Induction of Kallikrein-Related Peptidase 13 and TET2/3 by Anticancer Drugs and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Preoperative Treatment.

BACKGROUND: Preoperative chemotherapy/chemoradiotherapy has been generally considered for the treatment of esophageal squamous cell carcinoma (ESCC) to improve prognosis. We examined the effects of anticancer drugs on the expression of kallikrein-related peptidase 13 (KLK13), a potential ESCC prognostic marker, and its clinical relevance in patients who received chemotherapy/chemoradiotherapy for ESCC. METHODS: Overall, 105 patients with ESCC who received chemotherapy or chemoradiotherapy before esophagectomy were enrolled. The expression of KLK13 in biopsy samples obtained before chemotherapy/chemoradiotherapy and resected ESCC tumors was assessed by immunohistochemical staining. The effects of 5-fluorouracil (5-FU) and/or cisplatin (CDDP) exposure on the expressions of KLK13 and ten-eleven translocation dioxygenases (TET) in ESCC cells were examined by reverse transcription-polymerase chain reaction. RESULTS: Immunohistochemical staining of paired ESCC specimens before (biopsy samples) and after (resected specimens) chemotherapy/chemoradiotherapy demonstrated a change in KLK13 expression. KLK13 and TET2/3 transcriptions were induced when human ESCC cell lines were treated with 5-FU and/or CDDP. Among patients with KLK13-negative status before chemotherapy/chemoradiotherapy, those with KLK13-positive resected tumors had a significantly poorer prognosis than those with KLK13-negative resected tumors (p = 0.0477). By using tumor cells isolated from ESCC biopsy tissues obtained before chemotherapy/chemoradiotherapy, we established a primary culture system and detected the induction of KLK13 expression by anticancer drugs. CONCLUSIONS: Preoperative treatments alter KLK13 expression in ESCC. The conversion of KLK13 expression from a negative status in biopsy samples to a positive status in resected tumor samples is a predictor of poor prognosis. KLK13 status is a potential marker for decision making to avoid harmful chemotherapy/chemoradiotherapy in patients with ESCC.

Dosimetric impact of systematic spot position errors in spot scanning proton therapy of head and neck tumor.

Purpose: The spot position is an important beam parameter in the quality assurance of scanning proton therapy. In this study, we investigated dosimetric impact of systematic 15 spot position errors (SSPE) in spot scanning proton therapy using three types of optimization methods of head and neck tumor. Materials and Methods: The planning simulation was performed with ± 2 mm model SSPE in the X and Y directions. Treatment plans were created using intensity-modulated proton therapy (IMPT) and single-field uniform dose (SFUD). IMPT plans were created by two optimization methods: with worst-case optimization (WCO-IMPT) and without (IMPT). For clinical target volume (CTV), D95%, D50%, and D2cc were used for analysis. For organs at risk (OAR), Dmean was used to analyze the brain, cochlea, and parotid, and Dmax was used to analyze brainsetem, chiasm, optic nerve, and cord. Results: For CTV, the variation (1 standard deviation) of D95% was ± 0.88%, 0.97% and 0.97% to WCO-IMPT, IMPT, and SFUD plan. The variation of D50% and D2cc of CTV showed <0.5% variation in all plans. The dose variation due to SSPE was larger in OAR, and worst-case optimization reduced the dose variation, especially in Dmax. The analysis results showed that SSPE has little impact on SFUD. Conclusions: We clarified the impact of SSPE on dose distribution for three optimization methods. SFUD was shown to be a robust treatment plan for OARs, and the WCO can be used to increase robustness to SSPE in IMPT.

Streptobacillus notomytis Bacteremia after Exposure to Rat Feces.

To determine the source of Streptobacillus notomytis bacteremia in a woman in Japan with signs of rat-bite fever, we examined rat feces from her home. After culture and PCR failed to identify the causative organism in the feces, next-generation sequencing detected Streptobacillus spp., illustrating this procedure's value for identifying causative environmental organisms.

Catheter-related bloodstream infection caused by Tsukamurella ocularis: A case report.

Tsukamurella spp. causes mainly bacteremia and central venous catheter-related bloodstream infections. To the best of our knowledge, there is no documented evidence that Tsukamurella ocularis causes catheter-related bloodstream infections like other species of Tsukamurella. We present a novel case of T. ocularis bacteremia in a 69-year-old woman with malignant cancer, wherein the patient was successfully treated with a peripherally inserted central venous catheter. We administered combination antimicrobial therapy to the patient, which was terminated only after confirming the absence of infection. We identified T. ocularis by sequencing three housekeeping genes that could not be identified using conventional mass spectrometry and 16S rRNA gene analysis.

