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Ankylosing spondylitis (AS), primary sclerosing cholangitis (PSC), and autoimmune pancreatitis (AIP) are known as extraintestinal manifestations (EIMs) of ulcerative colitis (UC). A 74-year-old Japanese man visited our hospital because of white stool. He had been diagnosed with AS when he was 30 years old, and he was HLA-B27-positive. Based on various examination results, it was suspected that AIP had caused bile duct stricture. During the clinical course, he was diagnosed with UC and PSC. Then, AIP was diagnosed because he had localized pancreatic enlargement, irregular stenosis of the main pancreatic duct, PSC, and no tumor cells of pancreas. A patient with all four of these diseases, AS, AIP, PSC, and UC, is very rare. Therefore, we report a quite rare case with three EIMs (AS, PSC, and AIP) of UC., (© 2024. Japanese Society of Gastroenterology.)

We searched for antideuterons (d[over ¯]'s) in the 4.7×10^{9} cosmic-ray events observed during the BESS-Polar II flight at solar minimum in 2007-2008 but found no candidates. The resulting 95% C.L. upper limit on the d[over ¯] flux is 6.7×10^{-5}  (m^{2} s sr GeV/n)^{-1} in an energy range from 0.163 to 1.100  GeV/n. The result has improved by more than a factor of 14 from the upper limit of BESS97, which had a potential comparable to that of BESS-Polar II in the search for cosmic-origin d[over ¯]'s and was conducted during the former solar minimum. The upper limit of d[over ¯] flux from BESS-Polar II is the first result achieving the sensitivity to constrain the latest theoretical predictions.

A 59-year-old man presented to our hospital with a chief complaint of epigastric pain. Pertinent history included a distal gastrectomy for gastric cancer and alcohol dependence. He underwent contrast-enhanced computed tomography (CT) and esophagogastroduodenoscopy, which led to a diagnosis of esophageal cancer (cT2N2M1, stage IVb). Subsequently, he underwent chemotherapy using 5-fluorouracil and cis-diamminedichloroplatinum and radiotherapy. A total of 44 days after treatment initiation, the patient experienced nausea and hepatobiliary enzyme elevation. CT and abdominal ultrasonography were performed, and he was diagnosed with an abdominal aortic thrombus. Intravenous heparin was administered as an anticoagulant therapy. Twenty-two days after treatment initiation, the thrombus was no longer visible on abdominal ultrasonography. The patient was then treated with warfarin. It cannot be ruled out that the patient's hepatobiliary enzyme elevation was induced by the anticancer drugs. However, enzyme elevation improved with the disappearance of the abdominal aortic thrombus, suggesting that the aortic thrombus may have contributed to the hepatobiliary enzyme elevation. No thrombus recurrence was observed until the patient's death after an initial treatment with antithrombotic agents. This case indicates that malignant tumors and chemotherapy can cause aortic thrombi, and thus, care should be exercised in monitoring this potential complication.

Detailed measurements of the spectral structure of cosmic-ray electrons and positrons from 10.6 GeV to 7.5 TeV are presented from over 7 years of observations with the CALorimetric Electron Telescope (CALET) on the International Space Station. The instrument, consisting of a charge detector, an imaging calorimeter, and a total absorption calorimeter with a total depth of 30 radiation lengths at normal incidence and a fine shower imaging capability, is optimized to measure the all-electron spectrum well into the TeV region. Because of the excellent energy resolution (a few percent above 10 GeV) and the outstanding e/p separation (10^{5}), CALET provides optimal performance for a detailed search of structures in the energy spectrum. The analysis uses data up to the end of 2022, and the statistics of observed electron candidates has increased more than 3 times since the last publication in 2018. By adopting an updated boosted decision tree analysis, a sufficient proton rejection power up to 7.5 TeV is achieved, with a residual proton contamination less than 10%. The observed energy spectrum becomes gradually harder in the lower energy region from around 30 GeV, consistently with AMS-02, but from 300 to 600 GeV it is considerably softer than the spectra measured by DAMPE and Fermi-LAT. At high energies, the spectrum presents a sharp break around 1 TeV, with a spectral index change from -3.15 to -3.91, and a broken power law fitting the data in the energy range from 30 GeV to 4.8 TeV better than a single power law with 6.9 sigma significance, which is compatible with the DAMPE results. The break is consistent with the expected effects of radiation loss during the propagation from distant sources (except the highest energy bin). We have fitted the spectrum with a model consistent with the positron flux measured by AMS-02 below 1 TeV and interpreted the electron+positron spectrum with possible contributions from pulsars and nearby sources. Above 4.8 TeV, a possible contribution from known nearby supernova remnants, including Vela, is addressed by an event-by-event analysis providing a higher proton-rejection power than a purely statistical analysis.

We present the observation of a charge-sign dependent solar modulation of galactic cosmic rays (GCRs) with the Calorimetric Electron Telescope onboard the International Space Station over 6 yr, corresponding to the positive polarity of the solar magnetic field. The observed variation of proton count rate is consistent with the neutron monitor count rate, validating our methods for determining the proton count rate. It is observed by the Calorimetric Electron Telescope that both GCR electron and proton count rates at the same average rigidity vary in anticorrelation with the tilt angle of the heliospheric current sheet, while the amplitude of the variation is significantly larger in the electron count rate than in the proton count rate. We show that this observed charge-sign dependence is reproduced by a numerical "drift model" of the GCR transport in the heliosphere. This is a clear signature of the drift effect on the long-term solar modulation observed with a single detector.

We present the results of a direct measurement of the cosmic-ray helium spectrum with the CALET instrument in operation on the International Space Station since 2015. The observation period covered by this analysis spans from October 13, 2015, to April 30, 2022 (2392 days). The very wide dynamic range of CALET allowed for the collection of helium data over a large energy interval, from ∼40  GeV to ∼250  TeV, for the first time with a single instrument in low Earth orbit. The measured spectrum shows evidence of a deviation of the flux from a single power law by more than 8σ with a progressive spectral hardening from a few hundred GeV to a few tens of TeV. This result is consistent with the data reported by space instruments including PAMELA, AMS-02, and DAMPE and balloon instruments including CREAM. At higher energy we report the onset of a softening of the helium spectrum around 30 TeV (total kinetic energy). Though affected by large uncertainties in the highest energy bins, the observation of a flux reduction turns out to be consistent with the most recent results of DAMPE. A double broken power law is found to fit simultaneously both spectral features: the hardening (at lower energy) and the softening (at higher energy). A measurement of the proton to helium flux ratio in the energy range from 60  GeV/n to about 60  TeV/n is also presented, using the CALET proton flux recently updated with higher statistics.

