Regarding lymph node recurrence after surgery, recurrence was most frequently found at the peri-Ph lymph node (12%) in patients with Pb tumors who had undergone a distal pancreatectomy. CONCLUSIONS: The optimal extent of lymph node dissection should be estimated in regard to the tumor location.

Clinical Significance of Preoperative Albumin-Bilirubin Grade in Pancreatic Cancer.

BACKGROUND: No study has clarified the clinical significance of albumin-bilirubin (ALBI) grade in a large cohort of pancreatic cancer patients. METHODS: A total of 1006 consecutive patients diagnosed with pancreatic cancer and deemed eligible for surgical resection were analyzed. The ALBI score was calculated as: ALBI score = (log10 bilirubin [µmol/L] × 0.66) + (albumin [g/L] × - 0.0852). ALBI grade was assigned as grade 1, 2a, 2b, and 3. ALBI grade 1 was assigned to the ALBI low group (N = 566), and grades 2a, 2b, and 3 to the ALBI high group (N = 440). RESULTS: The primary lesion could not be resected in 129 patients. Among all patients, overall survival (OS) was significantly worse in the ALBI high group than in the ALBI low group (P = 0.024). Overall, 877 patients underwent pancreatectomy. In these patients, the ALBI high group was associated with high CA19-9 level (P < 0.001), lower morbidity rate (P < 0.001), and pancreatic head tumor (P = 0.001). Patients' OS after resection was significantly worse in the ALBI high group than in the ALBI low group (P < 0.001). Cox proportional hazard analysis revealed ALBI grade as an independent predictor for prognosis (hazard ratio, 1.33; P = 0.015). Even in the CA19-9 negative patients, OS was significantly worse in the ALBI high group than in the ALBI low group (P = 0.046). CONCLUSIONS: The ALBI grade is a clinically useful predictor for prognosis in pancreatic cancer patients.

Clinical Implication of Node-negative Resectable Pancreatic Cancer.

BACKGROUND: Lymph node metastasis is one of the strongest prognostic factors of pancreatic cancer. However, the clinical implication of pathologically node-negative pancreatic cancer (pN0-PC) has not been fully investigated. METHODS: Patients who underwent surgical resection for radiologically resectable pancreatic cancer between 2002 and 2018 were included in this study. A clinicopathological examination focusing on pN0-PC was performed. RESULTS: Of all 533 patients, 155 (29.1%) were diagnosed with pN0-PC and 378 (70.9%) were diagnosed with node-positive pancreatic cancer (pN1/2-PC). The 5-year survival rates of patients with pN0-PC and pN1/2-PC were 57.1% and 25.0%, respectively (p < 0.001). A multivariate analysis revealed six prognostic factors in pN0-PC: age ≥ 70 years, nonadministration of adjuvant chemotherapy, anterior serosal invasion, nerve plexus invasion, and microscopic lymphatic and venous invasions. The 5-year survival rates of patients who had pN0-PC with 0-1 risk factor, with 2-3 risk factors, and with 4-6 risk factors were 87.6%, 47.9%, and 16.4%, respectively. Survival of patients who had pN0-PC with 4-6 risk factors was comparable to that of pN1/2 patients. The diagnostic capability of metastasis-negative lymph node was unsatisfactory, with a predictive value of < 43%. CONCLUSIONS: Although the prognosis of patients with pN0-PC was better than that of patients with pN1/2-PC, it is not satisfactory. Survival of patients who had pN0-PC with 0-1 risk factors was extremely favorable; however, survival of patients who had pN0-PC with 4-6 risk factors was similar to those with pN1/2-PC.

Predictive factors of survival in patients with borderline resectable pancreatic cancer who received neoadjuvant therapy.

BACKGROUND/OBJECTIVES: This study aimed to develop the prognostic score (PS) based on clinical factors to stratify the prognosis in borderline resectable pancreatic cancer (BRPC) patients treated with neoadjuvant therapy (NAT). METHODS: This retrospective study included 57 BRPC patients who received NAT between April 2012 and December 2017. A score was assigned to each prognostic factor available before and after NAT, according to their ß coefficients. RESULTS: Multivariate analysis identified the following six prognostic factors, and scores were assigned as follows: being a familial PC patient (HR 4.98, p = 0.029), post-NAT CA19-9 ≥37 U/ml (HR 3.08, p = 0.020), reduction rate of CA19-9 <70% (HR 3.71, p = 0.008), pre-NAT neutrophil-to-lymphocyte ratio ≥2.8 (HR 4.32, p = 0.003), and non-resection (HR 3.98, p = 0.009) were scored as 1; and post-NAT albumin-to-globulin ratio <1.33 (HR 8.31, p < 0.001) was scored as 2. The PS was calculated by summing the scores assigned to each prognostic factor. Patients were then classified into three risk groups (low- [0-1 points], moderate- [2-3 points], and high-risk [4-6 points] groups). Median overall survival in the low-, moderate-, and high-risk groups were not reached, 37.5 months, and 11.8 months, respectively, and there were significant differences in survival among the three groups (p < 0.01 in each group). CONCLUSIONS: This study showed that the PS may be useful for predicting the prognosis of BRPC patients treated with NAT.

The Prognostic Relevance of the Number and Location of Positive Lymph Nodes for Ampulla of Vater Carcinoma.