Dosimetric effects of quality assurance-related setup errors in passive proton therapy for prostate cancer with and without a hydrogel spacer.

The purpose of this study was to evaluate the effect of quality assurance (QA)-related setup errors in passive proton therapy for prostate cancer with and without a hydrogel spacer. We used 20 typical computed tomography (CT) images of prostate cancer: 10 patients with and 10 patients without spacers. The following 12 model errors were assumed: output error ± 2%, range error ± 1 mm, setup error ± 1 mm for three directions, and multileaf collimator (MLC) position error ± 1 mm. We created verification plans with model errors and compared the prostate-rectal (PR) distance and dose indices with and without the spacer. The mean PR distance at the isocenter was 1.1 ± 1.3 mm without the spacer and 12.9 ± 2.9 mm with the spacer (P < 0.001). The mean rectum V53.5 GyE, V50 GyE, and V34.5 GyE in the original plan were 2.3%, 4.1%, and 12.1% without the spacer and 0.1%, 0.4%, and 3.3% with the spacer (P = 0.0011, < 0.001, and < 0.001). The effects of the range and lateral setup errors were small; however, the effects of the vertical/long setup and MLC error were significant in the cases without the spacer. The means of the maximum absolute change from original plans across all scenarios in the rectum V53.5 GyE, V50 GyE, and V34.5 GyE were 1.3%, 1.5%, and 2.3% without the spacer, and 0.2%, 0.4%, and 1.3% with the spacer (P < 0.001, < 0.001, and = 0.0019). This study indicated that spacer injections were also effective in reducing the change in the rectal dose due to setup errors.

Residual and Late Onset Symptoms Appeared in a Patient with Severe Fever with Thrombocytopenia in a Convalescence Stage.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by Dabie bandavirus (formerly SFTS virus, SFTSV). Its manifestations during the convalescent phase have not been widely described. We report a patient presenting with hematospermia, fatigue, myalgia, alopecia, insomnia, and depression during the recovery phase of SFTS. Since these symptoms are widely observed in patients with viral hemorrhagic fevers, there might be common mechanisms between SFTS and other viral hemorrhagic fevers. Close monitoring may be required during the recovery phase of SFTS.

Vonoprazan-based triple therapy is effective for Helicobacter pylori eradication irrespective of clarithromycin susceptibility.

BACKGROUND: Helicobacter pylori causes peptic ulcers and accounts for over 90% of gastric cancers; however, eradication rates have been declining due to antimicrobial resistance. Vonoprazan (VPZ), a potassium-competitive acid blocker, produces rapid and profound gastric acid suppression and has shown promising effects in the improvement of H. pylori eradication rates. The efficacy and safety of VPZ-based triple therapy as a first-line regimen for H. pylori eradication and its relationship with clarithromycin (CAM) susceptibility were evaluated. METHODS: From May 2015 to September 2017, H. pylori-infected patients who underwent esophagogastroduodenoscopy with CAM susceptibility testing were prospectively enrolled. Patients received a 7-day triple therapy regimen (VAC) of VPZ (20 mg), amoxicillin (750 mg), and CAM (200 mg) twice daily. Eradication rates, demographics, CAM susceptibility, and safety profiles were assessed. RESULTS: VAC was administered to 146 patients (median age: 63, range: 22-85 years) (60% of whom were females) who underwent CAM susceptibility testing, and 131 patients underwent 13C-urea breath testing to evaluate eradication success. The prevalence of CAM resistance was 34.2%. The overall eradication rates of VAC in per protocol (PP) and "intention to treat" (ITT) analyses were 90.8% (n = 131) and 81.5% (n = 146), respectively. In PP analysis for CAM susceptibility, the eradication rates of VAC were comparable between CAM-sensitive (91.6%, n = 83) and CAM-resistant (89.4%, n = 47) strains. The corresponding rates from the ITT analysis were 80.0% (n = 95) and 84.0% (n = 50), respectively. No adverse events requiring discontinuation of VAC were observed. CONCLUSIONS: CAM-resistant H. pylori was prevalent in one-third of patients in the Tokyo metropolitan area. VPZ-based triple therapy was highly effective and well-tolerated irrespective of CAM susceptibility. Therefore, it could be a valuable first-line treatment regimen for H. pylori infection.