We present the measurement of the energy dependence of the boron flux in cosmic rays and its ratio to the carbon flux in an energy interval from 8.4  GeV/n to 3.8  TeV/n based on the data collected by the Calorimetric Electron Telescope (CALET) during ∼6.4  yr of operation on the International Space Station. An update of the energy spectrum of carbon is also presented with an increase in statistics over our previous measurement. The observed boron flux shows a spectral hardening at the same transition energy E_{0}∼200  GeV/n of the C spectrum, though B and C fluxes have different energy dependences. The spectral index of the B spectrum is found to be γ=-3.047±0.024 in the interval 25

A precise measurement of the cosmic-ray proton spectrum with the Calorimetric Electron Telescope (CALET) is presented in the energy interval from 50 GeV to 60 TeV, and the observation of a softening of the spectrum above 10 TeV is reported. The analysis is based on the data collected during ∼6.2  years of smooth operations aboard the International Space Station and covers a broader energy range with respect to the previous proton flux measurement by CALET, with an increase of the available statistics by a factor of ∼2.2. Above a few hundred GeV we confirm our previous observation of a progressive spectral hardening with a higher significance (more than 20 sigma). In the multi-TeV region we observe a second spectral feature with a softening around 10 TeV and a spectral index change from -2.6 to -2.9 consistently, within the errors, with the shape of the spectrum reported by DAMPE. We apply a simultaneous fit of the proton differential spectrum which well reproduces the gradual change of the spectral index encompassing the lower energy power-law regime and the two spectral features observed at higher energies.

The relative abundance of cosmic ray nickel nuclei with respect to iron is by far larger than for all other transiron elements; therefore it provides a favorable opportunity for a low background measurement of its spectrum. Since nickel, as well as iron, is one of the most stable nuclei, the nickel energy spectrum and its relative abundance with respect to iron provide important information to estimate the abundances at the cosmic ray source and to model the Galactic propagation of heavy nuclei. However, only a few direct measurements of cosmic-ray nickel at energy larger than ∼3  GeV/n are available at present in the literature, and they are affected by strong limitations in both energy reach and statistics. In this Letter, we present a measurement of the differential energy spectrum of nickel in the energy range from 8.8  to 240  GeV/n, carried out with unprecedented precision by the Calorimetric Electron Telescope (CALET) in operation on the International Space Station since 2015. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The particle's energy is measured by a homogeneous calorimeter (1.2 proton interaction lengths, 27 radiation lengths) preceded by a thin imaging section (3 radiation lengths) providing tracking and energy sampling. This Letter follows our previous measurement of the iron spectrum [1O. Adriani et al. (CALET Collaboration), Phys. Rev. Lett. 126, 241101 (2021).PRLTAO0031-900710.1103/PhysRevLett.126.241101], and it extends our investigation on the energy dependence of the spectral index of heavy elements. It reports the analysis of nickel data collected from November 2015 to May 2021 and a detailed assessment of the systematic uncertainties. In the region from 20 to 240  GeV/n our present data are compatible within the errors with a single power law with spectral index -2.51±0.07.

A Japanese male in his 50s was presented to our hospital with the chief complaint of positive fecal immunochemical test. He had a history of hypertension. He underwent colonoscopy and was diagnosed with sigmoid colon cancer. He also underwent laparoscopic sigmoid colectomy with D3 lymph node dissection for sigmoid colon cancer. The inferior mesenteric artery and inferior mesenteric vein were amputated at the root of the vessels. The patient received adjuvant chemotherapy and was recurrence-free. Eleven months after the surgery, lower abdominal pain during defecation appeared. Contrast-enhanced computed tomography (CT) and colonoscopy showed marked rectal mucosal edema and increased fatty tissue density (dirty fat sign) around the anorectal side of the anastomosis. Intestinal blood flow was maintained. There were many fine blood vessels around the rectal wall, and the amputated distal part of the superior rectal artery was retrogradely contrasted. Amputated superior rectal artery and superior rectal vein were dilated than before. Colonoscopy revealed mucosal redness, edema, and easy bleeding on the anorectal side of the anastomosis. Abdominal contrast-enhanced 3D-CT showed increased arterial blood flow and increased fine blood vessels around the rectal wall. It suggested the presence of an arteriovenous fistula and venous congestion. Conservative treatment with total parenteral nutrition and prednisolone infusion did not improve the patient's condition, and a colostomy was performed. After colostomy, the pain improved, and the CT scan of the abdomen showed improvement in arterial blood flow and venous congestion. Colostomy was closed after 10 months. There has been no relapse since the closure of the colostomy. There are few reports on ischemic proctitis on the anorectal side of the anastomosis after colon cancer resection due to impaired venous blood flow.

The Calorimetric Electron Telescope (CALET), in operation on the International Space Station since 2015, collected a large sample of cosmic-ray iron over a wide energy interval. In this Letter a measurement of the iron spectrum is presented in the range of kinetic energy per nucleon from 10  GeV/n to 2.0  TeV/n allowing the inclusion of iron in the list of elements studied with unprecedented precision by space-borne instruments. The measurement is based on observations carried out from January 2016 to May 2020. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The energy is measured by a homogeneous calorimeter with a total equivalent thickness of 1.2 proton interaction lengths preceded by a thin (3 radiation lengths) imaging section providing tracking and energy sampling. The analysis of the data and the detailed assessment of systematic uncertainties are described and results are compared with the findings of previous experiments. The observed differential spectrum is consistent within the errors with previous experiments. In the region from 50  GeV/n to 2  TeV/n our present data are compatible with a single power law with spectral index -2.60±0.03.

