Methyl-11C-L-methionine positron emission tomography for radiotherapy planning for recurrent malignant glioma.

OBJECTIVE: To investigate differences in uptake regions between methyl-11C-L-methionine positron emission tomography (11C-MET PET) and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI), and their impact on dose distribution, including changing of the threshold for tumor boundaries. METHODS: Twenty consecutive patients with grade 3 or 4 glioma who had recurrence after postoperative radiotherapy (RT) between April 2016 and October 2017 were examined. The study was performed using simulation with the assumption that all patients received RT. The clinical target volume (CTV) was contoured using the Gd-enhanced region (CTV(Gd)), the tumor/normal tissue (T/N) ratios of 11C-MET PET of 1.3 and 2.0 (CTV (T/N 1.3), CTV (T/N 2.0)), and the PET-edge method (CTV(P-E)) for stereotactic RT planning. Differences among CTVs were evaluated. The brain dose at each CTV and the dose at each CTV defined by 11C-MET PET using MRI as the reference were evaluated. RESULTS: The Jaccard index (JI) for concordance of CTV (Gd) with CTVs using 11C-MET PET was highest for CTV (T/N 2.0), with a value of 0.7. In a comparison of pixel values of MRI and PET, the correlation coefficient for cases with higher JI was significantly greater than that for lower JI cases (0.37 vs. 0.20, P = 0.007). D50% of the brain in RT planning using each CTV differed significantly (P = 0.03) and that using CTV (T/N 1.3) were higher than with use of CTV (Gd). V90% and V95% for each CTV differed in a simulation study for actual treatment using CTV (Gd) (P = 1.0 × 10-7 and 3.0 × 10-9, respectively) and those using CTV (T/N 1.3) and CTV (P-E) were lower than with CTV (Gd). CONCLUSIONS: The region of 11C-MET accumulation is not necessarily consistent with and larger than the Gd-enhanced region. A change of the tumor boundary using 11C-MET PET can cause significant changes in doses to the brain and the CTV.

Measuring hepatic functional reserve using low temporal resolution Gd-EOB-DTPA dynamic contrast-enhanced MRI: a preliminary study comparing galactosyl human serum albumin scintigraphy with indocyanine green retention.

OBJECTIVE: To investigate if tracer kinetic modelling of low temporal resolution dynamic contrast-enhanced (DCE) MRI with Gd-EOB-DTPA could replace technetium-99 m galactosyl human serum albumin (GSA) single positron emission computed tomography (SPECT) and indocyanine green (ICG) retention for the measurement of liver functional reserve. METHODS: Twenty eight patients awaiting liver resection for various cancers were included in this retrospective study that was approved by the institutional review board. The Gd-EOB-DTPA MRI sequence acquired five images: unenhanced, double arterial phase, portal phase, and 4 min after injection. Intracellular contrast uptake rate (UR) and extracellular volume (Ve) were calculated from DCE-MRI, along with the ratio of GSA radioactivity of liver to heart-plus-liver and per cent of cumulative uptake from 15-16 min (LHL15 and LU15, respectively) from GSA-scintigraphy. ICG retention at 15 min, Child-Pugh cirrhosis score (CPS) and postoperative Inuyama fibrosis criteria were also recorded. Statistical analysis was with Spearman rank correlation analysis. RESULTS: Comparing MRI parameters with the reference methods, significant correlations were obtained for UR and LHL15, LU15, ICG15 (all 0.4-0.6, P < 0.05); UR and CPS (-0.64, P < 0.001); Ve and Inuyama (0.44, P < 0.05). CONCLUSION: Measures of liver function obtained by routine Gd-EOB-DTPA DCE-MRI with tracer kinetic modelling may provide a suitable method for the evaluation of liver functional reserve. KEY POINTS: • Magnetic resonance imaging (MRI) provides new methods of measuring hepatic functional reserve. • DCE-MRI with Gd-EOB-DTPA offers the possibility of replacing scintigraphy. • The analysis method can be used for preoperative liver function evaluation.