Totally implantable venous access port infection caused by Staphylococcus pseudintermedius: Possible transmission from a companion dog to a human.

S. pseudintermedius, recently identified as a novel Staphylococcus, causes a rare zoonotic infection that can be transmitted from dogs to humans. A 41-year-old man with atopic dermatitis receiving central parenteral nutrition through a totally implantable venous access port (TIVAP) after surgery for pseudomyxoma peritonei visited our outpatient clinic with a 2-day history of fever. The four strains isolated from the blood cultures from the TIVAP, dog's mouth, dog's nose, and dog's skin were all identified as S. pseudintermedius by partial heat shock protein (hsp60) gene sequencing. Initially, antibiotic-lock therapy with vancomycin (5 mg/mL in normal saline) through the catheter was administered concurrently with intravenous therapy. However, 52 days after the first discharge, he came back with a recurrent TIVAP infection with S. pseudintermedius bacteremia. He was successfully treated with intravenous antibiotic therapy after port removal and had no recurrence for 6 months without contact with the dog. The isolated strains were resistant to fluoroquinolone, which was consistent with trends in veterinary medicine in Japan. This case report raises awareness on S. pseudintermedius infections transmitted from domesticated dogs to patients with any implantable device, and the emerging resistance of S. pseudintermedius to current antibiotics.

Next endoscopic approach for acute lower gastrointestinal bleeding without an identified source on colonoscopy: upper or capsule endoscopy?

Background and study aims We evaluated the utility of esophagogastroduodenoscopy (EGD) or capsule endoscopy (CE) as the next diagnostic approach after negative colonoscopy (CS) results in acute-onset hematochezia. Patients and methods We retrospectively analyzed 401 patients emergently hospitalized for acute hematochezia who underwent CS within 48 hours of arriving at two large emergency hospitals and in whom a definitive bleeding source was not identified. The positive endoscopic findings, requirement for additional therapeutic procedures, and 30-day rebleeding rates were compared among three strategies: EGD following CS (CS-EGD), CE following CS (CS-CE), and CS alone. Predictors of positive endoscopic findings in the CS-EGD strategy were determined. Results The rates of positive endoscopic findings and requirement for additional therapeutic procedures were 22 % and 16 %, respectively, in CS-EGD and 50 % and 28 % in CS-CE. The 30-day rebleeding rate did not significantly decrease in CS-EGD (8 %) or CS-CE (11 %) compared with CS alone (12 %). The rate of additional endoscopic therapies was lower in patients with a colonic diverticulum than in those without (CS-EGD: 3 % vs. 33 %, P  = 0.007; CS-CE: 11 % vs. 44 %, P  = 0.147). A history of syncope, low blood pressure, blood urea nitrogen/creatinine ratio of ≥ 30, and low albumin level significantly predicted EGD findings after negative CS results ( P  < 0.05). Conclusions When the definitive bleeding source is not identified by colonoscopy in patients with acute hematochezia, adjunctive endoscopy helps to identify the etiology and enables subsequent therapy, especially for patients without a colonic diverticulum. Upper gastrointestinal endoscopy is indicated for severe bleeding; other patients may be candidates for capsule endoscopy.

Effects of bowel preparation on the human gut microbiome and metabolome.

Large bowel preparation may cause a substantial change in the gut microbiota and metabolites. Here, we included a bowel prep group and a no-procedure control group and evaluated the effects of bowel prep on the stability of the gut microbiome and metabolome as well as on recovery. Gut microbiota and metabolome compositions were analyzed by 16S rRNA sequencing and capillary electrophoresis time-of-flight mass spectrometry, respectively. Analysis of coefficients at the genus and species level and weighted UniFrac distance showed that, compared with controls, microbiota composition was significantly reduced immediately after the prep but not at 14 days after it. For the gut metabolome profiles, correlation coefficients between before and immediately after the prep were significantly lower than those between before and 14 days after prep and were not significantly different compared with those for between-subject differences. Thirty-two metabolites were significantly changed before and immediately after the prep, but these metabolites recovered within 14 days. In conclusion, bowel preparation has a profound effect on the gut microbiome and metabolome, but the overall composition recovers to baseline within 14 days. To properly conduct studies of the human gut microbiome and metabolome, fecal sampling should be avoided immediately after bowel prep.

Eradication therapy for Helicobacter pylori infection improves nutrition status in Japanese hemodialysis patients: a pilot study.