A man in his 20s visited a local physician because of upper abdominal pain, and an abdominal ultrasonography revealed hepatic tumors. He was then referred to our hospital. The patient had no history of blood transfusion, tattoos, habitual alcohol consumption, or narcotic drug use. Physical examination revealed abdominal fullness. Biochemical tests were negative for hepatitis virus markers and autoantibodies. Liver enzyme levels were high;further, the levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were elevated. Chest and abdominal dynamic enhanced computed tomography and magnetic resonance imaging scans showed multiple lung tumors and multiple liver tumors. An arterial phase contrast-enhanced computer tomography image showed multiple nodular heterogeneous hyperattenuating masses with washout in the equilibrium phase. A huge mass in the right hepatic lobe had a large area of central necrosis. We suspected hepatocellular carcinoma or undifferentiated mesenchymal tumor. Liver biopsy showed moderately differentiated hepatocellular carcinoma without fibrosis in the background liver. This patient was diagnosed with hepatocellular carcinoma that developed in a normal liver. The patient was treated with molecular-targeted drugs. Tumor enhancement decreased;however, the tumor size remained unchanged. The patient lived for 9 months. A search using the retrieval terms "non-hepatitis B virus/non-hepatitis C virus", "non-cirrhotic", "young adult", and "hepatocellular carcinoma" revealed 12 case reports in the Igaku Chuo Zasshi database. Many cases had multiple tumors that were large in size as well as had venous invasion, and surgeries were performed because liver functions were normal. The present case is noteworthy because hepatocellular carcinoma with a non-hepatitis B virus/non-hepatitis C virus and non-cirrhotic background in a young patient is rare.

A Japanese woman in her 40s came to our emergency room with vomiting and upper abdominal pain after drinking a bottle of milk tea at home. She had a history of bipolar disorder. Blood tests revealed hypercalcemia (calcium level of 18.6mg/dl). Abdominal computed tomography depicted thickening of the gastric wall and hyperabsorbed material in the stomach. Upper gastroduodenal endoscopy showed extreme mucosal redness from the gastric body to the pylorus. The hypercalcemia improved with intravenous infusion of zoledronic acid. The patient had not been taking any medication that could have caused hypercalcemia. Later, her father drank the same bottle of milk tea at home and developed upper abdominal pain. He was admitted to the hospital because of vomiting, and computed tomography showed hyperabsorbed material in the stomach, as in his daughter's case. Computed tomography of the bottle of milk tea revealed a highly absorbent substance. The bottle was sent to the forensics laboratory for testing, and it was found to contain calcium chloride. Thus both patients had consumed a beverage containing calcium chloride, and corrosive gastritis was diagnosed. Despite fasting and intravenous drip therapy, the first patient underwent a total gastrectomy because of severe stenosis and perforation of the gastric lumen.

In this paper, we present the measurement of the energy spectra of carbon and oxygen in cosmic rays based on observations with the Calorimetric Electron Telescope on the International Space Station from October 2015 to October 2019. Analysis, including the detailed assessment of systematic uncertainties, and results are reported. The energy spectra are measured in kinetic energy per nucleon from 10  GeV/n to 2.2  TeV/n with an all-calorimetric instrument with a total thickness corresponding to 1.3 nuclear interaction length. The observed carbon and oxygen fluxes show a spectral index change of ∼0.15 around 200  GeV/n established with a significance >3σ. They have the same energy dependence with a constant C/O flux ratio 0.911±0.006 above 25  GeV/n. The spectral hardening is consistent with that measured by AMS-02, but the absolute normalization of the flux is about 27% lower, though in agreement with observations from previous experiments including the PAMELA spectrometer and the calorimetric balloon-borne experiment CREAM.

The precise measurement of cosmic-ray antinuclei serves as an important means for identifying the nature of dark matter and other new astrophysical phenomena, and could be used with other cosmic-ray species to understand cosmic-ray production and propagation in the Galaxy. For instance, low-energy antideuterons would provide a "smoking gun" signature of dark matter annihilation or decay, essentially free of astrophysical background. Studies in recent years have emphasized that models for cosmic-ray antideuterons must be considered together with the abundant cosmic antiprotons and any potential observation of antihelium. Therefore, a second dedicated Antideuteron Workshop was organized at UCLA in March 2019, bringing together a community of theorists and experimentalists to review the status of current observations of cosmic-ray antinuclei, the theoretical work towards understanding these signatures, and the potential of upcoming measurements to illuminate ongoing controversies. This review aims to synthesize this recent work and present implications for the upcoming decade of antinuclei observations and searches. This includes discussion of a possible dark matter signature in the AMS-02 antiproton spectrum, the most recent limits from BESS Polar-II on the cosmic antideuteron flux, and reports of candidate antihelium events by AMS-02; recent collider and cosmic-ray measurements relevant for antinuclei production models; the state of cosmic-ray transport models in light of AMS-02 and Voyager data; and the prospects for upcoming experiments, such as GAPS. This provides a roadmap for progress on cosmic antinuclei signatures of dark matter in the coming years.

In this paper, we present the analysis and results of a direct measurement of the cosmic-ray proton spectrum with the CALET instrument onboard the International Space Station, including the detailed assessment of systematic uncertainties. The observation period used in this analysis is from October 13, 2015 to August 31, 2018 (1054 days). We have achieved the very wide energy range necessary to carry out measurements of the spectrum from 50 GeV to 10 TeV covering, for the first time in space, with a single instrument the whole energy interval previously investigated in most cases in separate subranges by magnetic spectrometers (BESS-TeV, PAMELA, and AMS-02) and calorimetric instruments (ATIC, CREAM, and NUCLEON). The observed spectrum is consistent with AMS-02 but extends to nearly an order of magnitude higher energy, showing a very smooth transition of the power-law spectral index from -2.81±0.03 (50-500 GeV) neglecting solar modulation effects (or -2.87±0.06 including solar modulation effects in the lower energy region) to -2.56±0.04 (1-10 TeV), thereby confirming the existence of spectral hardening and providing evidence of a deviation from a single power law by more than 3σ.

