Regression of Necrotic Lesions after Methotrexate Withdrawal in Patients with Methotrexate-Associated Lymphoproliferative Disorders: A Retrospective CT Study.

This retrospective study investigated whether necrotic lesions detected on a computed tomography (CT) scan are more regressive than non-necrotic lesions after methotrexate withdrawal in patients pathologically diagnosed with methotrexate-associated lymphoproliferative disorders (MTX-LPD). In total, 89 lesions extracted from 24 patients on CT scans were included in the analysis. All patients had been evaluated for the presence of necrosis within lesions via CT scan upon first suspicion of MTX-LPD (baseline CT scan). The percentage lesion size reduction between the baseline and initial follow-up CT scan was calculated. The association between necrosis within lesions and size changes was estimated via linear regression analyses using both crude and adjusted models. Necrosis was significantly more common in extranodal lesions (27 out of 30 lesions, 90%) than in nodal lesions (9 out of 59 lesions, 15%, p<0.001). In the crude model, the regression of necrotic lesions was 58.5% greater than that of non-necrotic lesions; the difference was statistically significant (p<0.001). Additionally, the longest diameter of necrotic lesions at the baseline CT scan was significantly greater than that of non-necrotic lesions (p<0.001). Based on the adjusted model, necrotic lesions showed 49.3% greater regression than non-necrotic lesions (p=0.017). Necrosis detected on a CT scan was found to be an independent predictor of regression after MTX withdrawal in patients with MTX-LPD.

Differentiation of Small (≤ 4 cm) Renal Masses on Multiphase Contrast-Enhanced CT by Deep Learning.

OBJECTIVE. This study evaluated the utility of a deep learning method for determining whether a small (≤ 4 cm) solid renal mass was benign or malignant on multiphase contrast-enhanced CT. MATERIALS AND METHODS. This retrospective study included 1807 image sets from 168 pathologically diagnosed small (≤ 4 cm) solid renal masses with four CT phases (unenhanced, corticomedullary, nephrogenic, and excretory) in 159 patients between 2012 and 2016. Masses were classified as malignant (n = 136) or benign (n = 32). The dataset was randomly divided into five subsets: four were used for augmentation and supervised training (48,832 images), and one was used for testing (281 images). The Inception-v3 architecture convolutional neural network (CNN) model was used. The AUC for malignancy and accuracy at optimal cutoff values of output data were evaluated in six different CNN models. Multivariate logistic regression analysis was also performed. RESULTS. Malignant and benign lesions showed no significant difference of size. The AUC value of corticomedullary phase was higher than that of other phases (corticomedullary vs excretory, p = 0.022). The highest accuracy (88%) was achieved in corticomedullary phase images. Multivariate analysis revealed that the CNN model of corticomedullary phase was a significant predictor for malignancy compared with other CNN models, age, sex, and lesion size. CONCLUSION. A deep learning method with a CNN allowed acceptable differentiation of small (≤ 4 cm) solid renal masses in dynamic CT images, especially in the corticomedullary image model.

Evaluating Low-kV Dual-source CT Angiography by High-pitch Spiral Acquisition and Iterative Reconstruction in Pediatric Congenital Heart Disease Patients.

We retrospectively evaluated the qualities of pediatric cardiovascular dual-source computed tomography (DSCT) images reconstructed by sinogram-affirmed iterative reconstruction (SAFIRE) and filtered back projection (FBP). We analyzed the cases of 287 congenital heart disease (CHD) patients < 5 years old, referred to our department in August 2013-March 2015. We divided them into two groups according to tube voltage (70 kVp, n=147; 80 kVp, n=140). All images were acquired by a CARE kV system and reconstructed by FBP and SAFIRE. The attenuation, noise, and signal-to-noise ratio (SNR) at each region of the heart and great vessels were measured. The volume CT dose index and dose-length product values were recorded. Compared to FBP, reconstruction by SAFIRE showed that the attenuation volume was significantly lower by 0.4% except for the ascending aorta (p<0.05), the noise value was lower by about 20% (p<0.05), and the SNR was higher by approx. 25% (p<0.05). The radiation dose in the 70 kVp group was significantly lower than that in the 80 kVp group. No significant differences in SNR were observed between the patient groups. DSCT image acquisition with SAFIRE using the CARE kV system results in low image noise and radiation dose in pediatric patients with CHD.

Efficacy of a diagnostic and therapeutic algorithm for Clostridium difficile infection.

In July 2012, metronidazole was approved for the treatment of Clostridium difficile infection (CDI). To clarify the selection criteria for the drug in terms of CDI severity, we established a diagnostic and therapeutic algorithm with reference to the SHEA-IDSA Clinical Practice Guidelines. We compared patients whose treatments were guided by the algorithm (29 cases, October 2012-September 2013) with patients treated prior to the development of the algorithm (37 cases, October 2011-September 2012). All cases treated with reference to the algorithm were diagnosed using enzyme immunoassay of C. difficile toxins A and B and glutamate dehydrogenase;an appropriate drug was prescribed in 93.1% of the cases. We found no significant between-group differences in the cure, recurrence, or complication rates. However, drug costs in cases wherein treatments were guided by the algorithm were markedly reduced. We have, thus, shown that algorithm-guided treatment is efficacious and cost-effective.

In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation.

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.

Imaging evaluation of hereditary renal tumors: a pictorial review.

