Development of high-efficiency superparamagnetic drug delivery system with MPI imaging capability.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

Usefulness of Body Position Change during Local Ablation Therapies for the High-Risk Location Hepatocellular Carcinoma.

Local ablation therapies are important treatment options for early-stage hepatocellular carcinoma (HCC). Various techniques have been used to perform these therapies efficiently and safely. However, few reports have discussed the usefulness of body position change (BPC). This study aimed to investigate the usefulness of BPC during local ablation therapies in patients with HCC. We evaluated 283 HCC nodules that underwent local ablation therapy. These nodules were categorized into high- or low-risk locations on the basis of their proximity to large vessels, adjacent extrahepatic organs, or poor visibility under ultrasound (US) guidance. The technical success rates, procedure time, and prognosis were evaluated. In this study, 176 (62%) nodules were classified in the high-risk location group. The high-risk location group was treated with techniques such as BPC, artificial pleural fluid, artificial ascites, fusion imaging, and contrast-enhanced US more frequently than the low-risk location group. The technical success rates were 96% and 95% for the high- and low-risk location groups, respectively. Within the high-risk location group, those without BPC had a lower success rate than those with BPC (91% vs. 99%, p = 0.015). Notably, BPC emerged as the sole contributing factor to the technical success rate in the high-risk location group (OR = 10, 95% CI 1.2-86, p = 0.034). In contrast, no differences were found in the procedure time, local tumor progression rates, intrahepatic distant recurrence rates, and overall survival between the groups with and without BPC in the high-risk location group. In conclusion, BPC during local ablation therapy in patients with HCC in high-risk locations was safe and efficient. The body position should be adjusted for HCC in high-risk locations to maintain good US visibility and ensure a safe puncture route in patients undergoing local ablation therapies.

A Simple Clinical Scoring System to Determine the Risk of Pancreatic Cancer in the General Population.

This study aimed to develop and validate a simple scoring system to determine the high-risk group for pancreatic cancer (PC) in the asymptomatic general population. The scoring system was developed using data from PC cases and randomly selected non-PC cases undergoing annual medical checkups between 2008 and 2013. The performance of this score was validated for participants with medical checkups between 2014 and 2016. In the development set, 45 PC cases were diagnosed and 450 non-PC cases were identified. Multivariate analysis showed three changes in clinical data from 1 year before diagnosis as independent risk factors: ΔHbA1c ≥ 0.3%, ΔBMI ≤ -0.5, and ΔLDL ≤ -20 mg/dL. A simple scoring system, incorporating variables and abdominal ultrasound findings, was developed. In the validation set, 36 PC cases were diagnosed over a 3-year period from 32,877 participants. The AUROC curve of the scoring system was 0.925 (95%CI 0.877-0.973). The positive score of early-stage PC cases, including Stage 0 and I cases, was significantly higher than that of non-PC cases (80% vs. 6%, p = 0.001). The simple scoring system effectively narrows down high-risk PC cases in the general population and provides a reasonable approach for early detection of PC.

A Novel Method of Calculating the Drained Liver Volume Using a 3D Volume Analyzer for Biliary Drainage of Unresectable Malignant Hilar Biliary Obstruction.

OBJECTIVES: In patients with unresectable malignant hilar biliary obstruction (UMHBO), drainage of ≥ 50% liver volume correlates with better clinical outcomes. Accurately measuring the liver volume to be drained by biliary stents is required. We aimed to develop a novel method for calculating the drained liver volume (DLV) using a 3D volume analyzer (3D volumetry), and assess the usefulness for drainage in patients with UMHBO. METHODS: Three-dimensional volumetry comprises the following steps: (1) manual tracing of bile duct using 3D imaging system; (2) 3D reconstruction of bile duct and liver parenchyma; and (3) calculating DLV according to the 3D distribution of bile ducts. Using 3D volumetry, we reviewed data of patients who underwent biliary drainage for UMHBO, calculated the DLV, and determined the association between DLV and biliary drainage outcome. RESULTS: There were 104 eligible cases. The mean DLV was 708 ± 393 ml (53% ± 21%). and 65 patients (63%) underwent drainage of ≥50% liver volume. The clinical success rate was significantly higher in patients with DLV ≥ 50% than in patients with DLV < 50% (89% vs. 28%, P < 0.001). The median time to recurrence of biliary obstruction (TRBO) and survival time were significantly longer in patients with DLV ≥ 50% than in patients with DLV < 50% (TRBO, 292 vs. 119 days, P = 0.03; survival, 285 vs. 65days, P = 0.004, log-rank test, respectively). CONCLUSIONS: Three-dimensional volumetry, a novel method to calculate DLV accurately according to bile duct distribution was useful for drainage in UMHBO patients.