Extended results on the cosmic-ray electron + positron spectrum from 11 GeV to 4.8 TeV are presented based on observations with the Calorimetric Electron Telescope (CALET) on the International Space Station utilizing the data up to November 2017. The analysis uses the full detector acceptance at high energies, approximately doubling the statistics compared to the previous result. CALET is an all-calorimetric instrument with a total thickness of 30 X_{0} at normal incidence and fine imaging capability, designed to achieve large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum in the region below 1 TeV shows good agreement with Alpha Magnetic Spectrometer (AMS-02) data. In the energy region below ∼300  GeV, CALET's spectral index is found to be consistent with the AMS-02, Fermi Large Area Telescope (Fermi-LAT), and Dark Matter Particle Explorer (DAMPE), while from 300 to 600 GeV the spectrum is significantly softer than the spectra from the latter two experiments. The absolute flux of CALET is consistent with other experiments at around a few tens of GeV. However, it is lower than those of DAMPE and Fermi-LAT with the difference increasing up to several hundred GeV. The observed energy spectrum above ∼1  TeV suggests a flux suppression consistent within the errors with the results of DAMPE, while CALET does not observe any significant evidence for a narrow spectral feature in the energy region around 1.4 TeV. Our measured all-electron flux, including statistical errors and a detailed breakdown of the systematic errors, is tabulated in the Supplemental Material in order to allow more refined spectral analyses based on our data.

A 78-year-old woman had undergone total gastrectomy and chemotherapy for gastric cancer (pT4N3bM0 Stage IIIC, poorly differentiated adenocarcinoma). She received S-1 monotherapy 3 times weekly (S-1 at 80mg twice daily for 14 days, every 3 weeks). She underwent routine examinations, including tumor markers and computed tomography. She had no signs of recurrent disease, but she suffered from a loss of eyesight 2 years and 8 months after the operation. A choked disc was found, but she had no headaches, nausea, or unconsciousness, which indicated high intraventricular pressure. Enhanced T2-weighted magnetic resonance imaging showed high intensity around the optic nerve. We performed cerebrospinal fluid cytological analysis, which showed poorly differentiated adenocarcinoma. She was diagnosed as having leptomeningeal carcinomatosis of gastric cancer. The patient chose best supportive care and died 2 months after symptoms appearance. Histological analysis during the autopsy showed moderately to poorly differentiated adenocarcinoma. The carcinoma had also infiltrated the spinal cord, peritoneum, and adrenal glands. Histologically, the carcinoma had infiltrated the optic nerve, which caused loss of eyesight. We have not yet established effective therapies for leptomeningeal carcinomatosis, and the prognosis is poor. Leptomeningeal carcinomatosis of gastric cancer that appears by loss of eyesight is very rare. This case illustrates that the possibility of leptomeningeal carcinomatosis should be considered when we treat patients with loss of eyesight of an unknown cause after surgery.

First results of a cosmic-ray electron and positron spectrum from 10 GeV to 3 TeV is presented based upon observations with the CALET instrument on the International Space Station starting in October, 2015. Nearly a half million electron and positron events are included in the analysis. CALET is an all-calorimetric instrument with total vertical thickness of 30 X_{0} and a fine imaging capability designed to achieve a large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum over 30 GeV can be fit with a single power law with a spectral index of -3.152±0.016 (stat+syst). Possible structure observed above 100 GeV requires further investigation with increased statistics and refined data analysis.

The BESS-Polar Collaboration measured the energy spectra of cosmic-ray protons and helium during two long-duration balloon flights over Antarctica in December 2004 and December 2007, at substantially different levels of solar modulation. Proton and helium spectra probe the origin and propagation history of cosmic rays in the galaxy, and are essential to calculations of the expected spectra of cosmic-ray antiprotons, positrons, and electrons from interactions of primary cosmic-ray nuclei with the interstellar gas, and to calculations of atmospheric muons and neutrinos. We report absolute spectra at the top of the atmosphere for cosmic-ray protons in the kinetic energy range 0.2-160 GeV and helium nuclei 0.15-80 GeV/nucleon. The corresponding magnetic rigidity ranges are 0.6-160 GV for protons and 1.1-160 GV for helium. These spectra are compared to measurements from previous BESS flights and from ATIC-2, PAMELA, and AMS-02. We also report the ratio of the proton and helium fluxes from 1.1 GV to 160 GV and compare to ratios from PAMELA and AMS-02.

Adenosquamous carcinoma of the duodenal papilla is rare. A 73-year-old man was referred to the Saiseikai-Matsusaka General Hospital with upper abdominal pain and liver dysfunction. Computed tomography (CT) revealed dilatation of the common bile duct (CBD) and intrahepatic bile duct along with a tumor in the distal CBD. The tumor showed enhancement in the arterial phase on contrast-enhanced CT. We performed endoscopic retrograde cholangiopancreatography and noted a red, erosive, bleeding mass in the duodenal papilla with obstruction of the distal CBD, and dilatation of the CBD. Histopathological inspection of a biopsy of the duodenal papilla showed a mixture of adenocarcinoma and squamous cell carcinoma, suggesting the presence of adenosquamous cell carcinoma in the duodenal papilla. Abdominal examinations including positron emission tomography/CT showed no metastasis or lymph node swelling. The clinical stage was determined to be cT2N0M0 Stage IB. We performed subtotal stomach-preserving pancreaticoduodenectomy. Histopathological inspection of the specimen showed a mixture of adenocarcinoma and squamous cell carcinoma, and squamous cell carcinoma accounted for 40% of the tumor. The tumor was defined as pathological Stage IIA, AcbBd, mixed type, med, pT3b, sci, INFb, ly2, v1, ne2, pN1, HM0, PM0, EM0, PV0, A0, R0, pT3N0M0. We suggested adjuvant chemotherapy, but the patient declined adjuvant chemotherapy and wished to be discharged. Abdominal ultrasonography revealed multiple liver metastases 3 months postoperatively. The patient opted for best supportive care and died 9 months postoperatively. Examination of 23 reports of adenosquamous cell carcinoma of the duodenal papilla in Japan suggested that adenosquamous cell carcinoma of the duodenal papilla has a poorer prognosis compared with adenocarcinoma of the duodenal papilla. Some reports have stated that the growth rate is faster for squamous cell carcinoma than for adenocarcinoma. In our case, the tumor was enhanced in the arterial phase and this represents a feature of adenosquamous cell carcinoma of the duodenal papilla. Chemotherapy has not been established for adenosquamous cell carcinoma of the duodenal papilla. We are confident that we can establish effective chemotherapies in the future.

