Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

Chemotherapy-induced neutropenia as a prognostic factor in patients with pancreatic cancer treated with gemcitabine plus nab-paclitaxel: a retrospective cohort study.

OBJECTIVES: Chemotherapy-induced neutropenia (CIN) is a common adverse event of chemotherapy. Several reports have suggested that CIN could be an important prognostic factor in chemotherapy of various cancers. However, whether CIN is a prognostic factor in unresectable pancreatic cancer (PC) treated with gemcitabine plus nab-paclitaxel (GnP) is unknown. The primary endpoint of this study was to compare overall survival (OS) between patients with severe CIN (grade ≥ 3) and those with absent/mild CIN (grade ≤ 2) in unresectable PC cases treated with GnP as first-line chemotherapy. METHODS: A retrospective, cohort study was conducted using data from a computerized database. A total of 290 patients with pathologically confirmed PC treated with GnP as first-line chemotherapy were analyzed (severe CIN: ≥ grade 3, n = 174; absent/mild CIN: ≤ grade 2, n = 116). RESULTS: The median OS was longer in the severe CIN group than in the absent/mild CIN group (19.2 months vs 11.3 months, respectively; P < 0.001). After adjustment, severe CIN was an independent predictive factor for OS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.38-0.74; P < 0.001). After adjustment by time-varying covariates, severe CIN was still a significant prognostic factor for OS (HR, 0.79; 95% CI 0.69-0.91, P = 0.001). CONCLUSION: The present results show that severe CIN is an independent and useful prognostic factor in PC patients treated with GnP.

Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer.

BACKGROUND: Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. METHODS: We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. RESULTS: GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice. CONCLUSIONS: GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.

Gallbladder cancer harboring ERBB2 mutation on the primary and metastatic site: A case report.

BACKGROUND: Bile duct cancer constitutes gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICA), and extrahepatic cholangiocarcinoma (ECA). These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC, which sometimes becomes a point of discussion in clinical practice. Although these cancers demonstrate significant differences in their mutational landscape, several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers. CASE SUMMARY: We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2 (ERBB2) activating mutation on next-generation sequencing (NGS)-based genomic testing. One year later, a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis. The histological findings of the hepatic lesion were similar to those of the primary lesion. Additionally, using NGS panel testing, the hepatic lesion was found to have ERBB2 activating mutation, which is the identical mutation detected in the sequencing result of the primary site. ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA. Therefore, in the present case, we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence. Additionally, this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit. CONCLUSION: This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.

Nivolumab-induced interstitial lung disease in a patient with gastric cancer.

We herein report a case of nivolumab-induced interstitial lung disease in a patient with gastric cancer. Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of programmed death-1. A 69-year-old woman with metastatic gastric cancer being treated with nivolumab as fifth-line therapy developed interstitial pneumonia 27 months after starting treatment with nivolumab. Chest computed tomography demonstrated a cryptogenic organizing pneumonia pattern in both lung lobes. This was thought as an immune-related adverse event (irAEs), but stopping the administration of nivolumab failed to resolve the presence of lung shadows. Treatment with steroid pulse therapy twice and subsequently with prednisolone gradually improved the pulmonary function. The administration of high-dose corticosteroid is recommended after the diagnosis of irAEs in nivolumab treatment. Since recovering from pulmonary dysfunction, the patient remains alive with no disease progression. The immediate diagnosis and treatment of irAEs are crucial for achieving a good outcome.

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-ß1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-ß/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-ß/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-ß1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-ß1 exposure. Invasion increased with TGF-ß1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-ß1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-ß signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

[A Case of Hepatocellular Carcinoma with Right Atrium Tumor Thrombus and Multiple Intrahepatic Metastases That Remarkably Responded to Combination Therapy Including Surgery].

The prognosis for hepatocellular carcinoma(HCC)with right atrium tumor thrombus(RATT)is dismal and necessary to be treated on as oncologic emergency. We report a case of HCC with RATT which was treated with multidisciplinary therapy including surgery. After repeated transarterial chemoembolization(TACE)and radiofrequency ablation(RFA), a 71-year-old man consulted to our hospital with multiple HCC, lung metastasis, and RATT. Left hemihepatectomy, thrombectomy of RATT, and 3 months of hepatic arterial infusion chemotherapy(HAIC)was performed, and intrahepatic HCCs were controlled. However, during treatment of lung metastasis by sorafenib, the patient died of brain metastasis, 3 years after the first treatment. Although surgery and HAIC may give a chance of further treatment by control of intrahepatic HCCs, stronger regimen for systemic HCC would be necessary.

Expression of carbonic anhydrase IX is associated with poor prognosis through regulation of the epithelial­mesenchymal transition in hepatocellular carcinoma.