Re-salvage focal low-dose rate brachytherapy for local recurrence of prostate cancer after salvage focal low-dose rate brachytherapy.

Introduction: Salvage brachytherapy represents an effective treatment for local recurrence of prostate cancer after prior external beam radiotherapy. However, the optimal therapeutic strategies for local recurrence after salvage brachytherapy have not yet been determined. Case presentation: We describe the case of a 77-year-old man who underwent re-salvage focal low-dose rate brachytherapy for local recurrence after carbon ion radiotherapy and salvage focal low-dose rate brachytherapy. We performed re-salvage focal low-dose rate brachytherapy for the recurrence with a different type of seed, which resulted in a significant reduction in the prostate-specific antigen level. During the 35-month follow-up after re-salvage focal low-dose rate brachytherapy, no recurrence of prostate cancer and no severe radiation-related toxicities were observed. Conclusion: Our patient was successfully treated with re-salvage focal low-dose rate brachytherapy for local recurrence after salvage focal low-dose rate brachytherapy. This treatment strategy might be effective for such patients and is not associated with sexual dysfunction or severe adverse events.

Chronic Spinal Cord Injury Regeneration with Combined Therapy Comprising Neural Stem/Progenitor Cell Transplantation, Rehabilitation, and Semaphorin 3A Inhibitor.

Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with transplantation and rehabilitation. As a result, our combined transplantation, Sema3Ai, and rehabilitation treatment have the potential to serve as a critical step forward for chronic SCI patients, improving their ability to regain motor function.

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma.

AIM: Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. METHODS: Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. RESULTS: Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n = 10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p = 0.047) and RF at baseline (HR 5.4, p = 0.035) and to achieve complete response (HR 5.8, p = 0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. CONCLUSION: In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

Development and Validation of a Preoperative Nomogram for Endoscopic Management Decision Making in Upper Urinary Tract Urothelial Carcinoma.

OBJECTIVE: We aimed to develop and validate a preoperative nomogram that predicts low-grade, non-muscle invasive upper urinary tract urothelial carcinoma (LG-NMI UTUC), thereby aiding in the accurate selection of endoscopic management (EM) candidates. METHODS: This was a retrospective study that included 454 patients who underwent radical surgery (Cohort 1 and Cohort 2), and 26 patients who received EM (Cohort 3). Utilizing a multivariate logistic regression model, a nomogram predicting LG-NMI UTUC was developed based on data from Cohort 1. The nomogram's accuracy was compared with conventional European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) models. External validation was performed using Cohort 2 data, and the nomogram's prognostic value was evaluated via disease progression metrics in Cohort 3. RESULTS: In Cohort 1, multivariate analyses highlighted the absence of invasive disease on imaging (odds ratio [OR] 7.04; p = 0.011), absence of hydronephrosis (OR 2.06; p = 0.027), papillary architecture (OR 24.9; p < 0.001), and lack of high-grade urine cytology (OR 0.22; p < 0.001) as independent predictive factors for LG-NMI disease. The nomogram outperformed the two conventional models in predictive accuracy (0.869 vs. 0.759-0.821) and exhibited a higher net benefit in decision curve analysis. The model's clinical efficacy was corroborated in Cohort 2. Moreover, the nomogram stratified disease progression-free survival rates in Cohort 3. CONCLUSION: Our nomogram ( https://kmur.shinyapps.io/UTUC_URS/ ) accurately predicts LG-NMI UTUC, thereby identifying suitable candidates for EM. Additionally, the model serves as a useful tool for prognostic stratification in patients undergoing EM.

