Clinical evaluation of deep learning and atlas-based auto-segmentation for organs at risk delineation.

Manual delineation of organs at risk and clinical target volumes is essential in radiotherapy planning. Atlas-based auto-segmentation (ABAS) algorithms have become available and been shown to provide accurate contouring for various anatomical sites. Recently, deep learning auto-segmentation (DL-AS) algorithms have emerged as the state-of-the-art in medical image segmentation. This study aimed to evaluate the effect of auto-segmentation on the clinical workflow for contouring different anatomical sites of cancer, such as head and neck (H&N), breast, abdominal region, and prostate. Patients with H&N, breast, abdominal, and prostate cancer (n = 30 each) were enrolled in the study. Twenty-seven different organs at four sites were evaluated. RayStation was used to apply the ABAS. Siemens AI-Rad Companion Organs RT was used to apply the DL-AS. Evaluations were performed with similarity indices using geometric methods, time-evaluation, and qualitative scoring visual evaluations by radiation oncologists. The DL-AS algorithm was more accurate than ABAS algorithm on geometric indices for half of the structures. The qualitative scoring results of the two algorithms were significantly different, and DL-AS was more accurate on many contours. DL-AS had 41%, 29%, 86%, and 15% shorter edit times in the HnN, breast, abdomen, and prostate groups, respectively, than ABAS. There were no correlations between the geometric indices and visual assessments. The time required to edit the contours was considerably shorter for DL-AS than for ABAS. Auto-segmentation with deep learning could be the first step for clinical workflow optimization in radiotherapy.

Dosimetric Comparison of 3D Conformal Radiotherapy (3D-CRT), Intensity-Modulated Radiotherapy (IMRT), and Volumetric-Modulated Arc Therapy (VMAT) in Cardiac-Sparing Whole Lung Irradiation.

Introduction Whole lung irradiation (WLI) is used for the treatment of lung metastasis in Wilms tumor and Ewing sarcoma; however, cardiac complications are one of the concerns. We report the dosimetric advantages of WLI using volumetric-modulated arc therapy (VMAT) and present a dosimetric comparison of VMAT with anteroposterior-posteroanterior (AP-PA) and static-field intensity-modulated radiation therapy (IMRT). Additionally, we evaluated the dosimetric impact of respiratory motion and intra-fractional motion during VMAT treatment. Methods Seven patients were recruited in this study. AP-PA, IMRT, one-isocenter (1-IC) VMAT, and 2-IC VMAT were planned on the maximum inspiration and expiration CT, respectively. The prescribed dose was 15 Gy in 10 fractions. To determine the effects of respiratory motion, the CT series was replaced and the dose was evaluated while maintaining the beam information. To determine the effect of patient motion, perturbed dose calculations were performed using a two-IC VMAT. The perturbation doses were calculated by shifting only the IC of the one side beam by 3 mm or 5 mm in the right-to-left (RL) direction. Results The mean heart dose was 1467.0 cGy, 790.0 cGy, 764.2 cGy, and 738.4 cGy for AP-PA, IMRT, 1-IC VMAT, and 2-IC VMAT, respectively. When the expiration CT plan was recalculated with inspiration CT, Dmax increased approximately by 8%. In the 2-IC VMAT plan, the D50%, D98%, and D2% dose differences were within ±2%, even with a 5 mm IC shift. Conclusion We confirmed a significant dosimetric advantage of VMAT over other techniques. 2-IC VMAT should be considered an effective treatment option during irradiation for large target volumes.

Correlation Between the Transient Elevation of Peripheral Eosinophil Count During Radiotherapy and Acute Diarrhea.