Twins with neonatal pemphigus vulgaris born to a mother with pemphigus vulgaris: a case report.

Dichorionic diamniotic twins were born at 37 weeks of gestation by cesarean section to a 34-year-old primigravid Japanese woman because the first twin was in breech presentation. The mother had been diagnosed with pemphigus vulgaris prior to her pregnancy. In addition to a high antidesmoglein 3 autoantibody titer, flaccid bullae and erosions on both of the twins' lips and in their oral cavities at 13 days of age led to the diagnosis of neonatal pemphigus vulgaris. This case highlights the need for awareness that pemphigus vulgaris may not occur immediately after birth.

(89)Sr imaging with bremsstrahlung in patients with metastatic breast cancer.

PURPOSE: In this study, we investigated the clinical and laboratory factors that may enhance (89)Sr uptake to strengthen its tumoricidal effect. METHODS: We enrolled 21 patients with multiple bone metastases (n = 23) from breast cancer and classified them into 2 groups according to their zoledronic acid (ZOL) treatment history. (89)Sr imaging with bremsstrahlung was performed 2 to 6 weeks after administration and (89)Sr index was measured using combined imaging with bone scintigraphy. We compared the Sr index with the levels of alkaline phosphatase, bone-specific alkaline phosphatase, serum cross-linked N-telopeptides, carboxy-terminal telopeptide of type 1 collagen, C-reactive protein, calcium, and hemoglobin on administration and evaluated the differences among the groups. RESULTS: The (89)Sr index ranged from 0.01 to 2.0 and was significantly correlated with C-reactive protein and alkaline phosphatase and moderately correlated with carboxy-terminal telopeptide of type 1 collagen, serum cross-linked N-telopeptides, and bone-specific alkaline phosphatase. The (89)Sr index was not significantly correlated with calcium or hemoglobin. The group with less than 1 year of ZOL treatment demonstrated a mean (SD) (89)Sr index of 1.11 (0.59), and the group with 1 or more years of ZOL treatment showed a mean (89)Sr index of 0.36 (0.26). The Wilcoxon signed-rank test demonstrated a significant difference between the 2 groups (P < 0.001). CONCLUSIONS: (89)Sr accumulation seemed to be associated with bone turnover, in particular bone resorption, and vascularization due to inflammation or tumor growth. Long-term ZOL treatment may reduce bone resorption and vascularization. To enhance the tumoricidal effect and palliation of bone pain by (89)Sr, combined therapy must be established.

Assessment of bone scans in advanced prostate carcinoma using fully automated and semi-automated bone scan index methods.

OBJECTIVE: As metastasis of prostate carcinoma occurs in approximately 80 % of terminal prostate carcinoma patients, the prognostic value of the prediction of prostate carcinoma by bone scintigraphy is important. We compared the automated and semi-automated bone scan index (BSI) system with extent of disease (EOD) grade if there is a possibility to substitute for EOD grading. MATERIALS AND METHODS: We evaluated the bone scintigraphic images of 158 prostate carcinoma patients (mean age, 69.2 years old; range 50-97). Bone scans were obtained approximately 3 h after the intravenous injection of 740 MBq technetium-99 m-methylene diphosphonate. EOD grade was evaluated by 2 experienced radiologists using bone scintigraphy, magnetic resonance imaging, and computed tomography. We calculated the BSI using the Bonenavi(®) system (Fujifilm RI Pharma Co., Ltd.), utilizing data from a Japanese database. The semi-automated BSI of the patients was obtained by modifying the automated BSI independently by 3 radiologists (referred to as "observers" in this study) with 25, 10, and 4 years of experience. We then compared the EOD with the corresponding 4 independent BSIs for each patient. We used the Steel-Dwass test for multiple comparisons of the BSI among different EOD groups of patients. We analyzed the receiver-operating characteristics (ROC) curve to determine the cutoff values of sensitivity and specificity, which were both set at 95 %. RESULTS: There were significant correlations observed among the mean EOD and BSI scores as determined using the Bonenavi(®) system for every patient group for all observers and the automated method. There was also a statistically significant difference in the mean BSI among all EOD groups (grades 0, 1, or 2-4) for all observers and the automated method. Each ROC curve showed an ideal shape and was within the optimal cutoff range. CONCLUSION: On the basis of the present results, BSI as calculated using the Bonenavi(®) system significantly correlated with EOD. Sensitivity and specificity as measured by the fully automated method were lower than those of semi-automated BSI with modification by radiologists. Therefore, semi-automated BSI is considered to have the possibility to substitute for EOD grading to predict the survival of prostate carcinoma patients with bone metastases, with only slight interobserver variation.