Automatic irrigation system with a fiber-optic pressure sensor regulating intrapelvic pressure for flexible ureteroscopy.

Increased intrapelvic pressure (IPP) due to irrigation during flexible ureteroscopy (f-URS) can pose a risk of postoperative severe urinary tract infection associated with pyelovenous backflow. An automatic regulation system for maintaining safe IPP levels could enable surgeons to perform f-URS safely without postoperative complications. This study aimed to assess the measurement accuracy of an ultra-miniature fiber-optic pressure sensor incorporated into a small-caliper ureteroscope for assessing IPP and to develop an automatic irrigation system linked to this sensor. A porcine kidney was used for the ex vivo experiment. The nephrostomy catheter, connected to the conventional pressure transducer, was placed on the renal pelvis to evaluate the actual IPP (a-IPP). For measuring IPP using the fiber-optic pressure sensor (fo-IPP) built into the f-URS, a diaphragm pressure sensor of Φ250 µm was used. To establish an irrigation system, the optimal proportional-integral-derivative (PID) controller was explored to accurately adjust the irrigation pump flow rate. A high correlation between a-IPP and fo-IPP was confirmed across irrigation pressure values of 60-180 mbar (all, r ≥ 0.7, p < 0.001). When performing bolus irrigation, although fo-IPP showed relatively a higher peak value than a-IPP, the response time of fo-IPP was equivalent to that of a-IPP. After PID parameter optimization, our automatic irrigation system based on fo-IPP smoothly and accurately regulated the intended IPP set in the 5-20 mmHg range without overshooting. We successfully developed and demonstrated an automatic irrigation system regulating IPP based on the PID controller for f-URS, utilizing a fiber-optic pressure sensor. Further research, including in vivo studies, will be needed to assess clinical feasibility.

Serological response 5 months after the BNT162b2 COVID-19 vaccination in patients with various hematological disorders in Japan.

Purpose: Patients with hematological malignancies are at an increased risk of severe infection with coronavirus disease 2019 (COVID-19). However, developing an adequate immune response after vaccination is difficult, especially in patients with lymphoid neoplasms. Since the long-term effects of the BNT162b2 vaccine are unclear, the humoral immune response 5 months after the two vaccinations in patients with hematological disorders was analyzed. Materials and Methods: Samples were collected from 96 patients vaccinated twice with BNT162b2 and treated with at least one line of an antitumor or immunosuppressive drug in our hospital from November 2021 to February 2022. Serum anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) spike (S) antibody titers were analyzed. Patients were age- and sex-matched using propensity matching and compared with a healthy control group. Patients with serum anti-SARS-CoV-2 S antibodies were defined as 'responder' if >50 U/mL. The patients had B-cell non-Hodgkin lymphoma (B-NHL), multiple myeloma, chronic myeloid leukemia, etc. Results: Patients had significantly low antibody levels (median, 55.3 U/mL vs. 809.8 U/mL; p<0.001) and a significantly low response rate (p<0.001). Multivariate analysis showed that patients with B-NHL, aged >72 years, were associated with a low response to vaccination. There were no significant differences between patients with chronic myeloid leukemia and healthy controls. Conclusion: Our study shows that patients with hematological disorders are at risk of developing severe COVID-19 infections because of low responsiveness to vaccination. Moreover, the rate of antibody positivity differed between the disease groups. Further studies are warranted to determine an appropriate preventive method for these patients, especially those with B-NHL.

Second-line Pembrolizumab for Metastatic Urothelial Carcinoma: Differences in Treatment Outcomes According to the Primary Site.