Background/Aim: This study aimed to evaluate the association between the change in peripheral eosinophil count during postoperative pelvic radiotherapy and gastrointestinal (GI) toxicities in patients with cervical cancer. Patients and Methods: The medical records of 163 patients with cervical cancer who underwent postoperative concurrent chemoradiotherapy between 2000 and 2016 were analyzed. Results: Among the peripheral blood cell counts, transient elevation of the eosinophil count was observed during radiotherapy. Of the 163 patients, 117 developed grade ≥2 diarrhea during radiotherapy, and 25 patients developed grade ≥2 late GI toxicities. In multivariate analysis, the maximum eosinophil count and age emerged as independent predictors of grade ≥2 acute diarrhea during radiotherapy, while bowel bag V 40 Gy and age were predictive of grade ≥2 late GI toxicities. Conclusion: Early detection of transient elevation of eosinophil may facilitate early treatment of acute diarrhea during radiotherapy.

Raltegravir-associated Diabetic Ketoacidosis in a Patient with HIV Infection: A Case Report.

Antiretroviral drugs, especially protease inhibitors (PI), are known to induce disorders of lipid and glucose metabolism. However, there are only a few reports of these side effects in patients treated with integrase strand transfer inhibitors (INSTI). We encountered the case of a 46-year-old man who had been treated for type 2 diabetes with diet and exercise. He contracted immunodeficiency virus (HIV) infection two years earlier and received highly active antiretroviral therapy (HAART). Three months before the current admission, HAART was switched from a non-nucleic acid reverse transcriptase inhibitor (NNRTI) to an INSTI (raltegravir: 800 mg/day). He developed diabetic ketoacidosis and was admitted for treatment. The state of health prior to admission was not well documented but he showed no clinical signs of acute infection. Accordingly, diabetic ketoacidosis was considered to be associated with INSTI. Diabetic ketoacidosis was treated appropriately and blood glucose level was controlled with medications before discharge from the hospital. Although the present case does not provide direct evidence for raltegravir-induced diabetic ketoacidosis, we caution physicians about the potential of such side effect associated with the use of INSTI.

Clinical Course of Eosinophilic Cellulitis.

The patient was a previously healthy 23-year-old woman who made an outpatient visit to our hospital's Department of General Internal Medicine after developing pain and edema of the lower legs a week earlier. The patient was diagnosed with eosinophilic cellulitis (EC) based on an increased eosinophil count of 5,418/mm3 and the results of a skin biopsy of the lower leg that showed eosinophilic infiltration of the dermal tissue. Her condition improved after oral prednisone therapy. EC presents clinically as edema and eosinophilia. Therefore, in many cases, patients make an outpatient visit to the internal medicine department. In the present study, the clinical course of nine patients diagnosed with EC as outpatients at our Department of General Internal Medicine over the past 10 years was examined.

Signatures in the gut microbiota of Japanese infants who developed food allergies in early childhood.

Bacterial colonization in infancy is considered crucial for the development of the immune system. Recently, there has been a drastic increase in childhood allergies in Japan. Therefore, we conducted a prospective study with 56 infants on the relationship between gut microbiota in the first year of life and the development of allergies during the first 3 years. In the lactation period, organic acid producers such as Leuconostoc, Weissella and Veillonella tended to be underrepresented in subjects who developed food allergies (FA, n = 14) within the first two years. In the weaning period, children in the FA group were highly colonized by unclassified Enterobacteriaceae and two Clostridium species closely related to Clostridium paraputrificum and C. tertium, and the whole tree phylogenetic diversity index was significantly lower in the FA group. All of these differences in the weaning period were statistically significant, even after adjusting for potential confounding factors. A higher abundance of unclassified Enterobacteriaceae was also found in the other allergic group (n = 15), whereas the two Clostridium species were highly specific to the FA group. The mode of action of these Clostridium species in childhood food allergies remains unknown, warranting further investigation.

Intervertebral disc calcification with ossification of the posterior longitudinal ligament.

A 6-year-old girl presented to hospital with a 4 day history of increasing neck pain. White blood cell count was normal with slightly raised C-reactive protein. The patient had a limited range of neck movement, and experienced enhanced pain with neck extension. X-ray and cervical computed tomography (CT) confirmed the diagnosis of cervical intervertebral disc calcification (IDC) and IDC with ossification of the posterior longitudinal ligament (OPLL), respectively. The symptoms improved after approximately 1 week following rest and oral acetaminophen. X-ray 6 months after onset confirmed the disappearance of the calcification. IDC is often reported in children, but IDC with OPLL is extremely rare and has not been previously reported in Japan. We believe that IDC with or without OPLL in children has a good prognosis when treated conservatively.