Plexiform schwannoma is a benign peripheral nerve sheath tumor composed exclusively of Schwann cells arranged in a plexiform pattern. Most plexiform schwannomas are skin tumors and visceral localization is very rare. To our knowledge, there are six cases localized in visceral organs. We describe herein the first known case of plexiform schwannoma of the rectum resected by endoscopic submucosal dissection (ESD). A 77-year-old woman presented with a short history of anal pain. Sigmoidoscopy demonstrated a submucosal tumor, 20 mm in diameter, of the rectum below the peritoneal reflection (Rb). We resected the tumorby ESD. The tumor consisted of multiple white nodules in the submucosal layer. Microscopic examination revealed that the tumor was composed mainly of Antoni A tissue, compatible with conventional schwannoma. Immunohistochemically, the tumor was positive for S-100, and negative for α-smooth muscle actin, c-kit and CD-34. No evidence of recurrence has been found in 2 years of follow up., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Background: We evaluated the clinical efficacy of transarterial infusion chemotherapy using a cisplatin-lipiodol emulsion for unresectable hepatocellular carcinoma (HCC)., Patients and Methods: Fifty-seven patients with advanced HCC, with no indications for surgical resection or local ablative therapy, such as percutaneous ethanol injection and radiofrequency ablation, were enrolled in this retrospective study., Results: Twelve patients were treated with cisplatin-alone at a dose of 65 mg/m(2) by infusion into the artery. Forty-two patients were treated with the same dose of cisplatin suspended in 1-10 ml of lipiodol (C/LPD). Cumulative survival rates in the cisplatin-treated group were 46.2% at one year, and 18.5% at two years, whereas these in the C/LPD group were 81.6% and 44.4%, respectively, with a significant difference between the two groups (p<0.01). In the cisplatin-treated group (n=13), no (0%) patients had a complete response (CR), two (15%) a partial response (PR), three (23%) no change (NC), and eight (62%) progressive disease (PD). In the C/LPD group (n=44), four (9%) patients had CR, 16 (35%) PR, 12 (26%) NC, and 12 (26%) PD. CR and PR were seen in 15% of the cisplatin-treated group and in 44% of the C/LPD group. C/LPD was significantly more effective than cisplatin-alone (p=0.039). Some patients showed tumor response to C/LPD after intra-arterial infusion of low-dose 5-fluorouracil., Conclusion: C/LPD produced superior effects compared to cisplatin-alone for unresectable HCC, causing no major side-effects, and increasing the survival rate.

In two long-duration balloon flights over Antarctica, the Balloon-borne Experiment with a Superconducting Spectrometer (BESS) collaboration has searched for antihelium in the cosmic radiation with the highest sensitivity reported. BESS-Polar I flew in 2004, observing for 8.5 days. BESS-Polar II flew in 2007-2008, observing for 24.5 days. No antihelium candidate was found in BESS-Polar I data among 8.4×10(6) |Z|=2 nuclei from 1.0 to 20 GV or in BESS-Polar II data among 4.0×10(7) |Z|=2 nuclei from 1.0 to 14 GV. Assuming antihelium to have the same spectral shape as helium, a 95% confidence upper limit to the possible abundance of antihelium relative to helium of 6.9×10(-8)} was determined combining all BESS data, including the two BESS-Polar flights. With no assumed antihelium spectrum and a weighted average of the lowest antihelium efficiencies for each flight, an upper limit of 1.0×10(-7) from 1.6 to 14 GV was determined for the combined BESS-Polar data. Under both antihelium spectral assumptions, these are the lowest limits obtained to date.

The energy spectrum of cosmic-ray antiprotons (p's) from 0.17 to 3.5 GeV has been measured using 7886 p's detected by BESS-Polar II during a long-duration flight over Antarctica near solar minimum in December 2007 and January 2008. This shows good consistency with secondary p calculations. Cosmologically primary p's have been investigated by comparing measured and calculated p spectra. BESS-Polar II data show no evidence of primary p's from the evaporation of primordial black holes.

We herein report a rare case of hepatocellular carcinoma (HCC) with sarcomatous changes. A 66-year-old man was admitted to our hospital with a high fever and upper abdominal pain. Initially, he was diagnosed as having a liver abscess; however, antibiotic treatment and drainage were ineffective. Further imaging studies revealed the typical appearance of HCC: the tumor had invaded the hepatic and portal veins. Surgical resection of the tumor was performed. A pathological examination demonstrated the presence of a sarcomatous hepatocellular carcinoma. Sarcomatous hepatocellular carcinoma with remittent fever is a rare disease entity.

We report a case of 72-year-old man found to have a primary malignant melanoma in the jejunum. The patient was noted to be anemic and had lower abdominal pain on his visit to the Department of Gastroenterology. However, an upper gastrointestinal series and colonofiberscopic examination revealed no abnormalities. After clinical examinations, the radiological workup, which included CT, X-ray of the small intestine and single-balloon enteroscopy, revealed an intraluminal polypoid tumor, with a patchy light gray and black pattern. Pre-operative biopsy specimens revealed a malignant melanoma. Segmental intestinal resection with regional lymph node dissection was performed. The tumor size was 7.0×9.5×5.8cm. Nodal metastasis was seen only in the mesenteric node draining from the tumor-bearing intestinal segment (stage IIIa). Adjuvant chemotherapy with dacarbazine, nimustine hydrochloride and vincristine sulfate was performed, and the patient was able to recover his level of activity of daily living for 6 months.