High-resolution computed tomography findings in a case of severe leptospira infection (Weil disease) complicated with Jarisch-Herxheimer reaction.

In this report, we describe a case of Weil disease. Chest x-ray and computed tomography (CT) findings showed temporary deterioration 1 day after the initiation of antibiotic treatment, and high-resolution CT findings with the patient's physical findings made us suspect pulmonary alveolar hemorrhage (PAH). We believed that the PAH had been induced by Weil disease and subsequently caused Jarisch-Herxheimer reaction. We confirmed the patient's contact history with mice, and symptoms improved immediately after starting appropriate treatments. Leptospirosis is a relatively rare cause of PAH. Therefore, the possibility of this disease should be included in the differential diagnosis, especially when high-resolution CT findings indicate PAH, and the imaging findings deteriorate rapidly after antibiotic therapy.

Troy binding to lymphotoxin-alpha activates NF kappa B mediated transcription.

Troy is a TNFR superfamily member that is highly expressed in developing hair follicles. Its possible function and ligand in skin have, however, been unknown. Here we demonstrate that an immunomodulatory cytokine, lymphotoxin-alpha (LTalpha), is a functional ligand of Troy by 3 biochemical approaches: (1) Immunoprecipitation assays revealed that LTalpha, but not LTbeta or any obligate combination of LTalpha and LTbeta, binds to Troy. (2) Co-transfection of LTalpha with Troy sharply upregulated NFkappaB reporter transcription, whereas LTbeta or a combination of LTalpha and LTbeta did not. (3) Recombinant LTalpha protein upregulated NFkappaB activity through Troy in a dosedependent manner. We further found that LTalpha is expressed in dermal papillae of developing hair follicles, whereas Troy was expressed in adjacent matrix region. This suggested involvement of LTalpha-Troy signaling in mesenchyme-epithelium interactions during hair follicle development. However, in Troy mutant mice that we generated, hair subtype composition and morphology were altered slightly if at all. The present study thus suggested a subtle function of the newly identified LTalpha-Troy pathway in skin appendage development, however, it may have an additional action compensated by a parallel EDA signaling pathway.

Ectodysplasin regulates the lymphotoxin-beta pathway for hair differentiation.

Mutations in the EDA gene cause anhidrotic/hypohidrotic ectodermal dysplasia, a disorder characterized by defective formation of hair, sweat glands, and teeth in humans and in a mouse model, "Tabby" (Ta). The gene encodes ectodysplasin, a TNF ligand family member that activates the NF-kappaB-signaling pathway, but downstream targets and the mechanism of skin appendage formation have been only partially analyzed. Comparative transcription profiling of embryonic skin during hair follicle development in WT and Ta mice identified critical anhidrotic/hypohidrotic ectodermal dysplasia (EDA) effectors in four pathways, three already implicated in follicle formation. They included Shh and its effectors, as well as antagonists for the Wnt (Dkk4) and BMP (Sostdc1) pathways. The fourth pathway was unexpected, a variant NF-kappaB-signaling cascade based on lymphotoxin-beta (LTbeta)/RelB. Previously known to participate only in lymphoid organogenesis, LTbeta was enriched in developing hair follicles of WT but not in Ta mice. Furthermore, in mice lacking LTbeta, all three types of mouse hair were still formed, but all were structurally abnormal. Guard hairs became wavy and irregular, zigzag/auchen hairs lost their kinks, and in a phenocopy of features of Ta animals, the awl hairs doubled in number and were characteristically distorted and pinched. LTbeta-null mice that received WT bone marrow transplants maintained mutant hair phenotypes, consistent with autonomous LTbeta action in skin independent of its expression in lymphoid cells. Thus, as an EDA target, LTbeta regulates the form of hair in developing hair follicles; and when EDA is defective, failure of LTbeta activation can account for part of the Ta phenotype.