A Comparison of the Abdominal Fat Distribution and Coronary Risk Markers in Body Mass Index-matched Subjects with and without Fatty Liver.

Objective The close relationship between fatty liver and metabolic syndrome suggests that individuals with fatty liver may have multiple coronary risk factors. In the present study, we investigated the relationships among fatty liver, abdominal fat distribution, and coronary risk markers. Methods and Results Eighty-seven pairs of men and 42 pairs of women who were matched for age and body mass index were enrolled in the present study. The obesity-related markers, abdominal fat distribution (examined by CT), and coronary risk markers were compared in subjects with and without fatty liver. The visceral fat area was significantly larger in the men with fatty liver than in the men without fatty liver. The plasma levels of triglyceride and low-density lipoprotein cholesterol (LDL-C), as well as the homeostasis model assessment-insulin resistance level, were higher in both males and females with fatty liver than in those without fatty liver, while the plasma levels of high-density lipoprotein cholesterol (HDL-C) and adiponectin were lower in the males and females with fatty liver. The plasma levels of apolipoprotein B, remnant-like particle cholesterol (RLP-C), and oxidized LDL were higher in men with fatty liver, but not in women with fatty liver. Conclusion Both males and females with fatty liver had lower insulin sensitivity, lower plasma levels of HDL-C and adiponectin, and higher triglyceride and LDL-C levels. However, the plasma levels of apolipoprotein B, RLP-C, and oxidized LDL were only higher and closely associated with fatty liver in men. Men with fatty liver had a higher risk of coronary disease than women with fatty liver.

Discriminating analysis of atypical squamous cells of undetermined significance of the uterine cervix using nuclear three-dimensional analysis.

OBJECTIVE: The Bethesda System (TBS) of uterine cervical cytology is a classification method that can improve accuracy in management and it includes descriptions on adequate specimens, human papillomavirus (HPV) involvement and estimated lesions. However, the judgment of atypical squamous cells of undetermined significance (ASC-US) using TBS features complicated diagnostic criteria and poor reproducibility due to the definition of ASC-US. Of patients diagnosed with ASC-US in the initial cytology, cervical intraepithelial neoplasia (CIN)1-2 cases positive for high-risk HPV (CIN+) and benign cases in histology negative for high-risk HPV (B-) were selected for discriminant analysis based on Mahalanobis distance, in order to improve the accuracy of the ASC-US diagnosis. STUDY DESIGN: ASC-US cases featuring koilocytosis with little nuclear atypia (koilocytosis) and squamous epithelial cells with nuclear atypia (SC with atypia), morphologically diagnosed with liquid-based cytology specimens prepared using ThinPrep were included. The nuclei of koilocytosis cases (CIN+, 8 cases, and B-, 10 cases) and SC with atypia (CIN+, 19 cases, and B-, 15 cases) were three-dimensionally analyzed to conduct a discriminant analysis based on Mahalanobis distance. RESULTS: Discrimination rates were 78.9% for CIN+ and 66.7% for B- in koilocytosis, and 50.7% for CIN+ and 72.1% for B- in SC with atypia. CONCLUSION: The present method allows the objective analysis of nuclear chromatin, providing effective cytology regarding CIN+ in koilocytosis and B- in SC with atypia of ASC-US cases.

Significance of binucleated cells with compression in atypical squamous cells of undetermined significance.

