Physical characteristics of deep learning-based image processing software in computed tomography: a phantom study.

PURPOSE: This study aimed to assess the image characteristics of deep-learning-based image processing software (DLIP; FCT PixelShine, FUJIFILM, Tokyo, Japan) and compare it with filtered back projection (FBP), model-based iterative reconstruction (MBIR), and deep-learning-based reconstruction (DLR). METHODS: This phantom study assessed the object-specific spatial resolution (task-based transfer function [TTF]), noise characteristics (noise power spectrum [NPS]), and low-contrast detectability (low-contrast object-specific contrast-to-noise ratio [CNRLO]) at three different output doses (standard: 10 mGy; low: 3.9 mGy; ultralow: 2.0 mGy). The processing strength of DLIPFBP with A1, A4, and A9 was compared with those of FBP, MBIR, and DLR. RESULT: The standard dose with high-contrast TTFs of DLIPFBP exceeded that of FBP. Low-contrast TTFs were comparable to or lower than that of FBP. The NPS peak frequency (fP) of DLIPFBP shifts to low spatial frequencies of up to 8.6% at ultralow doses compared to the standard FBP dose. MBIR shifted the most fP compared to FBP-a marked shift of up to 49%. DLIPFBP showed a CNRLO equal to or greater than that of DLR in standard or low doses. In contrast, the CNRLO of the DLIPFBP was equal to or lower than that of the DLR in ultralow doses. CONCLUSION: DLIPFBP reduced image noise while maintaining a resolution similar to commercially available MBIR and DLR. The slight spatial frequency shift of fP in DLIPFBP contributed to the noise texture degradation suppression. The NPS suppression in the low spatial frequency range effectively improved the low-contrast detectability.

Repeat endoscopic third ventriculostomy combined with choroid plexus cauterization as salvage surgery for failed endoscopic third ventriculostomy.

PURPOSE: Although the endoscopic third ventriculostomy (ETV) is an effective treatment for hydrocephalus, failures do on occasion occur. In such cases, a repeat ETV or shunt insertion is usually performed. However, there is, as of yet, no clear consensus on the best measure to take in the event of a failed ETV. We herein examined the outcomes of a repeat ETV combined with choroid plexus cauterization for ETV failure. METHODS: All patients who underwent an ETV at the Department of Neurosurgery at Tokyo Metropolitan Children's Medical Center between April 2013 and March 2019 were retrospectively analyzed. RESULTS: In total, 36 patients received an ETV. Six patients experienced ETV failure; three of these underwent a repeat ETV combined with choroid plexus cauterization. Three of the six patients who experienced early ETV failure received a ventriculoperitoneal shunt. During the median follow-up period of 42 months (range: 32-73 months), all repeat ETVs were successful. CONCLUSION: A repeat ETV combined with choroid plexus cauterization can be an effective salvage therapy in the event of ETV failure.

Comprehensive efficacy of ipragliflozin on various conditioned type 2 diabetes compared with dipeptidyl peptidase-4 inhibitors and with both agents, based on a real-world multicenter trial.

AIMS: The effects of ipragliflozin, the first sodium-glucose co-transporter 2 inhibitors (SGLT2i) launched in Japan in 2014, and with dipeptidyl peptidase-4 inhibitors (DPP-4i) on glycemic control and metabolic changes were investigated comprehensively on various conditioned type 2 diabetes (T2DM) by evaluating various clinical parameters in a real-world setting. MATERIALS AND METHODS: A total of 101 patients with T2DM aged 20-80 years with 7.0% ≤ HbA1c < 10.0% were followed in this 52-week, open-label, prospective, real-world, multicenter study. RESULTS: HbA1c decreased significantly in all groups. In ipragliflozin using groups, body weight, waist circumference, blood pressure, HOMA-IR, AST, ALT, γ-GTP, uric acid and leptin levels decreased, in contrast, HDL-cholesterol, total ketone bodies, blood urea nitrogen, creatinine, RBC, hemoglobin and hematocrit levels increased, however, in DPP-4i sole group, no significant trends were observed in these parameters. Change in leptin positively correlated with insulin, while change in total ketone bodies inversely correlated with ALT in ipragliflozin using groups. Fasting active gastric inhibitory polypeptide levels decreased in ipragliflozin sole group. Glucagon showed no changes. No significant safety concerns were observed in this study. CONCLUSIONS: Ipragliflozin is useful and safe, showing some contrastive effects on several clinical parameters which are not shown with DPP-4i, resulting several clinical benefits. The co-administration of ipragliflozin and a DPP-4i has a better clinical outcome than either single-agent therapy.