BACKGROUND/AIM: To evaluate the difference in the clinical efficacy and safety of pembrolizumab between patients with metastatic upper tract urothelial carcinoma (UTUC), which includes renal pelvic urothelial carcinoma (UC) and ureteral UC, and those with metastatic lower tract urothelial carcinoma (LTUC). PATIENTS AND METHODS: A total of 752 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. We compared progression-free survival (PFS), overall survival (OS) and adverse events (AEs) in patients with renal pelvic UC, ureteral UC, and LTUC. RESULTS: The median follow-up period was 42.5 [interquartile range (IQR)=35.1-47.4] months. The primary tumor site was in the upper tract in 362 (48.1%) patients [renal pelvis, n=219 (60.5%); ureter, n=143 (39.5%)] and in the lower tract in 390 (51.9%) patients. The estimated glomerular filtration rate before pembrolizumab treatment in the UTUC group was significantly lower than that in the LTUC group (p<0.001). The median PFS in the UTUC and LTUC groups was 3.4 months, respectively (p=0.271). The median OS in the UTUC and LTUC groups was 10.1 months and 11.7 months, respectively (p=0.195). In an analysis of UTUC divided into renal pelvic UC, ureteral UC, and LTUC, patients with renal pelvic UC had a significantly poorer prognosis in comparison to the other two groups (p=0.041). The incidence of any-grade AEs (51.7% vs. 47.9%, p=0.343) and grade ≥3 AEs (12.2% vs. 12.8%, p=0.826) in the two groups was not statistically significantly different. CONCLUSION: No significant differences were found between the UTUC and LTUC groups with regard to the oncological outcomes and safety of pembrolizumab. Patients with renal pelvic UC had a significantly poorer prognosis than those with other ureteral UCs and LTUCs.

Hypoxia-inducible factor 2α protein and mRNA expression correlate with histomorphological features in clear cell renal cell carcinoma.

Hypoxia-inducible factor 2α (HIF2α) has been identified as a potential biomarker and novel target for systemic therapy in clear cell renal cell carcinoma (ccRCC). The present study aims to evaluate the association of HIF2α protein and HIF2A mRNA expression with clinicopathological factors and histomorphological features related to vasculature and inflammation of ccRCC using a localized ccRCC cohort (n = 428) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 433). HIF2α protein expression was immunohistochemically assessed using tissue microarrays and HIF2A mRNA expression was assessed using the TCGA RNA-sequencing data. Positive HIF2α protein and high HIF2A mRNA expression were observed in 145 (33.9 %) and 142 (32.8 %) patients, respectively. Positive nuclear HIF2α protein expression was significantly associated with the clear histological phenotype and architectural patterns related to rich vascular networks (p < 0.001), and no tumor-associated immune cells status (p < 0.05) in addition to favorable prognostic factors such as lower TNM stage, lower WHO/ISUP grade, or the absence of necrosis (p < 0.001). The HIF2A mRNA expression profile by the TCGA cohort showed similar trends as the HIF2α protein profile. In addition, positive HIF2α protein and high HIF2A mRNA expression were associated with higher recurrence-free survival and overall survival, respectively (both p < 0.001). In conclusion, we comprehensively demonstrated the association of HIF2α profiles with clinicopathological factors and histomorphological features related to vasculature and inflammation at both protein and mRNA levels. Histomorphological features expressing HIF2α may provide information on HIF2α targeted therapeutic response as well as prognosis in ccRCC patients.

Diagnosis of a SMARCA4-deficient undifferentiated tumor using multigene panel testing: A case report.

Key Clinical Message: SMARCA4-deficient thoracic carcinoma is a malignant tumor that may present as cancer of unknown primary. This tumor is refractory and requires a novel approach. In addition to identifying therapeutic targets, multigene panel testing can reveal novel genetic mutations, leading to more pathologically relevant diagnoses and appropriate tumor care. Abstract: SMARCA4-deficient undifferentiated tumors are characterized by SMARCA4 inactivation. We present a case of a 74-year-old man with an undifferentiated tumor and a novel SMARCA4 mutation detected using multigene panel testing. The tumor was multiagent and refractory to three chemotherapy lines. The test results helped guide appropriate medical management.

Learning from the past and present to change the future: Endoscopic management of upper urinary tract urothelial carcinoma.