OBJECTIVE: To increase the accuracy of the diagnosis of atypical squamous cells of undetermined significance (ASC-US), ASC-US were divided into high-risk human papillomavirus (HPV HR+) and non-high-risk HPV (HPV HR-) cases to analyze the significance of binucleated cells with compression. STUDY DESIGN: ThinPrep specimens of ASC-US were examined. This study included 21 CIN and HPV HR+ (CIN+), 19 benign and HPV HR- (B-) and 10 benign and HPV HR+ (B+) cases. The number of cells were examined by defining binucleated cells with their nuclei pressing against each other as positive compression, and their relation to the relative light units (RLUs) of the DNA Hybrid capture 2 (HC2) was determined. RESULTS: 95.2% of CIN+ and 15.8% of B- cases were compression positive, while 4.8% of CIN+ and 84.2% of B- cases were compression negative, which was significantly different. The average number of cells with positive compression was 5.7 ± 5.3 in CIN+, 2.0 ± 0.7 in B- and 5.5 ± 1.5 in B+ cases, with significant differences between CIN+ and B- and between B- and B+ cases. The number of compression-positive cells increased as HPV HC2 RLUs became higher. CONCLUSION: Positive compression is useful in determining ASC-US with HPV HR+. The identification of positive compression is highly practical because it can be observed morphologically.

World wide web-based cytological analysis of atypical squamous cells cannot exclude high-grade intraepithelial lesions.

OBJECTIVE: It has been reported that the low level of consistency of diagnosis of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H) in uterine cervical cancer screening using the Bethesda System, indicating the necessity of a large-scale survey. We presented cases cytologically judged as ASC-H on our website and invited our members to give their opinions regarding the diagnosis by voting online. The Web voting results were analyzed and ASC-H was cytologically investigated. STUDY DESIGN: Virtual slides of atypical cells in cytology preparations of 53 cases were prepared and presented on a website. ASC-H cases were divided into 42 cases sampled by brush scraping and 11 cases sampled by cotton swab scraping. Fifty-three cases cytologically judged as ASC-H were classified into benign and CIN2/3, and their patterns of arrangement of atypical cells and 8 cytological parameters were morphologically investigated. RESULTS: The frequency of ASC-H diagnosis in the Web votes was low: 29.2% for brush-scraped and 26.2% for cotton swab-scraped cases. Three-dimensionality, coarse chromatin and irregular nuclei were significantly different between high-grade squamous intraepithelial lesions and benign cases. CONCLUSION: Web-based surveys showed the difference of cytological findings between high-grade squamous intraepithelial lesions and benign cases. To increase interobserver consistency, it may be useful to share information online, which avoids geographical and temporal limitations.

Expression of transcription factor Snai1 and tubulointerstitial fibrosis in progressive nephropathy.

BACKGROUND: Tubulointerstitial fibrosis (TIF) is seen as the final stage of progressive nephropathy, and the degree of TIF is reported to be a major determinant in renal outcomes. In recent years, epithelial-mesenchymal transition (EMT) and the zinc-finger transcription factor snail homolog 1 (Snai1) have each been implicated in the mechanism of TIF. The relationship between EMT and these transcription factors is unclear, however, so in this study we attempted to elucidate the correlation between the expression of Snai1 and clinical markers. METHODS: We performed immunohistochemical staining on human renal tissue obtained from patients with diabetic nephropathy (DN), IgA nephropathy (IgAN), minimal change disease (MCD) and minor glomerular abnormality (MGA) using anti-Snai1 and anti-vimentin antibodies. We counted Snai1-positive and Snai1/vimentin double positive tubular epithelial cells. RESULTS: Snai1 protein was mainly observed in the nuclei of flattened, damaged tubular epithelial cells, especially in IgAN and DN, and positive cell numbers were significantly higher in IgAN than in MGA, MCD or DN. Snai1/vimentin double staining showed that some vimentin-positive tubular epithelial cells also contained Snai1-positive nuclei, and double positive cell numbers were increased in IgAN and DN. Statistical analysis revealed positive correlations between Snai1/vimentin double positive cell numbers and proteinuria and creatinine in IgAN. Positive correlations were also seen between Snai1/vimentin double positive cell numbers and the severity of proteinuria in DN. CONCLUSIONS: The results of this study indicate that Snai1 plays an important role in TIF in patients with progressive nephropathy.

Aberrant structures of fecal bacterial community in allergic infants profiled by 16S rRNA gene pyrosequencing.