Plasma ghrelin level is influenced by Helicobacter pylori (H. pylori) status and the severity of gastric mucosal atrophy, and the ghrelin level is associated with nutrition status in hemodialysis patients. Here, we investigated the efficacy of H. pylori eradication therapy in improving nutrition status in relation to the ghrelin level in H. pylori-positive hemodialysis patients. Of H. pylori-positive patients receiving hemodialysis at 8 dialysis center, 21 patients underwent gastroduodenoscopy for evaluation of the severity of gastric atrophy, and nutrition markers and plasma ghrelin levels before and 1 year after H. pylori eradication therapy were evaluated. Serum cholinesterase level was significantly increased after H. pylori eradication compared with the level before eradication (303.2 ± 76.0 vs 287.3 ± 68.1 IU/L, p = 0.029). In particular, cholesterol (before, 196.6 ± 23.2 mg/dl; after, 206.1 ± 25.9 mg/dl, p = 0.042) and cholinesterase levels (before, 296.9 ± 70.8 IU/L; after, 316.4 ± 73.8 IU/L, p = 0.049) increased more strongly in patients with mild-moderate atrophy than those with severe atrophy, irrespective of improvement of plasma acyl-ghrelin and desacyl-ghrelin levels after eradication therapy. In conclusion, H. pylori eradication may improve nutrition status by increasing serum cholinesterase and cholesterol levels in hemodialysis patients, especially those with mild and moderate gastric mucosal atrophy.

A quality assurance for respiratory gated proton irradiation with range modulation wheel.

The purpose of this study was to provide periodic quality assurance (QA) methods for respiratory-gated proton beam with a range modulation wheel (RMW) and to clarify the characteristics and long-term stability of the respiratory-gated proton beam. A two-dimensional detector array and a solid water phantom were used to measure absolute dose, spread-out Bragg peak (SOBP) width and proton range for monthly QA. SOBP width and proton range were measured using an oblique incidence beam to the lateral side of a solid water phantom and compared between with and without a gating proton beam. To measure the delay time of beam-on/off for annual QA, we collected the beam-on/off signals and the dose monitor-detected pulse. We analyzed the results of monthly QA over a 15-month period and investigated the delay time by machine signal analysis. The dose deviations at proximal, SOBP center and distal points were -0.083 ± 0.25%, 0.026 ± 0.20%, and -0.083 ± 0.35%, respectively. The maximum dose deviation between with and without respiratory gating was -0.95% at the distal point and other deviations were within ±0.5%. Proximal and SOBP center doses showed the same trend over a 15-month period. Delay times of beam-on/off for 200 MeV/SOBP 16 cm were 140.5 ± 0.8 ms and 22.3 ± 13.0 ms, respectively. Delay times for 160 MeV/SOBP 10 cm were 167.5 ± 15.1 ms and 19.1 ± 9.8 ms. Our beam delivery system with the RMW showed sufficient stability for respiratory-gated proton therapy and the system did not show dependency on the energy and the respiratory wave form. The delay times of beam-on/off were within expectations. The proposed QA methods will be useful for managing the quality of respiratory-gated proton beams and other beam delivery systems.

New predictive model for acute gastrointestinal bleeding in patients taking oral anticoagulants: A cohort study.

BACKGROUND AND AIM: The study developed a predictive model of long-term gastrointestinal (GI) bleeding risk in patients receiving oral anticoagulants and compared it with the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratios, Elderly, Drugs/alcohol concomitantly) score. METHODS: The study periodically followed a cohort of 508 patients taking oral anticoagulants (66 direct oral anticoagulants users and 442 warfarin users). Absence of GI bleeding at an initial examination and any subsequent GI bleeding were confirmed endoscopically. The bleeding model was developed by multivariate survival analysis and evaluated by Harrell's c-index. RESULTS: During a median follow-up of 31.4 months, 42 GI bleeds (8.3%) occurred: 42.8% in the upper GI tract, 50.0% in the lower GI tract, and 7.1% in the middle GI tract. The cumulative 5 and 10-year probability of GI bleeding was 12.6% and 18.5%, respectively. Patients who bled had a significantly higher cumulative incidence of all-cause mortality (hazard ratio 2.9, P < 0.001). Multivariate analysis revealed that absence of proton pump inhibitor therapy, chronic kidney disease, chronic obstructive pulmonary disease, history of peptic ulcer disease, and liver cirrhosis predicted GI bleeding. The c-statistic for the new predictive model using these five factors was 0.65 (P < 0.001), higher than the HAS-BLED score of 0.57 (P = 0.145). CONCLUSIONS: Gastrointestinal bleeding increased the risk of subsequent mortality during follow-up of anticoagulated patients, highlighting the importance of prevention. The study developed a new scoring model for acute GI bleeding risk based on five factors (no-proton pump inhibitor use, chronic kidney disease, chronic obstructive pulmonary disease, history of peptic ulcer disease, and liver cirrhosis), which was superior to the HAS-BLED score.