BACKGROUND: Lymph node metastasis (LNM) has been regarded as one of the prognostic factors in patients with ampulla of Vater carcinoma (AC). However, the consensus about an optimal cutoff value of the number of LNMs and the definition of the regional lymph nodes (RLNs) has not been achieved. METHODS: This study included 114 consecutive patients who underwent pancreatoduodenectomy for AC between January 2002 and March 2019. RESULTS: The minimum p value approach for the greatest difference in the overall survival classified the number of LNM into none (N0, n = 66), from 1 to 2 (N1, n = 32), and ≥3 LNM (N2, n = 11) (p = 0.004). Distant LNM was defined as M1 (n = 5). Significant differences in relapse-free survival (RFS) were found between N0 and N1 (p < 0.001), N1 and N2 (p = 0.047), and N1 and M1 (p = 0.044) but not between N2 and M1 (p = 0.683). Moreover, the patients with regional LNM were classified into two groups: Np group (n = 35, LNM only in pancreatic head region) and Nd group (n = 8, LNM in other regional location). Significant differences in the RFS were found between N0 and Np (p < 0.001), Np and Nd (p = 0.004), and Np and M1 (p = 0.033) but not between Nd and M1 (p = 0.883). A Cox proportional hazards analysis for RFS revealed that ≥ 3 LNMs (hazards ratio [HR], 3.22) and LNM except for pancreatic head region (HR, 4.27) were individually independent worse prognostic factors. CONCLUSIONS: ≥3 LNMs and regional LNM except for pancreatic head region were associated with poor prognosis comparable to that of the patients with M1.

Description of the Vascular Anatomy of Livers with Absence of the Portal Bifurcation.

BACKGROUND: The absence of the portal bifurcation (APB) is a rare anatomic variation, in which the horizontal part of the left portal vein (PV) is missing. The aim of this study was to identify the vascular architecture in livers with APB. METHODS: Computed tomography data for 17,651 patients were reviewed; five patients (0.03%) were found to present with APB. The liver volume and anatomy of APB patients were compared with those of 30 patients with normal livers. RESULTS: All the APB patients exhibited an independent posterior branch of the PV. The intrahepatic left PV (LPV) ran through either the ventral (n = 2, 40%) or dorsal side (n = 3, 60%) of the middle hepatic vein. The frequency of medial branches diverging from the LPV was higher in patients with APB than in normal patients (p < 0.001). The left hepatic duct (LHD) ran through the inside of the left lobe along the left PV in 40% of the patients with APB, whereas in the remaining 60% of the patients with APB, the LHD ran on the outside of the liver separately from the left PV and joined the right hepatic duct. The liver volume of the left lateral section was significantly smaller (p = 0.014), and the posterior section was significantly larger (p = 0.014) in patients with APB than in patients with normal livers. CONCLUSION: The unique anatomical characteristics and the positional relation of the vessels should be considered preoperatively in patients with APB.

Prognostic Impact of Paraaortic Lymph Node Metastasis in Extrahepatic Cholangiocarcinoma.

BACKGROUND: Surgical resection in patients with extrahepatic cholangiocarcinoma (EHCC) with paraaortic lymph node metastasis (PALNM) remains controversial. The objective of this study was to investigate the prognostic impact of PALNM in resected EHCC. METHODS: The present retrospective study included 410 patients, including 16 patients with PALNM, who underwent surgical resection of EHCC between September 2002 and December 2018. These were compared to 9 patients in whom EHCC was not resected due to PALNM. The clinicopathological features and survival outcomes were investigated to identify the prognostic factors in resected EHCC. RESULTS: The overall survival in the resected patients with PALNM was significantly better than that in unresected patients (median survival time [MST] 33.7 vs. 16.7 months, p=0.009) and was not significantly worse than that of patients with regional lymph node metastasis (LNM) (MST 33.7 vs 36.0 months, p=0.278). The multivariate analysis identified age > 70 years, male sex, tumor location (perihilar), residual tumor status, histological grade, microscopic venous invasion, and regional LNM as independent prognostic factors. CONCLUSIONS: There was no significant difference in survival between the resected patients with PALNM and patients with regional LNM, and PALNM was not a significant prognostic factor in the multivariate analysis. Surgical resection may be considered an acceptable approach for EHCC with PALNM in selected patients.

INSM1 immunostaining in solid papillary carcinoma of the breast.

Solid papillary carcinoma (SPC) is a histological subtype of breast carcinomas. At least 50% of SPC show neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a transcription factor now employed as a useful neuroendocrine marker. It is suppressed by the Notch signaling pathway in other neuroendocrine tumors. However, the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC of the breast currently remain unclear. To clarify the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC, we performed immunohistochemistry using 19 tissue specimens of SPC of the breast. We complementarily analyzed public RNA sequencing data on breast carcinomas. Immunohistochemical examinations revealed that the staining intensity of INSM1 was significantly higher in the neuroendocrine group than in the non-neuroendocrine group. Positive correlations were observed between INSM1 and synaptophysin (SYP), or chromogranin-A (CHGA). In all cases, NOTCH 2 and 3 were positive, while NOTCH 1 and 4 were negative. According to public RNA data analyses, there were positive correlations between INSM1 and SYP, or CHGA, and negative correlations between INSM1 and NOTCH1-3. INSM1 is useful as a diagnostic marker for SPC with neuroendocrine differentiation in the breast.