Alteration of gut microbiota by a Westernized lifestyle and its correlation with insulin resistance in non-diabetic Japanese men.

AIMS/INTRODUCTION: The severity of insulin resistance is higher in Japanese-American people with American lifestyles than in native Japanese people with Japanese lifestyles. Recently, the role of gut microbiota in the control of host metabolic homeostasis and organ physiology has been recognized. In addition, gut microbiota alterations have been suggested to contribute to pathogenesis of insulin resistance. The principle aim of the present study was to evaluate the impact of a Westernized lifestyle on the gut microbiota of Japanese-Americans versus native Japanese, and its correlation with insulin resistance. MATERIALS AND METHODS: A total of 14 native Japanese men living in Hiroshima, Japan, and 14 Japanese-American men living in Los Angeles, USA, were included. A 75-g oral glucose tolerance test was carried out for all participants to assess their glucose tolerance, and normal glucose tolerance was observed. We compared the insulin response with oral glucose load, the Matsuda Index, and the composition of the gut microbiota between the native Japanese and Japanese-American men. RESULTS: Japanese-American men showed higher area under the curve values for serum insulin concentrations during the oral glucose tolerance test and lower Matsuda Index than native Japanese men. Gut microbiota composition of the Japanese-American men was different; in particular, they showed a relatively lower abundance of Odoribacter than native Japanese men. The ratio between relative abundance of Odoribacter and Matsuda Index was positively correlated between the two groups. CONCLUSIONS: Our findings suggest that Westernized lifestyles alter gut microbiota, and its alteration might induce insulin resistance in non-diabetic Japanese men.

Association between circulating tumor necrosis factor-related biomarkers and estimated glomerular filtration rate in type 2 diabetes.

Chronic inflammation plays a crucial role in the development/progression of diabetic kidney disease. The involvement of tumor necrosis factor (TNF)-related biomarkers [TNFα, progranulin (PGRN), TNF receptors (TNFR1 and TNFR2)] and uric acid (UA) in renal function decline was investigated in patients with type 2 diabetes (T2D). Serum TNF-related biomarkers and UA levels were measured in 594 Japanese patients with T2D and an eGFR ≥30 mL/min/1.73 m2. Four TNF-related biomarkers and UA were negatively associated with estimated glomerular filtration rate (eGFR). In a logistic multivariate model, each TNF-related biomarker and UA was associated with lower eGFR (eGFR <60mL /min/1.73 m2) after adjustment for relevant covariates (basic model). Furthermore, UA and TNF-related biomarkers other than PGRN added a significant benefit for the risk factors of lower eGFR when measured together with a basic model (UA, ΔAUC, 0.049, p < 0.001; TNFα, ΔAUC, 0.022, p = 0.007; TNFR1, ΔAUC, 0.064, p < 0.001; TNFR2, ΔAUC, 0.052, p < 0.001) in receiver operating characteristic curve analysis. TNFR ligands were associated with lower eGFR, but the associations were not as strong as those with TNFRs or UA in patients with T2D and an eGFR ≥30 mL/min/1.73 m2.

Clinical predictive biomarkers for normoalbuminuric diabetic kidney disease.

