Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets.

Decreased pancreatic ß-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic ß-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic ß-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic ß-cell protection.

Perioperative renal function change and oncological outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma: A multicenter retrospective study.

BACKGROUND: The effect of radical nephroureterectomy (RNUx) on postoperative renal function in patients diagnosed with upper tract urothelial carcinoma (UTUC) has not been thoroughly explored. METHODS: We conducted a retrospective analysis including 785 patients who underwent RNUx for UTUC. We assessed the preoperative and postoperative estimated glomerular filtration rates (eGFRs) and factors related to the decline in eGFR. Additionally, we examined the effect of comorbidities (diabetes or hypertension) on the postoperative eGFR at 1 year. Cox proportional hazard models were employed to investigate the clinical effect of RNUx on oncological outcomes, including non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median preoperative and postoperative eGFR levels were 54.7 and 40.6 ml/min/1.73 m2 respectively. The proportions of patients with preoperative and postoperative eGFR ≥60 mL/min/1.73 m2 were 35.9% and 5.1%, respectively. The median decline in the eGFR after surgery was 26.8%. Patients with preoperative eGFR <60 ml/min/1.73 m2 demonstrated significantly lower odds of a postoperative decline in eGFR of 25% or more. The effect of comorbidities on postoperative eGFR at 1 year was significant (P = 0.048). The 3-year NUTRFS, CSS, and OS rates were 72.9%, 85.2%, and 81.5%, respectively. Preoperative chronic kidney disease was an independent factor associated with inferior NUTRFS, CSS, and OS. CONCLUSION: Different degrees of impairment of renal function occur among UTUC patients. Only 5.1% of patients retain a postoperative eGFR ≥60 ml/min/1.73 m2. Preoperative renal impairment was linked to reduced odds of postoperative eGFR decrease and associated with survival. In addition, the presence of comorbidities had a significant effect on the decline in eGFR. These findings emphasize the importance of developing evidence-based perioperative treatment strategies for UTUC patients with impaired renal function.

Effectiveness and safety of enzalutamide and apalutamide in the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC): a multicenter retrospective study.

OBJECTIVE: Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10 months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. METHODS: This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. RESULTS: No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10 months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. CONCLUSION: In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.

Clinical Significance of Intraductal Carcinoma of the Prostate After High-Dose Brachytherapy With External Beam Radiation Therapy: A Single Institution Series and an Updated Meta-Analysis.

BACKGROUND: We compared oncological outcomes between prostate cancer (PCa) patients with and without intraductal carcinoma of the prostate (IDC-P) after high-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT). METHODS: We performed a retrospective analysis of 138 patients with clinically high-risk, very high-risk, or locally advanced PCa who received HDR-BT with EBRT. Of these, 70 (50.7 %) patients were diagnosed with IDC-P; 68 (49.3 %) patients with acinar adenocarcinoma of prostate. The oncological outcomes, including biochemical recurrence-free survival (BCRFS) and clinical progression-free survival (CPFS), were assessed using Kaplan-Meier curves. Additionally, Cox proportional hazards models were used to identify significant prognostic indicators or biochemical recurrence (BCR). Meta-analysis of existing literatures was performed to evaluate the risk of BCR in patients with IDC-P after radiation therapy, compared to those without IDC-P. RESULTS: Kaplan-Meier curves demonstrated significantly inferior BCRFS and CPFS in patients with IDC-P. Multivariate analysis revealed that IDC-P and Grade Group 5 status were associated with increased BCR risk. in our meta-analysis, IDC-P was associated with BCR (HR = 2.13, P = .003). CONCLUSION: Amongst the patients who received HDR-BT, patients with IDC-P displayed significantly more rapid disease progression, compared with patients who did not have IDC-P.

The clinical impact of ureteroscopy for upper tract urothelial carcinoma: A multicenter study.