Current guidelines recommend endoscopic management (EM) for patients with low-risk upper urinary tract urothelial carcinoma, as well as those with an imperative indication. However, regardless of the tumor risk, radical nephroureterectomy is still mainly performed worldwide despite the benefits of EM, such as renal function maintenance, no hemodialysis requirement, and treatment cost reduction. This might be explained by the association of EM with a high risk of local recurrence and progression. Furthermore, the need for rigorous patient selection and close surveillance following EM may be relevant. Nevertheless, recent developments in diagnostic modalities, pathological evaluation, surgical devices and techniques, and intracavitary regimens have been reported, which may contribute to improved risk stratification and treatments with superior oncological outcomes. In this review, considering recent advances in endourology and oncology, we propose novel treatment strategies for optimal EM.

Relationship between Plasma IP-10/CXCL10 Levels and the Initial Therapeutic Response in Patients Treated with Atezolizumab plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab plus bevacizumab combination therapy (AB) was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). IFN-γ-induced protein 10 (IP-10/CXCL10) is a chemokine to inhibit HCC proliferation by promoting the migration of cytotoxic T cells. We focused on the relationship between plasma IP-10/CXCL10 levels and the initial therapeutic response in patients receiving AB therapy. METHODS: Forty-six patients receiving AB therapy were enrolled. Plasma IP-10/CXCL10 levels were measured at baseline, 3-7 days, 3 weeks, 6 weeks, and 8-12 weeks after the start of AB therapy. The initial therapeutic response was evaluated at 8-12 weeks. RESULTS: The baseline IP-10/CXCL10 levels of partial response (PR) group was higher than that of stable disease (SD) or progressive disease (PD) group. Patients with the baseline IP-10/CXCL10 of 84 pg/mL or higher were likely to present PR than patients below (71 vs. 35%, p = 0.031), but prediction of PD using the baseline IP-10/CXCL10 levels was difficult. In contrast, IP-10/CXCL10 ratio of the PR group was lower than that of the SD/PD group at 3, 6, and 8-12 weeks. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 0.4, and 0.4 or lower were likely to present PR than patients with ≥1.3, 0.4, and 0.4 (88, 35, 35 vs. 30, 3.8, 0%, p < 0.001, 0.011, 0.002). In other hand, the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio for PD group was higher than that for non-PD group. Patients with the 3, 6, and 8-12 weeks IP-10/CXCL10 ratio of 1.3, 1.7, and 1.9 or higher were likely to present PD than patients below (85, 62, 57 vs. 32, 23, 14%, p = 0.002, 0.034, 0.009). CONCLUSION: High baseline IP-10/CXCL10 levels may be associated with better outcome, and high IP-10/CXCL10 ratio after 3-12 weeks may be associated with worse outcome in u-HCC patients receiving AB therapy.

Indication for Achilles Tenotomy in Congenital Clubfoot: Effectiveness of Using the Tibio-Plantar Fascia Angle as a Radiographic Parameter.

Congenital clubfoot is one of the most common deformities in children, and currently, the Ponseti method is used worldwide because of its favorable short-term results. With the Ponseti method, the indication for Achilles tenotomy is traditionally based on only physical examination findings; however, some surgeons have also utilized plain radiographs. Because using physical examinations to determine the degree of hindfoot dorsiflexion for the indication of tenotomy can lead to underestimation. We developed and utilized the effectiveness of the tibio-plantar fascia angle (Ti-P angle) in the lateral maximum dorsiflexion view in determining the need for Achilles tenotomy. A retrospective analysis of consecutive 26 patients with congenital idiopathic clubfeet (37 feet) was performed. Whether Achilles tenotomy was indicated was determined based on physical examination for a former period (Group P). For the latter period, whether tenotomy was indicated was determined by referencing radiographs (Group X). No significant differences were found in any of the background factors or severity between Group P and Group X. Cases with larger tibiocalcaneal and Ti-P angles were more likely to require Achilles tenotomy or additional soft tissue release. An angle of more than 72° of the Ti-P angle demonstrated adequate specificity for the indication of Achilles tenotomy. The radiographic lateral tibio-plantar fascia angle is useful for deciding whether a tenotomy needs to be performed.