We investigated the correlation between fecal bacteria composition in early infancy and the prevalence of allergic diseases in late infancy. The fecal microbiota in the first 2 months was profiled using the 16S rRNA V6 short-tag sequences in the community and statistically compared between two groups of subjects who did and did not show allergic symptoms in the first 2 years (n = 11 vs. 11). In the allergic group, genus Bacteroides at 1 month and genera Propionibacterium and Klebsiella at 2 months were more abundant, and genera Acinetobacter and Clostridium at 1 month were less abundant than in the nonallergic group. Allergic infants who showed high colonization of Bacteroides and/or Klebsiella showed less colonization of Clostridium perfringens/butyricum, suggesting antagonism between these bacterial groups in the gastrointestinal tract. It was also remarkable that the relative abundance of total Proteobacteria, excluding genus Klebsiella, was significantly lower in the allergic than in the nonallergic group at the age of 1 month. These results indicate that pyrosequence-based 16S rRNA gene profiling is valid to find the intestinal microbiotal disorder that correlates with allergy development in later life.

Hypertrophy and loss of podocytes in diabetic nephropathy.

OBJECTIVE: The loss of podocytes has been reported to have a role in the onset and progression of diabetic nephropathy (DN). Although structural changes such as podocyte hypertrophy are considered to be associated with podocyte loss, the relationship has not been thoroughly investigated using human DN renal tissues. METHODS: The subjects were 17 patients with DN diagnosed histopathologically by renal biopsy. Immunostaining was performed with antibodies for Wilm's tumor 1 (WT1) and synaptopodin (SPD), which are markers of podocytes, to determine the number of podocytes and assess podocyte hypertrophy. RESULTS: The number of podocytes was decreased in DN patients compared with the controls. An inverse correlation was observed between the number of podocytes and both the urinary protein excretion and the extent of mesangial expansion. Podocyte hypertrophy was also more marked in DN patients compared with controls. CONCLUSION: Based on these results, podocyte loss and hypertrophy were suggested to be involved in the development and progression of human DN.

Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota.

The influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota was monitored in 26 infants including five antibiotic-treated (AT) subjects orally administered a broad-spectrum antibiotic for the first 4 days of life and three caesarean-delivered (CD) subjects whose mothers were intravenously injected by the similar type of antibiotics in the same period. The faecal bacterial composition was analysed daily for the first 5 days and monthly for the first 2 months. Terminal restriction fragment length polymorphisms in the AT subjects showed less diversity with the attenuation of the colonization of some bacterial groups, especially in Bifidobacterium and unusual colonization of Enterococcus in the first week than the control antibiotic-free infants (AF, n=18). Quantitative real-time PCR showed overgrowth of enterococci (day 3, P=0.01; day 5, P=0.003; month 1, P=0.01) and arrested growth of Bifidobacterium (day 3, P=0.03) in the AT group. Furthermore, after 1 month, the Enterobacteriaceae population was markedly higher in the AT group than in the AF group (month 1, P=0.02; month 2, P=0.02). CD infants sustained similar, although relatively weaker, alteration in the developing microbiota. These results indicate that antibiotic exposure at the beginning of life greatly influences the development of neonatal intestinal microbiota.

Lectin-like oxidized LDL receptor-1 (LOX-1) expression in the tubulointerstitial area likely plays an important role in human diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy (DN) is a common cause of end-stage renal disease. However, the precise mechanism of DN, which involves the role of lipid, is still not fully understood. Lectin-like oxidized LDL receptor-1 (LOX-1) is a type II single-transmembrane protein that binds oxidized low density lipoprotein (Ox-LDL). This study examined the expression of LOX-1 mRNA in renal tissues from type 2 diabetes patients with DN using in situ hybridization (ISH). PATIENTS AND METHODS: Renal tissues were obtained from 15 type 2 patients with DN and 5 minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN) and normal human kidney (NHK). Glomerular and tubulointerstitial LOX-1 mRNA expression was evaluated by ISH. Results The cells positive for LOX-1 mRNA were identified in the glomeruli of DN, MCNS, MN and NHK, however, there was no positive signal in the tubulointerstitial area in MCNS and NHK. Some cells positive for LOX-1 mRNA were detectable in the tubulointerstitial area in DN and MN. In the results of glomerular staining, there was no significant difference between them. There was a significant correlation between the tubulointerstitial LOX-1 expression and the degree of the tubulointerstitial damage and urinary protein in DN. CONCLUSION: Increased expression of LOX-1 mRNA in the tubulointerstitial area may be closely linked to the development and progression of human DN, and in particular the tubulointerstitial damage.