Purpose: To evaluate survival, recurrence-free survival, technical success, technique effectiveness, and safety of radiofrequency (RF) ablation combined with chemoembolization in patients with hepatocellular carcinomas (HCCs) larger than 5 cm., Materials and Methods: Patients with Child-Pugh class A or B cirrhosis and three or fewer HCCs with a maximum tumor diameter of 5.1-10 cm were included. Twenty patients with 32 HCCs were included. There were 16 men and four women with mean age of 69 years +/- 7.4 (range, 46-79 years).The maximum mean tumor diameter was 6.2 cm (range, 5.1-9.5 cm). RF ablation was performed under computed tomographic (CT) fluoroscopic guidance 1-2 weeks after chemoembolization. The primary endpoint of this study was survival., Results: RF electrodes were placed in the planned sites, and RF ablation was completed with a planned protocol (technical success rate, 100%). Tumor enhancement was eradicated in all patients after 32 RF sessions. The primary and secondary technique effectiveness rates were 40% and 100%, respectively. There were two major complications in the 32 RF sessions (6%)--hepatic abscess and diaphragm perforation. Local tumor progression developed in five of the 20 patients (25%) during the mean follow-up of 30 months. The overall and recurrence-free survival rates were, respectively, 100% and 74% at 1 year, 62% and 28% at 3 years, and 41% and 14% at 5 years. The serum bilirubin level of 1.0 mg/dL (17.1 micromol/L) or less was a significantly better prognostic factor in the univariate analysis., Conclusions: This combination therapy may enhance survival in patients with HCCs larger than 5 cm.

Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). TLR3 expression and function in cancer cells are not well understood. We investigated the expression of TLR3 in hepatocellular carcinoma (HCC) cells and the function of TLR3 signaling by stimulation and transfection with polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA. TLR3 mRNA was expressed in HCC tissues as well as in non-tumor tissues. Positive immunohistochemical staining for TLR3 was observed in 52.7% of HCC tissues, and in HCC cells we found both membranous and cytoplasmic expression of TLR3. While cell surface stimulation of TLR3 with Poly I:C did not affect cell viability, it did activate NF-kappaB levels. In contrast, cytoplasmic stimulation with transfected Poly I:C significantly induced apoptosis accompanied by the down-regulation of anti-apoptotic protein. Transfected Poly I:C also synergistically augmented TRAIL-induced apoptosis, but only with low levels of transfected Poly I:C was IFN-beta production not observed. In conclusion, our results indicate that TLR3 expression in HCC plays an important role with regard to cell survival and proapoptotic activity. Endogenously expressed TLR3 may provide new clinical prospects for TLR3 agonists as cytotoxic agents in HCC.

Interleukin (IL)-18 plays an important role in the pathogenesis of several liver diseases as well as Fas-mediated apoptosis. However, the effects of IL-18 on Fas-mediated liver injury have not been well elucidated. Therefore, we examined the effects of IL-18 on Fas-mediated apoptosis in in vitro and in vivo experiments. We found that recombinant IL-18 protected mouse hepatocellular carcinoma cell lines, BNL5, from Fas-mediated apoptosis in a dose-dependent manner with up-regulation of both nuclear factor (NF) kappaB and X-linked inhibitors of apoptosis (XIAP). IL-18 transgenic (Tg) mice were also protected from Fas-mediated liver injury and this was further confirmed by histological study and TUNEL staining. In IL-18 Tg mice, up-regulation of XIAP and down-regulation of caspase 3 were observed after injection of anti-Fas, which was consistent with the in vitro findings. These results suggest that IL-18 suppresses Fas-mediated apoptosis of hepatocytes by up-regulation of NFkappaB and XIAP, following inhibition of caspase-3 activity. This observation raises the possibility that IL-18 could be a therapeutic strategy for Fas-mediated liver injury as a negative regulator of XIAP.

Background: Radiofrequency ablation (RFA) therapy for hepatocellular carcinoma has enabled good local control to be possible. However, after successful local control, distant recurrences frequently occur in the remnant liver., Aim: To identify the predictive factors for distant recurrence after RFA., Methods: A total of 117 patients with initial non-advanced hepatocellular carcinoma with HCV who underwent RFA in our hospital were selected for this study. After transcatheter chemoembolization, RFA was performed under real-time computed tomography-fluoroscopic guidance. We studied survival rates, local (adjacent to treated tumour) and distant (intrahepatic site distant from the treated tumours) recurrence rates, as well as predictive factors for distant recurrence., Results: After RFA, survival rates were 98.2% and 64.7% at 1 and 5 years, respectively. Child B patients had a significantly worse survival than Child A. Recurrence rates were 2.4% at 5 years for local, and 17.1% and 76.9% at 1 and 5 years, respectively, for distant. The Kaplan-Meier method revealed significantly high recurrence rates in cases with low albumin levels (Alb < 3.5 g/dL), high aspartate aminotransferase levels (AST > 60 IU/L), high alanine aminotransferase levels (ALT > 60 IU/L), low platelet counts (Plt < 10 x 10(4)/microL), and high alpha-fetoprotein levels (AFP > 50 ng/mL). On multivariate analysis, low Alb levels and high AST levels were independent predictive factors for distant recurrence., Conclusions: Although RFA enables good local control for initial hepatocellular carcinoma, distant recurrence is observed at high rates in HCV patients. Low albumin and high AST levels are predictive factors for distant recurrence.

Purpose: To retrospectively evaluate the long-term results of radiofrequency (RF) ablation combined with chemoembolization (combination therapy) as compared with hepatectomy for the treatment of early-stage hepatocellular carcinoma (HCC)., Materials and Methods: The study was approved by the institutional review board, and informed consent was waived. Patients with early-stage HCC were included if they underwent either combination therapy or hepatectomy and met the following inclusion criteria: no previous treatment for HCC, three or fewer tumors with a maximum diameter of 3 cm or less each or a single tumor with a maximum diameter of 5 cm or less, Child-Pugh class A liver profile, no vascular invasion, and no extrahepatic metastases. The primary endpoint was overall survival, and the secondary endpoint was recurrence-free survival., Results: One hundred four patients (mean age, 66.5 years +/- 8.7 [standard deviation]; 79 men, 25 women) underwent combination therapy, and 62 patients (mean age, 64.5 years +/- 9.6; 51 men, 11 women) underwent hepatectomy. The 1-, 3-, and 5-year overall survival rates following combination therapy (98%, 94%, and 75%, respectively) were similar (P = .87) to those following hepatectomy (97%, 93%, and 81%, respectively). The 1-, 3-, and 5-year recurrence-free survival rates were also comparable (P = .70) for combination therapy (92%, 64%, and 27%, respectively) and hepatectomy (89%, 69%, and 26%, respectively)., Conclusion: RF ablation combined with chemoembolization in patients with early-stage HCC provides overall and disease-free survival rates similar to those achieved by hepatectomy.