AIMS: A portion of patients with diabetes mellitus follow the progression of a non-albuminuria-based pathway; i.e., normoalbuminuric diabetic kidney disease (NA-DKD). However, the risk factors which determine NA-DKD are not yet fully understood. This cross-sectional study was therefore aimed to investigate the association between various biomarker levels and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus and normoalbuminuria (T2D-NA). METHODS: We measured cardiovascular disease (CVD) [serum osteoprotegerin (OPG), plasma brain natriuretic peptide (BNP), cardio-ankle vascular index (CAVI)], tubular damage [urinary L-type fatty acid binding protein (L-FABP)], and inflammatory [serum tumornecrosis factor (TNF) α and its receptors (TNFRs)] biomarkers in 314 patients with T2D-NA. RESULTS: The biomarkers of CVD and inflammation showed a significant negative correlation with eGFR. In a logistic multivariate model, none of the biomarkers, except TNFα and TNFRs, were associated with reduced renal function (eGFR < 60 mL/min/1.73 m2) after adjustment for possible biological and clinical covariates. However, the association observed in TNFα was lost after adjusting for TNFR and other covariates. CONCLUSIONS: In patients with T2D-NA, elevated levels of circulating TNFRs, but not of TNFα, were strongly associated with reduced renal function, independently of all relevant covariates.

Lipidation of BmAtg8 is required for autophagic degradation of p62 bodies containing ubiquitinated proteins in the silkworm, Bombyx mori.

p62/Sequestosome-1 (p62/SQSTM1, hereafter referred to as p62) is a major adaptor that allows ubiquitinated proteins to be degraded by autophagy, and Atg8 homologs are required for p62-mediated autophagic degradation, but their relationship is still not understood in Lepidopteran insects. Here it is clearly demonstrated that the silkworm homolog of mammalian p62, Bombyx mori p62 (Bmp62), forms p62 bodies depending on its Phox and Bem1p (PB1) and ubiquitin-associated (UBA) domains. These two domains are associated with Bmp62 binding to ubiquitinated proteins to form the p62 bodies, and the UBA domain is essential for the binding, but Bmp62 still self-associates without the PB1 or UBA domain. The p62 bodies in Bombyx cells are enclosed by BmAtg9-containing membranes and degraded via autophagy. It is revealed that the interaction between the Bmp62 AIM motif and BmAtg8 is critical for the autophagic degradation of the p62 bodies. Intriguingly, we further demonstrate that lipidation of BmAtg8 is required for the Bmp62-mediated complete degradation of p62 bodies by autophagy. Our results should be useful in future studies of the autophagic mechanism in Lepidopteran insects.

Preoperative and Postoperative Pituitary Function in Patients with Tuberculum Sellae Meningioma -Based on Pituitary Provocation Tests.

Given the anatomical proximity of tuberculum sellae meningioma (TSM) to the hypothalamo-pituitary system, pituitary function impairments are of great concern. We retrospectively investigated pituitary function changes following surgery in patients with TSM using pituitary provocation tests (PPTs). Thirty-one patients (27 females and 4 males) with TSM underwent initial transcranial surgery (29 patients) or transsphenoidal surgery (two patients); surgeries were performed carefully to avoid injuring the pituitary stalk. In 24 patients, the PPTs were performed via a triple bolus injection with regular insulin, thyrotropin-releasing hormone (TRH), and luteinizing hormone releasing hormone (LH-RH). Seven patients underwent a quadruple test (growth-hormone-releasing factor, corticotrophin-releasing hormone, TRH, and LH-RH). The preoperative and postoperative target hormone levels of the anterior pituitary were normal in 93.5% and 96.8% of patients, respectively. At least one hormonal axis demonstrated impaired PPT responses in two patients (6.5%) preoperatively and in one patient (3.2%) postoperatively. The growth hormone (GH) response was also well preserved. A compromised GH peak level was only observed in one patient (3.2%) preoperatively. Postoperatively, transient diabetes insipidus and transient hyponatremia were observed in four (12.9%) and eight (25.8%) patients, respectively. No patients needed permanent postoperative hormone replacement. The preoperative pituitary function was well preserved in most patients, including those with large tumors pushing against the pituitary stalk considerably or embedded in it. After careful surgery to avoid damaging the pituitary stalk, pituitary function was preserved. However, transient postoperative hyponatremia occurred in 25.8% of patients; thus, surgeons should pay careful attention to this issue.

Characterization of Recombinant Thermococcus kodakaraensis (KOD) DNA Polymerases Produced Using Silkworm-Baculovirus Expression Vector System.