Carbonic anhydrase 9 (CA9) is a plasma membrane-associated isoenzyme that catalyzes pH regulation under hypoxic conditions. CA9 is transcriptionally regulated by hypoxia-inducible factor 1. Recent studies reported that hypoxia also promoted the epithelial-mesenchymal transition (EMT) in various cancers. In the present study, we evaluated the relationship between CA9 expression and EMT in vitro with two hepatoma cell lines. We also examined the clinical significance of CA9 expression in 117 consecutive patients that underwent hepatectomies for hepatocellular carcinoma (HCC). We evaluated CA9 expression and EMT induction under hypoxia with quantitative RT-PCR, western blot analysis and immunofluorescence staining, in HuH7 and HepG2 cells. We knocked down CA9 expression with small interfering RNA to evaluate the relationship between CA9 and EMT. We found that hypoxia induced CA9 expression in HCC cells and promoted EMT, evidenced by a loss of E-cadherin and an increase in N-cadherin. Twist, a transcriptional regulator of EMT, was also upregulated with hypoxia. The CA9 deficiency attenuated hypoxia-induced changes in E-cadherin and N-cadherin. Immunohistochemical evaluations of patient samples showed that CA9 was expressed in 50.4% of patients (59/117). However, patients with and without CA9 expression were not significantly different in clinicopathological factors. Nevertheless, a multivariate analysis showed that CA9 expression was an independent factor for both recurrence and prognosis among patients that underwent curative surgery for HCC. In conclusion, this study revealed that CA9 expression was a pivotal predictive factor for poor prognosis after radical surgery for HCC. Moreover, the CA9 regulation of the expression of EMT-related molecules represented a mechanism that enhanced malignant potential.

[A Case of Small Intestinal Cancer Repeating an Ileus Symptom Complicated with Refractory Arrhythmia].

A 56-year-old man had been treated for hypertrophic cardiomyopathy since childhood. He had been treated for refractory ventricular tachycardia (VT) with interventricular septum cauterization, catheter ablation, and implantation of a defibrillator. He had been treated at home for several years. The ileus that developed in July 2014 was relieved by conservative medical treatment once, but it recurred after oral intake of food a short time later. The obstruction was due to a small intestine cancer that was diagnosed by enteroscopy. After considering the risks of surgery due to the cardiac problem and the quality of life due to ileus caused by the mass, we resected it. This surgery was not a radical resection because of peritoneal dissemination. He started oral food intake postoperatively, and returned to home care. Three months after surgery, oral chemotherapy was administered after considering his stable cardiac function in addition to his coherent mental status. An adverse event of severe watery diarrhea developed, and VT caused by dehydration occurred. After the chemotherapy was discontinued, he recovered in intensive care. He returned to home care at his prior status for 9 months postoperatively.

[A case of resection of pancreatic head lymph node metastasis of rectal carcinoid].

An 80-year-old woman was treated with low anterior resection and D3 lymph node dissection for rectal carcinoid in August 2007. Pathological diagnosis was a tumor 23 × 22 mm in size with muscularis propria invasion, ly1, v0, n1 (No. 251[1/12]). Partial hepatectomy was performed for liver metastasis in March 2010 and September 2011. In June 2013, an isolated tumor of 17 mm in diameter was detected between the inferior vena cava and the stomach using abdominal ultrasonography. The tumor was diagnosed as pancreatic head lymph node metastasis using abdominal enhanced computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), and positron emission tomography (PET); fluorodeoxyglucose (FDG) uptake was noted at the site of the tumor, but not at other parts of the body. Curative resection was the chosen treatment option. Open surgery was performed in September 2013, and a tumor 30 mm in diameter located at the ventral side of the inferior vena cava, lateral side of the portal vein, and cranial side of duodenum was resected. No surrounding tissue infiltration was found. Pathological analysis of the resected specimen indicated lymph node metastasis of the rectal carcinoid. The patient has been disease free for 9 months after surgery.

Application of modified integration rule to time-domain finite-element acoustic simulation of rooms.

The applicability of the modified integration rule for time-domain finite-element analysis is tested in sound field analysis of rooms involving rectangular elements, distorted elements, and finite impedance boundary conditions. Dispersion error analysis in three dimensions is conducted to evaluate the dispersion error in time-domain finite-element analysis using eight-node hexahedral elements. The results of analysis confirmed that fourth-order accuracy with respect to dispersion error is obtainable using the Fox-Goodwin method (FG) with a modified integration rule, even for rectangular elements. The stability condition in three-dimensional analysis using the modified integration rule is also presented. Numerical experiments demonstrate that FG with a modified integration rule performs much better than FG with the conventional integration rule for problems with rectangular elements, distorted elements, and with finite impedance boundary conditions. Further, as another advantage, numerical results revealed that the use of modified integration rule engenders faster convergence of the iterative solver than a conventional rule for problems with the same degrees of freedom.

Ensemble averaged surface normal impedance of material using an in-situ technique: preliminary study using boundary element method.

An in-situ measurement technique of a material surface normal impedance is proposed. It includes a concept of "ensemble averaged" surface normal impedance that extends the usage of obtained values to various applications such as architectural acoustics and computational simulations, especially those based on the wave theory. The measurement technique itself is a refinement of a method using a two-microphone technique and environmental anonymous noise, or diffused ambient noise, as proposed by Takahashi et al. [Appl. Acoust. 66, 845-865 (2005)]. Measured impedance can be regarded as time-space averaged normal impedance at the material surface. As a preliminary study using numerical simulations based on the boundary element method, normal incidence and random incidence measurements are compared numerically: results clarify that ensemble averaging is an effective mode of measuring sound absorption characteristics of materials with practical sizes in the lower frequency range of 100-1000 Hz, as confirmed by practical measurements.