Different RNA species are rigorously discriminated and exported by distinct export factors, but this discrimination mechanism remains largely unknown. We previously showed, by RNA microinjection experiments, that intronless mRNAs are discriminated from U snRNAs based on their difference in RNA length. However, it was unclear how they are discriminated in the natural situation in which their nascent transcripts emerge progressively during transcription. We hypothesized that transcription from the corresponding promoters is important for this discrimination. Here we show that contrary to our hypothesis, the discrimination process was not significantly influenced by whether transcription occurred from an mRNA- versus a U snRNA-type promoter. Rather, the features of transcribed RNAs determined the RNA identity, consistent with our previous results of RNA microinjection. Moreover, we found that the poly (A) tail can function as an identity element for mRNA export. The presence of a poly (A) tail of an appropriate length committed otherwise short Pol II transcripts to the mRNA export pathway in a dominant manner, indicating that the poly (A) tail either contributes to increasing the RNA length or functions as a platform to recruit mRNA export factors. Our results reveal a novel function of the poly (A) tail in mRNA export.

A 51-year-old man developed type 1 diabetes mellitus following 24 weeks of treatment with recombinant alpha-2b peginterferon plus ribavirin for chronic hepatitis C. Pancreatic autoantibody tests were negative before the start of therapy, but a significant increase in glutamic acid decarboxylase (GAD) antibody titer was seen after 24 weeks of treatment. Six months after the onset of type 1 diabetes mellitus, the patient continues to receive 40 units of insulin daily. The clinical course suggested that recombinant alpha-2b peginterferon plus ribavirin provoked type 1 diabetes mellitus, therefore, in patients who are candidates for interferon therapy the presence of pancreatic autoantibodies and the fasting plasma glucose level should be investigated before and during treatment.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease primarily affecting middle-aged women. Although little is known about the etiology of PBC, it may be induced by an autoimmune response. Here, we describe a rare case of appearance of PBC following chemotherapy for Hodgkin's lymphoma.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various cancers and plays a crucial role in oncogensis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. We investigated the biological significance of the Janus kinase (Jak)-STAT pathway in human hepatocellular carcinoma (HCC). Constitutive activation of STAT3 was seen in 49.4% of human HCC specimens and in HCC cell lines. Jak inhibitor AG490 inhibited activation of STAT3 and markedly reduced cell viability without significant apoptosis. AG490 also induced S phase cell-cycle arrest with down-regulation of cyclin D1, A, E and up-regulation of p21, p27, phospho-Chk2. AG490 also inhibited caspase inhibitory proteins, such as XIAP and survivin, and augmented TRAIL-induced apoptosis. Our study suggests that the Jak-STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis. Inhibition of the Jak-STAT pathway may thus be a therapeutic target for HCC.

Autoimmune pancreatitis is a chronic fibroinflammatory condition primarily affecting the pancreas. Recent accumulating evidence suggested that autoimmune pancreatitis is a systemic autoimmune disease (immunoglobulin G4 [IgG4]-related autoimmune disease) affecting various organs with dense infiltration of IgG4-positive mononuclear cells. Tubulointerstitial nephritis is still a mysterious disease with an unknown cause. We report 2 cases of tubulointerstitial nephritis associated with autoimmune pancreatitis. In these patients, dense infiltrations of IgG4-positive mononuclear cells were observed in renal interstitium, with high serum IgG4 levels. Furthermore, in patient 1, who had sclerosing cholangitis, serum alkaline phosphatase and serum creatinine levels changed synchronously. Steroid therapy was followed by improved renal function and serum IgG4 levels in both patients. Because tubulointerstitial nephritis associated with IgG4-related autoimmune disease shows a favorable response to steroids and the renal dysfunction and pancreatic dysfunction are reversible, awareness of this entity is necessary for early diagnosis and prompt treatment. In addition, these cases support the hypothesis that IgG4-related autoimmune disease could be one cause of tubulointerstitial nephritis.

Purpose: To investigate the risk factors for local tumor progression after radiofrequency (RF) ablation combined with chemoembolization for the treatment of hepatocellular carcinoma (HCC)., Materials and Methods: A total of 255 HCC lesions 5 cm or less in maximum diameter were treated by RF ablation in 173 patients within 2 weeks after chemoembolization was performed. Therapeutic response was evaluated by contrast medium-enhanced computed tomography studies. The disappearance of tumor enhancement was considered to indicate complete necrosis. Local tumor progression was defined by the appearance of enhanced tumor adjacent to the zone of ablation. The risk factors for local tumor progression after RF ablation were retrospectively assessed by univariate and multivariate analyses., Results: All tumors showed complete necrosis after RF ablation. Local tumor progression was found in 18 of the 255 lesions (7%) during a mean follow-up period of 23 months (range, 1-63 months). The cumulative local tumor progression rate was 12% at 5 years. Larger tumor (3.1-5 cm), infiltrating tumor, and previous treatments were found to increase the risk of local tumor progression in univariate and multivariate analyses., Conclusions: The combination of chemoembolization with RF ablation is an effective treatment to control HCC lesions. The factors identified in the present study may help to predict the therapeutic response.

Background/aims: We evaluated the efficacy of lamivudine therapy for treatment of spontaneous exacerbation and reactivation after immunosuppressive therapy in patients with hepatitis B virus infection. Lamivudine is an effective therapy if used in early stages of both spontaneous exacerbation and reactivation after immunosuppressive therapy., Methodology: In our study, twelve patients experienced flares of chronic hepatitis B over a three-year period., Results: Three patients whose pretreatment total bilirubin levels were more than 7mg/dL died of fatal liver failure despite lamivudine therapy., Conclusions: We concluded that if pretreatment serum bilirubin levels are higher than 7 mg/dL, lamivudine therapy alone may be insufficient and more effective therapies should be considered concomitantly with lamivudine.

We report a case of 65-year-old man with alcoholic cirrhosis and diabetes mellitus, in whom a cervical mycotic aneurysm suddenly developed after sepsis with methicillin-resistant staphylococcus aureus. Severe infection associated with alcoholic cirrhosis may cause a typical mycotic aneurysm.