BACKGROUND: With the development of kidney-sparing surgery and neoadjuvant chemotherapy, ureteroscopic biopsy (URSBx) has become important for the management of upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analyzed data from 744 patients with UTUC who underwent radical nephroureterectomy (RNU), stratified into no ureteroscopy (URS), URS alone, and URSBx groups. Intravesical recurrence-free survival (IVRFS) was examined using the Kaplan-Meier method. We conducted Cox regression analyses to identify risk factors for IVR. We investigated differences between clinical and pathological staging to assess the ability to predict the pathological tumor stage and grade of RNU specimens. RESULTS: Kaplan-Meier curves and multivariate Cox regression revealed significantly more IVR and inferior IVRFS in patients who underwent URS and URSBx. Superficial, but not invasive, bladder cancer recurrence was more frequent in the URS and URSBx groups than in the no URS group. Clinical and pathological staging agreed for 55 (32.4%) patients. Downstaging occurred for 48 (28.2%) patients and clinical understaging occurred for 67 (39.4%) patients. Upstaging to muscle-invasive disease occurred for 39 (35.8%) of 109 patients with ≤cT1 disease. Clinical and pathological grading were similar for 72 (42.3%) patients. Downgrading occurred for 5 (2.9%) patients, and clinical undergrading occurred for 93 (54.7%) patients. CONCLUSION: URS and URSBx instrumentation will be risk factors for superficial, but not invasive, bladder cancer recurrence. Clinical understaging/undergrading and upstaging to muscle-invasive disease occurred for a large proportion of patients with UTUC who underwent RNU. These data emphasize the challenges involved in accurate UTUC staging and grading.

Presurgical immune-oncology/tyrosine kinase inhibitor combination therapy for renal cell carcinoma with a vena cava tumor thrombus: a single-institution case series.

Background: Although current guidelines recommend administering adjuvant immunotherapy following resection of advanced primary renal cell carcinoma (RCC), the clinical benefit of presurgical immunotherapy for patients with RCC remains uncertain. Case Description: We conducted a retrospective analysis of five patients diagnosed with RCC who developed inferior vena cava (IVC) tumor thrombus and were treated with radical nephrectomy following combined immunotherapy with a tyrosine kinase inhibitor. The median follow-up after nephrectomy was 23 months (range, 19-30 months). In all cases, the size of the IVC tumor thrombus decreased, and three of the cases demonstrated a decrease in the tumor thrombus level. Surgical margins were negative in all cases, and none of the patients experienced any major intraoperative complications. However, adhesions were encountered at the operative sites during surgery in all cases. One patient required a lymphatic intervention due to abdominal lymphatic leakage (Clavien IIIa) within 90 days after operation. Our case series demonstrated a median progression-free survival (PFS) of 11 months [95% confidence interval (CI)]: 5.5-22.5 months). No patient died during the follow-up period. Conclusions: Presurgical therapy combined with immunotherapy and tyrosine kinase inhibitors warrants consideration. Nevertheless, surgeons should be mindful of the difficulties that may arise beyond the clinical stage.

Comparison of neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma in real-world practice: a multicenter retrospective study.

BACKGROUND: Multiple studies have demonstrated the effectiveness of neoadjuvant chemotherapy and adjuvant chemotherapy in patients with upper tract urothelial carcinoma compared with surgery alone. However, no clinical trial has established the superiority of neoadjuvant chemotherapy or adjuvant chemotherapy in terms of perioperative outcomes. METHODS: We conducted a retrospective analysis encompassing 164 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy and received perioperative chemotherapy. Of these patients, 65 (39.6%) and 99 (60.4%) received neoadjuvant chemotherapy and adjuvant chemotherapy, respectively. Recurrence-free survival and cancer-specific survival were computed using the Kaplan-Meier method. Additionally, we conducted Cox regression analyses to evaluate the risk factors for recurrence-free survival and cancer-specific survival. RESULTS: Pathological downstaging was seen in 37% of the neoadjuvant chemotherapy group. However, no pathological complete response was observed in this cohort. The Kaplan-Meier curves demonstrated significantly lower recurrence-free survival and cancer-specific survival in patients who received adjuvant chemotherapy. Multivariate Cox regression analysis revealed patients treated with adjuvant chemotherapy exhibited a marked association with inferior recurrence-free survival and cancer-specific survival. CONCLUSION: Our study has suggested that neoadjuvant chemotherapy would be more effective in high-risk upper tract urothelial carcinoma patients compared with adjuvant chemotherapy.

Clinical characteristics of secondary bladder cancer developing after low-/high-dose-rate brachytherapy to treat localized prostate cancer.