Long-term intensive insulin therapy for Japanese patients with type 2 diabetes mellitus.

OBJECTIVE: To determine the clinical usefulness of long-term intensive insulin therapy in Japanese patients with type 2 diabetes. PATIENTS AND METHODS: Various clinical indicators and potential of withdrawal from insulin therapy were investigated in 20 type 2 diabetic patients receiving treatment in the outpatient clinic over a period of 8 years after starting intensive insulin therapy between April 1997 and March 1999. RESULTS: The mean glycated hemoglobin (HbA1c) was approximately 6.5%, and there was no significant increase in insulin dose over a period of 8 years after commencement of intensive insulin therapy. Withdrawal from insulin therapy could be sustained in previously untreated patients. CONCLUSION: Our results indicated the clinical usefulness of intensive insulin therapy over the long term in Japanese patients with type 2 diabetes and that such therapy could be especially useful for previously untreated patients.

Expression of alpha-actinin-4 in human diabetic nephropathy.

BACKGROUND: Alpha-actinin-4 is an actin filament crosslinking protein that interacts with intercellular adhesion molecules. Recent animal studies suggested that alpha-actinin-4 is an essential component of the glomerular filtration barrier. However, little is known about its expression in human diabetic nephropathy (DN). METHODS: Renal biopsy tissues were obtained from 17 patients with DN. We determined the mRNA and protein expression levels of alpha-actinin-4 by in situ hybridization and immunohistochemistry. The histopathological severity of DN was classified into two groups: mild and moderate mesangial expansion groups. We also measured urinary protein excretion and creatinine clearance. RESULTS: Podocytes were positively stained for alpha-actinin-4 mRNA and protein. In the glomeruli, the percentage of cells positive for alpha-actinin-4 mRNA was significantly lower in moderate mesangial expansion group than in mild mesangial expansion group and control. The percentage of immunohistochemically positive area for alpha-actinin-4 protein in moderate mesangial expansion group was significantly lower than in mild mesangial expansion group and control. The percentage of cells positive for alpha-actinin-4 mRNA and area positive for the protein correlated inversely with severity of proteinuria. CONCLUSION: Our results suggest that low expression levels of alpha-actinin-4 mRNA and protein are linked to the progression of glomerulopathy and proteinuria in human DN.

Intensive insulin therapy for Japanese patients with type 2 diabetes mellitus--results in the patients from single hospital.

OBJECTIVE: We investigated the clinical characteristics of intensive insulin therapy in Japanese type 2 diabetes patients who commenced intensive insulin therapy during the in-hospital diabetes education program at Tokai university hospital. METHODS: 81 type 2 diabetes patients who received intensive insulin therapy and in-hospital diabetes education program were examined their clinical features. RESULTS: Intensive insulin therapy maintained HbA(1C) below 7% at all time points during the 2-year follow-up, though it was not necessary to increase the insulin dose, thus highlighting the clinical utility of the therapy in preventing diabetic complications. Insulin therapy could be withdrawn from more than 25% of patients. The diabetic morbid period was shorter and urinary C-peptide level at admission was higher in patients of the withdrawal group than those of the non-withdrawal group, suggesting that patients with well maintained pancreatic ß cell reserve could be withdrawn from insulin therapy. CONCLUSIONS: Based on our results of the efficacy of strict glycemic control for preventing the development and progression of diabetic complications, we recommend early introduction of intensive insulin therapy to achieve better glycemic control.