Repertoire of mouse ectodysplasin-A (EDA-A) isoforms.

Mutations in ectodysplasin-A (EDA) cause loss of hair, sweat glands, and teeth in man and mouse. Isoform EDA-A1 protein shows partial rescue of the affected Tabby mouse phenotypes, suggesting that other isoforms may be required for full function. We describe genomic structure for five EDA isoforms, EDA-A1', A5, A5', A6, and A6', in addition to the previously known EDA-A1, A2, A3, and A4. The novel isoforms together account for approximately 12% of total EDA transcripts. The most different, EDA-A6 and A6', which lack the critical domain for interaction with NF-kappaB-activating receptors, were nevertheless confirmed to be present in mouse and human skin tissue. Other isoforms, EDA-A5 and A5', for example, activated NF-kappaB through receptors EDAR and XEDAR. These properties make new isoforms candidates for modulators of EDA function.

Successful treatment of a patient with penetrating injury of the esophagus and brachiocephalic artery due to migration of Kirschner wires.

Pins and wires offer the simplest and most effective tools for managing bone fractures and dislocations. Migration of these devices within the chest is rare, but can cause serious problems. The spontaneous migration of Kirschner wires from the right clavicle to the mediastinum resulted in penetrating injury of the esophagus and pseudo-aneurysm of the brachiocephalic artery in an 84-year-old patient. Two Kirschner wires were removed via a vertical incision on the right shoulder without thoracotomy and the brachiocephalic artery was replaced with a Dacron graft.

Is a metallic stent useful for non resectable esophageal cancer?

A flexible nitinol stent was inserted to treat malignant stricture of the esophagus in 28 patients. Stenting was successful in all 28 patients, leading to an improved oral intake that was maintained for >80% of the survival period in 26 patients. Patients with tumors arising in the esophagus (n=24) were divided into two groups to compare complications and prognosis: patients who underwent stenting only (n=10); and patients who underwent stenting after radiochemotherapy (n=14). Fatal complications associated with stenting were seen in four patients (28.6%) who underwent stenting after radiochemotherapy and in one patient (10.0%) who underwent stenting only. Although survival was significantly longer for patients who underwent prior radiochemotherapy than for patients who did not, the incidence of fatal complications tended to be higher. No significant differences in background factors other than radiochemotherapy before stenting were observed between patients with fatal and non-fatal complications. Stenting was shown to represent a useful treatment for malignant stricture of the esophagus, as oral intake improved and was maintained for a long period of time in most patients. However, incidence of fatal complications was high among patients who underwent radiochemotherapy, and caution must be exercised due to the difficulty in predicting fatal complications.

A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene.

Hypohidrotic ectodermal dysplasia (HED) is a genetic disease characterized by abnormal hair, teeth, and sweat gland development. Although most cases of HED display X-linked recessive inheritance, autosomal dominant and autosomal recessive forms also exist. X-linked HED is caused by mutations in the EDA gene, and the autosomal forms result from mutations in either the EDAR gene or the EDARADD gene. In this study, we identified compound heterozygous mutations in the EDAR gene in a Japanese female patient with HED. On the maternal allele is a novel splice donor site mutation of intron 2 leading to the generation of unstable transcripts with exon 2 skipping; on the paternal allele is a novel R375H transition within the death domain of EDAR. Using expression studies in tissue culture cells, we found that the R375H substitution in EDAR caused loss of its affinity for EDARADD and reduced activation of the downstream target NF-kappaB. Our findings indicate that both alleles of EDAR are non-functional in our patient, resulting in the HED phenotype.