Evaluation of dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy for the shallow depth tumor.

In this study, we evaluate dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy (IMPT) for head and neck tumors at the shallow depth. We used four types of patient-specific aperture system (PSAS) to irradiate shallow regions less than 4 g/cm2 with a sharp lateral penumbra. Ten head and neck IMPT plans with or without aperture were optimized separately with the same 95% prescription dose and same dose constraint for organs at risk (OARs). The plans were compared using dose volume histograms (DVHs), dose distributions, and some dose indexes such as volume receiving 50% of the prescribed dose (V50 ), mean or maximum dose (Dmean and Dmax ) to the OARs. All examples verified in this study had decreased V50 and OAR doses. Average, maximum, and minimum relative reductions of V50 were 15.4%, 38.9%, and 1.0%, respectively. Dmax and Dmean of OARs were decreased by 0.3% to 25.7% and by 1.0% to 46.3%, respectively. The plans with the aperture over more than half of the field showed decreased V50 or OAR dose by more than 10%. The dosimetric advantage of patient-specific apertures with IMPT was clarified in many cases. The PSAS has some dosimetric advantages for clinical use, and in some cases, it enables to fulfill dose constraints.

A proton therapy system in Nagoya Proton Therapy Center.

The purpose of this paper is to describe an outline of a proton therapy system in Nagoya Proton Therapy Center (NPTC). The NPTC has a synchrotron with a linac injector and three treatment rooms: two rooms are equipped with a gantry and the other one is equipped with a fixed horizontal beamline. One gantry treatment room has a pencil beam scanning treatment delivery nozzle. The other two treatment rooms have a passive scattering treatment delivery nozzle. In the scanning treatment delivery nozzle, an energy absorber and an aperture system to treat head and neck cancer have been equipped. In the passive treatment delivery nozzle, a multi-leaf collimator is equipped. We employ respiratory gating to treat lung and liver cancers for passive irradiation. The proton therapy system passed all acceptance tests. The first patient was treated on February 25, 2013, using passive scattering fixed beams. Respiratory gating is commonly used to treat lung and liver cancers in the passive scattering system. The MLCs are our first choice to limit the irradiation field. The use of the aperture for scanning irradiation reduced the lateral fall off by half or less. The energy absorber and aperture system in scanning delivery is beneficial to treat head and neck cancer.

A patient-specific aperture system with an energy absorber for spot scanning proton beams: Verification for clinical application.

PURPOSE: In the authors' proton therapy system, the patient-specific aperture can be attached to the nozzle of spot scanning beams to shape an irradiation field and reduce lateral fall-off. The authors herein verified this system for clinical application. METHODS: The authors prepared four types of patient-specific aperture systems equipped with an energy absorber to irradiate shallow regions less than 4 g/cm(2). The aperture was made of 3-cm-thick brass and the maximum water equivalent penetration to be used with this system was estimated to be 15 g/cm(2). The authors measured in-air lateral profiles at the isocenter plane and integral depth doses with the energy absorber. All input data were obtained by the Monte Carlo calculation, and its parameters were tuned to reproduce measurements. The fluence of single spots in water was modeled as a triple Gaussian function and the dose distribution was calculated using a fluence dose model. The authors compared in-air and in-water lateral profiles and depth doses between calculations and measurements for various apertures of square, half, and U-shaped fields. The absolute doses and dose distributions with the aperture were then validated by patient-specific quality assurance. Measured data were obtained by various chambers and a 2D ion chamber detector array. RESULTS: The patient-specific aperture reduced the penumbra from 30% to 70%, for example, from 34.0 to 23.6 mm and 18.8 to 5.6 mm. The calculated field width for square-shaped apertures agreed with measurements within 1 mm. Regarding patient-specific aperture plans, calculated and measured doses agreed within -0.06% ± 0.63% (mean ± SD) and 97.1% points passed the 2%-dose/2 mm-distance criteria of the γ-index on average. CONCLUSIONS: The patient-specific aperture system improved dose distributions, particularly in shallow-region plans.