Flavopiridol was one of the first cyclin-dependent kinase inhibitors demonstrated to have an antitumor effect in several cancer types. Here, we investigated the effects of flavopiridol on TNF-related apoptosis-inducing ligand (TRAIL) in the human hepatocellular carcinoma (HCC) cell lines HLE and HepG2, and evaluated the role of flavopiridol in apoptosis. To better understand the mechanism of increased TRAIL sensitivity in HCC cells, we determined the effect of flavopiridol on cell surface expression of TRAIL and TRAIL receptors using flow cytometry analysis. The levels of survivin, FLIP, Bcl-xL and X-chromosome-linked IAP (XIAP) in treated and untreated cells was also determined. Flavopiridol decreased cell viability in a dose-dependent manner in the two HCC cell lines tested. The pan-caspase inhibitor z-VAD-FMK did not inhibit the effect. However, subtoxic levels of flavopiridol dramatically enhanced TRAIL-induced apoptosis in both cells. Flavopiridol up-regulated TRAIL, TRAIL-R1 and TRAIL-R2 in both cell lines. In addition, flavopiridol down-regulated expression of survivin in both cell lines, and expression of FLIP and Bcl-xL were down-regulated in HLE cells. In summary, flavopiridol augmented TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of survivin, FLIP and Bcl-xL. Thus, combining flavopiridol with a TRAIL agonist may prove to be an effective new strategy for treatment of HCC.

Caspase-8 belongs to the cysteine protease family and is known to be activated at the initial step in the cascade of TRAIL-induced apoptosis. The activation of procaspase-8 can be blocked by a relatively large amount of c-FLIP, which renders resistance to death receptor-mediated apoptosis in many types of cancer cells. To ask if extrinsic over-expression of caspase-8 contributes to the induction of apoptosis, we introduced the caspase-8 gene into HCC cells using an adenoviral (Adv) vector (Adv-Casp8). We demonstrated that Adv-Casp8 increased expression of active forms of caspase-8 in MOI-dependent manner. A large amount of Adv-Casp8 (MOI of 50) induced apoptosis significantly in HCC cells and resulted in downregulation of c-FLIP (in SK-Hep1, HLE, and HepG2 cells), XIAP, survivin, and Bcl-xL (in HLE cells) and dynamic release of cytochrome c and Smac from the mitochondria into the cytosol. On the other hand, a small amount of Adv-Casp8 (MOI of 10) causes a slight but detectable increase in the level of apoptosis with only a small effect on anti-apoptotic proteins and mitochondrial activation. However, small amounts of Adv-Casp8 augmented TRAIL- or chemotherapeutic agent-induced cell death (with an MOI of 10 or 20, respectively). These results suggest both that exogenous over-expression of caspase-8 by Adv-Casp8 may be essential for induction of HCC cell death and that the combination of Adv-Casp8 and TRAIL or chemotherapeutic agents could provide a useful strategy for treatment of HCC.

Cyclooxygenase (COX)-2 is upregulated in a variety of human cancers, including in hepatocellular carcinoma (HCC), whereas it is undetectable in most normal tissue. Evidence suggests that COX-2 is likely to be involved in hepatocarcinogenesis and, thus, COX-2 may be involved in an early process in carcinogenesis, dedifferentiation. To address this possibility, we investigated the effect of COX-2 inhibitors on TNF-related apoptosis, inducing ligand (TRAIL) sensitivity and its molecular mechanisms, with special attention to anti-apoptotic proteins. We used the highly selective COX-2 inhibitors, NS398 and CAY10404. We also used the MTT assay and cytological analysis of DAPI-stained DNA to assess viability and apoptosis in two HCC cells (SK-Hep1 and HLE). In order to ask what led to increased sensitivity to TRAIL in HCC cells, cell surface expression of TRAIL and TRAIL-receptors was investigated using flow cytometry analysis. Expression of survivin, X-chromosome-linked IAP (XIAP), Bcl-xL, AKT and phospho-AKT was also investigated using immunoblotting. COX-2 inhibitors resulted in a concentration-dependent decrease in cell viability in the two HCC cell lines tested. Subtoxic levels of COX-2 inhibitors did not significantly augment TNFalpha-induced apoptosis but did dramatically enhance TRAIL-induced apoptosis in both cell lines. TRAIL receptor 2/death receptor 5 (TRAIL-R2/DR5) expression was significantly up-regulated in SH-Hep1 and HLE cells. TRAIL receptor 1/death receptor 4 (TRAIL-R1/DR4) expression was up-regulated only in SK-Hep1. Expression of survivin and Bcl-xL was down-regulated in SK-Hep1 and HLE cells in the presence of CAY10404 but XIAP was not affected. Expression of survivin, Bcl-xL and XIAP was down-regulated in SK-Hep1 cells in the presence of NS398. Survivin expression was also down-regulated in the presence of NS398 in HLE cells. Finally, NS398 also decreased phospho-AKT in SK-Hep1 cells. These results demonstrate that COX-2 inhibitors can induce apoptosis and augment TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of both survivin and AKT signaling.

In 1.5 Harmonic Imaging ultrasonography (1.5 HI US), images are obtained in a band intermediate between the fundamental and 2nd harmonic components, resulting in stronger contrast enhancement than in conventional harmonic imaging. We attempted to assess the hemodynamics of hepatocellular carcinomas (HCC) with special attention to blood drainage using 1.5 HI US. Forty-two HCC nodules, metastatic liver tumors and hepatic hemangiomas were studied. In contrast studies, intermittent ultrasound transmission was performed for a period of up to 45 sec after the injection of contrast agent, which was regarded as the vascular phase. The time point of 5 min later was specified as the post-vascular phase, and images were obtained by single manual transmission for comparison of contrast enhancement with surrounding hepatic parenchyma. In addition, histological examination was performed. 1.5 HI US clearly demonstrated the strong tumor vessels in most HCCs. Corona enhancement, in which the areas surrounding the tumor are enhanced, was observed in 71.4% (30/42) of HCC nodules during the post-vascular phase. This sign was not observed in any other tumors. Histological findings revealed that CD34-positive-endothelial cells were prominent in the surrounding area of HCC. In conclusion, 1.5 HI US is an effective tool for evaluating hemodynamics in both early- and post-vascular phase. Corona enhancement may be due to the trapping of contrast agent in the endothelial cells in the surround of HCC nodules and be a novel specific sign for HCC.