More than 10 hereditary renal tumor syndromes (HRTSs) and related germline mutations have been reported with HRTS-associated renal and extrarenal manifestations with benign and malignant tumors. Radiologists play an important role in detecting solitary or multiple renal masses with or without extrarenal findings on imaging and may raise the possibility of an inherited predisposition to renal cell carcinoma, providing direction for further screening, intervention and surveillance of the patients and their close family members before the development of potentially lethal renal and extrarenal tumors. Renal cell carcinomas (RCCs) associated with von Hippel-Lindau disease are typically slow growing while RCCs associated with HRTSs, such as hereditary leiomyomatosis and renal cell carcinoma syndrome, are highly aggressive. Therefore, radiologists need to be familiar with clinical and imaging findings of renal and extrarenal manifestations of HRTSs. This article reviews clinical and imaging findings for the evaluation of patients with well-established HRTSs from a radiologist's perspective to facilitate the clinical decision-making process for patient management.

Cytomegalovirus Reactivation Induced Acute Hepatitis and Gastric Erosions in a Patient with Rheumatoid Arthritis under Treatment with an Anti-IL-6 Receptor Antibody, Tocilizumab.

Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.

Clinical utility of endoscopic ultrasound-guided fine-needle aspiration in mixed adenoneuroendocrine carcinoma with signet-ring cells of the pancreas: a case report and review of the literature.

A man in his 60s visited our hospital because of a pancreatic head tumor. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed that the tumor consisted of a neuroendocrine carcinoma (NEC) and adenocarcinoma, including signet-ring cell carcinoma, and that the ratio of these components was approximately 50:50. Therefore, he was diagnosed with mixed adenoneuroendocrine carcinoma (MANEC). Because of liver and lymph node metastases, systemic chemotherapy was initiated using a regimen for the NEC component based on an increase in neuron-specific enolase (NSE). Although the patient achieved stable disease after two chemotherapy cycles, the tumor increased in size after three cycles, which was associated with a gradual increase in carcinoembryonic antigen and a decrease in NSE level. An EUS-FNA reexamination revealed that the adenocarcinoma component accounted for 90 % of the tumor. Thus, an adenocarcinoma chemotherapy regimen was started, and a slight reduction in tumor size was observed. Here, we report an extremely rare and remarkable case of MANEC of the pancreas that demonstrates the effectiveness of EUS-FNA for helping to decide the chemotherapy regimen.

Prolonged, NK cell-mediated antitumor effects of suicide gene therapy combined with monocyte chemoattractant protein-1 against hepatocellular carcinoma.

Tumor recurrence rates remain high after curative treatments for hepatocellular carcinoma (HCC). Immunomodulatory agents, including chemokines, are believed to enhance the antitumor effects of tumor cell apoptosis induced by suicide gene therapy. We therefore evaluated the immunomodulatory effects of a bicistronic recombinant adenovirus vector (rAd) expressing both HSV thymidine kinase and MCP-1 on HCC cells. Using an athymic nude mouse model (BALB/c-nu/nu), primary s.c. tumors (HuH7; human HCC cells) were completely eradicated by rAd followed by treatment with ganciclovir. The same animals were subsequently rechallenged with HCC cells, tumor development was monitored, and the recruitment or activation of NK cells was analyzed immunohistochemically or by measuring IFN-gamma mRNA expression. Tumor growth was markedly suppressed as compared with that in mice treated with a rAd expressing the HSV thymidine kinase gene alone (p < 0.001). Suppression of tumor growth was associated with the elevation of serum IL-12 and IL-18. During suppression, NK cells were recruited exclusively, and Th1 cytokine gene expression was enhanced in tumor tissues. The antitumor activity, however, was abolished either when the NK cells were inactivated with anti-asialo GM1 Ab or when anti-IL-12 and anti-IL-18 Abs were administered. These results indicate that suicide gene therapy, together with delivery of MCP-1, eradicates HCC cells and exerts prolonged NK cell-mediated antitumor effects in a model of HCC, suggesting a plausible strategy to prevent tumor recurrence.

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma.

Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. hTERT is expressed in most tumor cells but seldom expressed in most human adult cells. It has been reported that 80% to 90% of hepatocellular carcinomas (HCCs) express hTERT, making the enzyme a potential target in immunotherapy for HCC. In the current study, we identified hTERT-derived, HLA-A*2402-restricted cytotoxic T cell (CTL) epitopes and analyzed hTERT-specific CTL responses in patients with HCC. Peptides containing the epitopes showed high affinity to bind HLA-A*2402 in a major histocompatibility complex binding assay and were able to induce hTERT-specific CTLs in both hTERT cDNA-immunized HLA-A*2402/Kb transgenic mice and patients with HCC. The CTLs were able to kill hepatoma cell lines depending on hTERT expression levels in an HLA-A*2402-restricted manner and induced irrespective of hepatitis viral infection. The number of single hTERT epitope-specific T cells detected by ELISPOT assay was 10 to 100 specific cells per 3 x 10(5) PBMCs, and positive T cell responses were observed in 6.9% to 12.5% of HCC patients. hTERT-specific T cell responses were observed even in the patients with early stages of HCC. The frequency of hTERT/tetramer+ CD8+ T cells in the tumor tissue of patients with HCC was quite high, and they were functional. In conclusion, these results suggest that hTERT is an attractive target for T-cell-based immunotherapy for HCC, and the identified hTERT epitopes may be valuable both for immunotherapy and for analyzing host immune responses to HCC.