The KOD DNA polymerase from Thermococcus kodakarensis (Tkod-Pol) has been preferred for PCR due to its rapid elongation rate, extreme thermostability and outstanding fidelity. Here in this study, we utilized silkworm-baculovirus expression vector system (silkworm-BEVS) to express the recombinant Tkod-Pol (rKOD) with N-terminal (rKOD-N) or C-terminal (rKOD-C) tandem fusion tags. By using BEVS, we produced functional rKODs with satisfactory yields, about 1.1 mg/larva for rKOD-N and 0.25 mg/larva for rKOD-C, respectively. Interestingly, we found that rKOD-C shows higher thermostability at 95 °C than that of rKOD-N, while that rKOD-N is significantly unstable after exposing to long period of heat-shock. We also assessed the polymerase activity as well as the fidelity of purified rKODs under various conditions. Compared with commercially available rKOD, which is expressed in E. coli expression system, rKOD-C exhibited almost the same PCR performance as the commercial rKOD did, while rKOD-N did lower performance. Taken together, our results suggested that silkworm-BEVS can be used to express and purify efficient rKOD in a commercial way.

Symptom relief effect of palliative high dose rate intracavitary radiotherapy for advanced esophageal cancer with dysphagia.

Intracavitary radiotherapy (ICRT) for the palliative treatment of advanced esophageal cancer with dysphagia is currently performed at the University of Tokyo Hospital (Tokyo, Japan). In the present study, 24 patients exhibiting advanced esophageal cancer with dysphagia received palliative ICRT. ICRT, which was delivered 5 mm below the esophageal mucous membrane, with the exception of one case, was administered at a dose of 6 Gy/fraction. Specific patients additionally underwent definitive or palliative external beam radiation therapy for esophageal cancer a minimum of three months prior to ICRT. The effect of treatment on symptom alleviation was examined by comparing the dysphagia score prior to and following ICRT, with the patients' medical records and a questionnaire used to calculate a dysphagia score ranging from zero (no dysphagia) to four (total dysphagia). In consideration of the individual efficacy of the treatment, the maximum number of repeated ICRT fractions was four (median, 1.7 times). A trend in the improvement of the symptom of dysphagia was observed in response to esophageal ICRT, with the average dysphagia score markedly decreasing from 2.54 to 1.65, however, the difference was not significant (P=0.083). Furthermore, pain was the most frequent side-effect of the esophageal ICRT and no patients exhibited severe complications. Thus, esophageal ICRT at a dose of 6 Gy/fraction may present an effective strategy for relieving the symptom of dysphagia in cases of advanced esophageal cancer.

Individually wide range of renal motion evaluated by four-dimensional computed tomography.

OBJECTIVES: Assessment of physiologic renal motion in order to optimize abdominal intensity-modulated radiation therapy and stereotactic body radiation therapy. METHODS AND MATERIALS: Twenty patients with a median age of 47 years underwent computed tomography simulation and four-dimensional computed tomography acquisition. Thirty-nine kidneys were contoured during ten phases of respiration to estimate renal motion. RESULTS: Kidney motion was not related to age (p = 0.42), sex (p = 0.28), height (p = 0.75), or body weight (p = 0.63). The average +/- standard deviation (SD) of movement of the center of gravity for all subjects was 11.1 +/- 4.8 mm in the cranio-caudal (CC) direction (range, 2.5-20.5 mm), 3.6 +/- 2.1 mm in the anterior-posterior (AP) direction (range, 0.6-8.0 mm), and 1.7 +/- 1.4 mm in the right-left (RL) direction (range, 0.4-5.9 mm). Renal motion strongly correlated with the respiratory phases (r > 0.97 and p < 0.01 in all three directions). CONCLUSIONS: Renal motion was independent of age, sex, height, or body weight. Renal motion in all directions was strongly respiration dependent, but motion in the cranio-caudal direction showed wide individual variation. In a clinical setting, it will be necessary to evaluate renal respiratory motion separately in each individual.

Extended cancer-free survival after palliative chemoradiation for metastatic esophageal cancer.

