Association between BRCA Gene Variants and the Response to Modified FOLFIRINOX in Patients with Unresectable Pancreatic Cancer

We investigated the effect of modified FOLFIRINOX (mFFX) in unresectable pancreatic cancer by retrospectively analyzing the cases of 43 patients who underwent BRCA testing (germline, n=11; somatic, n=26; both germline and somatic, n=6). The association between BRCA mutations and therapeutic effect was clarified. Six patients tested positive for germline pathogenic variants. Familial pancreatic cancer (33% vs. 3%, p=0.006) and peritoneal disseminated lesions (66% vs. 8%, p<0.001) were significantly more common in patients with germline pathogenic variants. The partial response (PR) rate was 100% in the germline BRCA-positive patients, and 27% in the germline BRCA-negative patients (p<0.001). The median progression-free survival (PFS) was not reached for any germline BRCA-positive patients but was 9.0 months for the germline BRCA-negative patients (p=0.042). Patients with stage IV BRCA-associated pancreatic cancer had better overall survival than those with non-BRCA-associated pancreatic cancer, although the difference was nonsignificant (not reached vs. 655 days, p=0.061). Our results demonstrate that a PR and prolonged PFS can be expected in germline BRCA-positive patients after treatment with mFFX. Our findings also suggest that germline BRCA pathogenic variants may be useful as biomarkers for the therapeutic effect of mFFX in patients with pancreatic cancer

Mao-to Prolongs the Survival of and Reduces TNF-α Expression in Mice with Viral Myocarditis

Goal of this study was to evaluate effects of Mao-to on development of myocarditis induced by encephalomyocarditis (EMC) virus in mice. Mice were randomly divided into five groups. Group N included uninfected controls (n = 18), while group A, B and C underwent intraperitoneal injection of EMC virus. Group A was administered oral saline from day 0 to day 4. Group B was administered oral Mao-to (500 mg−1 kg−1 day−1) from day 0 to day 4. Group C was administered Mao-to from day 2 to day 6. Group D was administered Mao-to from day 5 to day 10. Treated mice were followed for survival rates during 2 weeks after infection. Body weight (BW) and organ weights including heart (HW), lungs, thymus and spleen were examined on days 4, 6 and 14. Survival rate of group C (36.4%) was significantly improved compared with group A, B or D (0% of each, P < 0.05). HW and HW/BW ratio in group C was significantly (P < 0.05) lower than those in group A, B or D. Viral titers of hearts were significantly different among groups A, B and C. Cardiac expression in tumor necrosis factor-α (TNF-α) was significantly reduced in group C in comparison with group A, B or D on day 6 by immunohistochemical study. Administration of Mao-to starting on day 2 improves mortality resulting from viral myocarditis in mice with reduced expression of cardiac TNF-α. These findings suggest that timing of Mao-to is crucial for preventing cardiac damage in mice with viral myocarditis

Liquid biopsy for patients with IBD-associated neoplasia

Background It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. Methods Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. Results Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. Conclusion Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia

シンコウセイ ドウミャク コウカセイ ビョウヘン ニ タイシ ショウサイナ ビョウリ ソシキガクテキ ケントウ オ オコナイ エタ コウLp（a） ケッショウ ガッペイ 2ガタ トウニョウビョウ ノ 1レイ

We report a case of type 2 diabetes mellitus showing elevated plasma lipoprotein（a）［Lp（a）］levels with various atherosclerotic lesions. A 54-year-old woman diagnosed as having type 2 diabeteswas treated with oral antidiabetic drugs. She had various atherosclerotic lesions, includingcerebral infarction, occlusion of the middle carotid artery and myocardial infarction, along withdiabetes mellitus, hyperlipemia and hypertension and additionally showed a high level of serum Lp（a）. A high plasma level of Lp（a）is considered to be an independent risk factor for atherosclerosis,and it is associated with the development of cerebral infarction, occlusion of the middlecarotid artery and coronary atherosclerosis. Plasma Lp（a）level is predominantly determined bygenetic factors and is not affected by diet or drugs. Aspirin treatment（100 mg/day）lowered theplasma level of Lp（a）by 60%. Pathological findings of the vascular lesions showed that apolipoprotein（a）［apo（a）］, a major apoprotein component of Lp（a）, was deposited in the tunica media ofthe radial artery with rare atherosclerotic lesions and in the inner rim of the fibrous capsular regionwithin the plaque with a large lipid core of the carotid artery. This suggests that Lp（a）stimulatesthe transformation of vascular smooth muscle cells in the tunica media in the early stage of atherosclerosisand that it is associated with fragility of the atherosclerotic lesion in the progressive stage.Hence, plasma Lp（a）levels should be measured for diabetic patients with various atheroscleroticlesions, and aspirin may need to be given to those who have elevated plasma Lp（a）levels in orderto prevent the development of atherosclerotic complications

Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA

Background and Aim Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. Methods Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. Results Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were −124bp G > A and 10 were −146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des‐gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P Conclusions TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC

Relativistic Expansion of Magnetic Loops at the Self-similar Stage II: Magnetized outflows interacting with the ambient plasma

We obtained self-similar solutions of relativistically expanding magnetic loops by assuming axisymmetry and a purely radial flow. The stellar rotation and the magnetic fields in the ambient plasma are neglected. We include the Newtonian gravity of the central star. These solutions are extended from those in our previous work (Takahashi, Asano, & Matsumoto 2009) by taking into account discontinuities such as the contact discontinuity and the shock. The global plasma flow consists of three regions, the outflowing region, the post shocked region, and the ambient plasma. They are divided by two discontinuities. The solutions are characterized by the radial velocity, which plays a role of the self-similar parameter in our solutions. The shock Lorentz factor gradually increases with radius. It can be approximately represented by the power of radius with the power law index of 0.25. We also carried out magnetohydrodynamic simulations of the evolution of magnetic loops to study the stability and the generality of our analytical solutions. We used the analytical solutions as the initial condition and the inner boundary conditions. We confirmed that our solutions are stable over the simulation time and that numerical results nicely recover the analytical solutions. We then carried out numerical simulations to study the generality of our solutions by changing the power law index \delta of the ambient plasma density \rho_0 \propto r^{-\delta}. We alter the power law index \delta from 3.5 in the analytical solutions. The analytical solutions are used as the initial conditions inside the shock in all simulations. We observed that the shock Lorentz factor increases with time when \delta is larger than 3, while it decreases with time when \delta is smaller than 3. The shock Lorentz factor is proportional to t^{(\delta-3)/2}. These results are consistent with the analytical studies by Shapiro (1979).Comment: 19 pages, 13 figures, Accepted for publication in MNRA

Gastric linitis plastica with autoimmune pancreatitis diagnosed by an endoscopic ultrasonography-guided fine-needle biopsy: A case report

BACKGROUND Gastric linitis plastica (GLP) is a subset of gastric cancer with a poor prognosis. It is difficult to obtain a definitive diagnosis by endoscopic mucosal biopsies, and the usefulness of an endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) for GLP has been recently reported. Meanwhile, autoimmune diseases are occasionally known to coexist with malignant tumors as paraneoplastic syndrome. We herein report the usefulness of an EUS-FNB for detecting GLP and the possibility of paraneoplastic syndrome coexisting with GLP. CASE SUMMARY An 81-year-old man was admitted to our hospital for a 1-mo history of epigastric pain that increased after eating. His laboratory data revealed high levels of serum carbohydrate antigen 19-9 and immunoglobulin-G4. Endoscopic examinations showed giant gastric folds and reddish mucosa; however, no epithelial changes were observed. The gastric lumen was not distensible by air inflation, suggesting GLP. Computed tomography showed the thickened gastric wall, the diffuse enlargement of the pancreas, and the peripancreatic rim, which suggested autoimmune pancreatitis (AIP) coexisting with GLP. Because the pathological findings of the endoscopic biopsy showed no malignancy, he underwent an EUS-FNB and was diagnosed with GLP. He received chemotherapy for unresectable gastric cancer due to peritoneal metastasis, after which both the gastric wall thickening and diffuse enlargement of the pancreas were improved. CONCLUSION An EUS-FNB for GLP with a negative endoscopic biopsy is useful, and AIP may develop as a paraneoplastic syndrome

Optimal liver drainage rate for survival in patients with unresectable malignant hilar biliary obstruction using 3D-image volume analyzer

Background: Drainage exceeding 50% of total liver volume is a beneficial prognostic factor in patients with unresectable malignant hilar biliary obstruction (UMHBO). However, it is unclear what threshold percentage of total liver volume drained ('liver drainage rate') significantly improves survival in patients with UMHBO who received systemic chemotherapy. Objectives: We aimed to assess the optimal liver drainage rate that improves survival in patients with UMHBO receiving chemotherapy using a three-dimensional (3D)-image volume analyzer. Design: This study was a single-center retrospective cohort study. Methods: Data from 90 patients with UMHBO who received chemotherapy after endoscopic biliary drainage using metal stents at Okayama University Hospital from January 2003 to December 2020 were reviewed. The liver drainage rate was calculated by dividing the drained liver volume by the total liver volume using a 3D-image volume analyzer. The primary endpoint was overall survival by liver drainage rate. The secondary endpoints were time to recurrent biliary obstruction (TRBO) and prognostic factors. Results: The median total liver volume was 1172 (range: 673-2032) mL, and the median liver drainage rate was 83% (range: 50-100). Overall survival was 376 (95% CI: 271-450) days, and patients with >80% drainage (n = 67) had significantly longer survival than those with 80% liver drainage [hazard ratio (HR): 0.35, 95% CI: 0.20-0.62, p = 0.0003] and hilar cholangiocarcinoma (HR: 0.30, 95% CI: 0.17-0.50, p Conclusion: In patients with UMHBO scheduled for chemotherapy, >80% drainage is associated with improved survival. Further prospective multicenter studies are needed to verify the results of this study