The organization of the lamina muscularis mucosae in the human esophagus.

The structural organization of the lamina muscularis mucosae of the human esophagus was studied by light microscopy and scanning electron microscopy (SEM). The organization of the lamina muscularis mucosae varied considerably among the cervical, the thoracic, and the abdominal part of the esophagus. In the cervical part, the lamina muscularis mucosae was not well developed and only islets of the smooth muscle bundles were scattered within the connective tissue. In the thoracic part, the lamina muscularis mucosae consisted of several layers of smooth muscle bundles, individual muscle cells of which ran in a longitudinal direction. In the abdominal esophagus near the cardia, the muscular bundles in the lamina muscularis mucosae ran in various directions forming a reticular configuration. The differences in density and arrangement of the lamina muscularis mucosae are discussed in relation to the swallowing of food and submucosal invasion of esophageal cancer.

Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles.

EDA splice isoforms EDA-A1 and EDA-A2 belong to the TNF ligand family and regulate skin appendage formation by activating NF-kappa B- and JNK- promoted transcription. To analyze their action further, we conditionally expressed the isoforms as tetracycline ('Tet')-regulated transgenes in Tabby (EDA-negative) and wild-type mice. Expression of only the mEDA-A1 transgene had two types of effects during embryogenesis: (1) determinative effects on sweat glands and hair follicles. In Tabby mice, one type of hair follicle ('guard hair') was restored, whereas a second type, the dominant undercoat hair follicle ('zigzag') was not; furthermore, the transgene sharply suppressed zigzag hair formation in wild-type mice, with the overall numbers of back hair follicles remaining the same; and (2) trophic effects on sebaceous and Meibomian glands. Marked hyperplasia resulted from expansion of the sebocyte-producing zone in sebaceous glands, with particularly high expression of the transgene and the replication marker PCNA, and correspondingly high production of sebum. The phenotypic effects of mEDA-A1 on sebaceous glands, but not on hair follicles, were reversed when the gene was repressed in adult animals. The results thus reveal both initiating and trophic isoform-specific effects of the EDA gene, and suggest a possible balance of isoform interactions in skin appendage formation.

Clinical usefulness of iodine-123-MIBG scintigraphy for patients with neuroblastoma detected by a mass screening survey.

UNLABELLED: The purpose of this study was to evaluate the usefulness in a clinical setting of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, planar and single photon emission computed tomography (SPECT) images, in patients with neuroblastoma as detected by a mass screening survey. METHODS: 123I-MIBG planar whole body images, and regional SPECT images of patients with neuroblastoma in 51 studies were reviewed. They were all detected by a mass screening survey performed in the 6th month after birth using vanil mandelic acid (VMA), and homovanillic acid (HVA) and the neuroblastoma had been confirmed by surgery. Scintigraphy was performed 24 hours after injection of 111 MBq of 123I-MIBG. We assessed the accuracy of the planar whole body images in order to demonstrate the extent of the lesion and the correlation between the degree and extent of the lesions of 123I-MIBG accumulation and clinical staging with tumor markers, such as urinary VMA, urinary HVA, serum neuron specific enolase (NSE) and serum lactate dehydrogenase (LDH). Additionally, we evaluated SPECT how useful supplemental SPECT might be in a clinical setting as compared with planar whole body images. RESULTS: 123I-MIBG planar whole body images revealed all 33 (100%) primary lesions, 4 of the 5 cases (80%) with liver metastasis, 3 of the 13 (23%) with lymph nodes metastasis and 1 of 3 (33%) with bone marrow infiltration. The extent and degree of accumulation correlated with the values of urinary VMA, urinary HVA and serum NSE. SPECT images helped to understand the positional relation in all cases and provided useful additional information for clinical staging in 7 cases. CONCLUSION: 123I-MIBG scintigraphy with planar and SPECT images is useful for evaluating patients with neuroblastoma, following detection by a mass screening survey.