We report on a patient who remained cancer-free for an extended time after palliative radiotherapy (RT) and chemotherapy (nedaplatin plus 5-fluorouracil) treatment for stage IV (cT3N3M1) esophageal squamous cell carcinoma. Although multiple lymph nodes outside the RT field recurred, the local primary tumor within the RT field did not recur, even 17 mo after palliative RT of 30 Gy in 10 fractions. In this case, acute toxicity, such as myelosuppression or esophagitis, was not enhanced by increasing the fraction dose from 1.8-2.0 Gy to 3.0 Gy. Because 30 Gy in 10 fractions can be completed within a shorter time and is less expensive than 50.4 Gy in 28 fractions, we think that 30 Gy without oblique beams is a more favorable RT method for patients.

Semi-radical chemoradiotherapy for 53 esophageal squamous cell carcinomas with supraclavicular lymph node metastasis in a single institutional retrospective study.

OBJECTIVE: Outcomes were examined for the cases that received radiotherapy (RT) for esophageal cancer with metastasis to supraclavicular lymph nodes (ScLN) in a single institutional retrospective study. MATERIALS AND METHODS: Cases examined were 53 consecutive patients with pathologically confirmed esophageal cancer enrolled from our institution who received semi-radical RT from 2001 to 2013. Radiotherapy consisted of a total dose of from 50-50.4 Gy given in 25-28 fractions of 1.8-2.0 Gy with five fractions per week. The chemotherapy regimen included nedaplatin and 5-fluorouracil. All had ScLN metastasis, and all diseases were included in the RT field. RESULTS: The median follow up time was 42 months for survival patients. Overall survival (OS) and progression free survival (PFS) for 1-, 2-, and 3 years were 39%, 19%, and 12% and 14%, 9%, and 6%, respectively. Acute grade 3-5 esophagitis and neutropenia was seen in 11% and 81%, respectively. Late grade 3-5 toxicity in esophagus, lung, and heart was seen in 4%, 0%, and 0%. Five patients (9%) survived more than 4 year. CONCLUSION: Although the 2-year PFS was less than 10% and very poor, long term survival for over 4 year was seen in 9% cases. In other words, despite the poor results, the fact remains that some patients were cured with CRT.

A novel fully automated molecular diagnostic system (AMDS) for colorectal cancer mutation detection.

BACKGROUND: KRAS, BRAF and PIK3CA mutations are frequently observed in colorectal cancer (CRC). In particular, KRAS mutations are strong predictors for clinical outcomes of EGFR-targeted treatments such as cetuximab and panitumumab in metastatic colorectal cancer (mCRC). For mutation analysis, the current methods are time-consuming, and not readily available to all oncologists and pathologists. We have developed a novel, simple, sensitive and fully automated molecular diagnostic system (AMDS) for point of care testing (POCT). Here we report the results of a comparison study between AMDS and direct sequencing (DS) in the detection of KRAS, BRAF and PI3KCA somatic mutations. METHODOLOGY/PRINCIPAL FINDING: DNA was extracted from a slice of either frozen (n = 89) or formalin-fixed and paraffin-embedded (FFPE) CRC tissue (n = 70), and then used for mutation analysis by AMDS and DS. All mutations (n = 41 among frozen and 27 among FFPE samples) detected by DS were also successfully (100%) detected by the AMDS. However, 8 frozen and 6 FFPE samples detected as wild-type in the DS analysis were shown as mutants in the AMDS analysis. By cloning-sequencing assays, these discordant samples were confirmed as true mutants. One sample had simultaneous "hot spot" mutations of KRAS and PIK3CA, and cloning assay comfirmed that E542K and E545K were not on the same allele. Genotyping call rates for DS were 100.0% (89/89) and 74.3% (52/70) in frozen and FFPE samples, respectively, for the first attempt; whereas that of AMDS was 100.0% for both sample sets. For automated DNA extraction and mutation detection by AMDS, frozen tissues (n = 41) were successfully detected all mutations within 70 minutes. CONCLUSIONS/SIGNIFICANCE: AMDS has superior sensitivity and accuracy over DS, and is much easier to execute than conventional labor intensive manual mutation analysis. AMDS has great potential for POCT equipment for mutation analysis.