BACKGROUND: To explore correlations between the clinical attributes of secondary bladder cancer and brachytherapy, we retrospectively reviewed our institutional database on patients with localized prostate cancer who underwent low-dose-rate brachytherapy (LDR-BT) or high-dose-rate brachytherapy (HDR-BT) with or without external beam radiation therapy (EBRT) or radical prostatectomy (RP). METHODS: From October 2003 to December 2014, 2551 patients with localized prostate cancer were treated at our institution. Of these, data on 2163 were available (LDR-BT alone: n = 953; LDR-TB with EBRT: n = 181; HDR-BT with EBRT: n = 283; RP without EBRT: n = 746). The times of secondary bladder cancer development subsequent to radical treatment, and their clinical characteristics, were studied. RESULTS: Age-adjusted Cox's regression analyses indicated that brachytherapy did not significantly impact the incidence of secondary bladder cancer. However, the pathological characteristics of such cancer differed between patients treated via brachytherapy and RP without EBRT; invasive bladder cancer was more common in such patients. CONCLUSION: The risk for secondary bladder cancer was not significantly increased after brachytherapy compared to non-irradiation therapy. However, brachytherapy patients exhibited a higher incidence of invasive bladder cancer. Therefore, meticulous follow-up is crucial for early detection and treatment of bladder cancer in such patients.

Usefulness of contrast-enhanced ultrasonography for biliary tract disease.

Conventional ultrasonography (US) for biliary tract disease shows high time and spatial resolution. In addition, it is simple and minimally invasive, and is selected as a first-choice examination procedure for biliary tract disease. Currently, contrast-enhanced US (CEUS), which facilitates the more accurate assessment of lesion blood flow in comparison with color and power Doppler US, is performed using a second-generation ultrasonic contrast agent. Such agents are stable and provide a timeline for CEUS diagnosis. Gallbladder lesions are classified into three types: gallbladder biliary lesion (GBL), gallbladder polypoid lesion (GPL), and gallbladder wall thickening (GWT). Bile duct lesions can also be classified into three types: bile duct biliary lesion (BBL), bile duct polypoid lesion (BDPL), and bile duct wall thickening (BDWT). CEUS facilitates the differentiation of GBL/BBL from tumorous lesions based on the presence or absence of blood vessels. In the case of GPL, it is important to identify a vascular stalk attached to the lesion. In the case of GWT, the presence or absence of a non-contrast-enhanced area, the Rokitansky-Aschoff sinus, and continuity of a contrast-enhanced gallbladder wall layer are important for differentiation from gallbladder cancer. In the case of BDWT, it is useful to evaluate the contour of the contrast-enhanced medial layer of the bile duct wall for differentiating IgG4-related sclerosing cholangitis from primary sclerosing cholangitis. CEUS for ampullary carcinoma accurately reflects histopathological findings of the lesion. Evaluating blood flow in the lesion, continuity of the gallbladder wall, and contour of the bile duct wall via CEUS provides useful information for the diagnosis of biliary tract disease.

Effect of Adequate Local Radiation Dose on Oncological Outcomes in Localized Prostate Cancer Patients Treated With Low-dose-rate Brachytherapy.

BACKGROUND/AIM: We retrospectively investigated the effect of a biologically effective dose (BED) of Low-dose rate brachytherapy (LDR-BT) and its possible interaction with androgen deprivation therapy (ADT) during LDR-BT treatment for intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: A total of 693 patients with localized, intermediate-risk PCa, who underwent LDR-BT with or without supplemental external beam radiotherapy, were included in this study. We stratified patients into two groups according to BED (<180 Gy2, lower BED group; ≥180 Gy2, higher BED group) and evaluated the effect of ADT duration on the oncological outcomes of each group. RESULTS: In total, 431 patients received BED ≥180 Gy2. Significant differences in biochemical recurrence-free survival (BCRFS) and clinical progression-free survival (CPFS) were observed among the non-ADT, ADT ≤3 months, and ADT >3 months subgroups of the lower BED group (p=0.005 and 0.049, respectively). However, no significant differences in BCRFS or CPFS were detected in the higher BED group (p=0.63 and 0.76, respectively). Multivariate analysis of BCR and CP in the lower BED group revealed a significant decreasing trend in the BCRFS (p for trend=0.001) and CPFS rates (p for trend=0.015) as ADT duration increased, which was associated with favorable outcomes. However, no significant trend was observed in the BCRFS or CPFS rate in the higher BED group. CONCLUSION: An adequate local radiation dose provides favorable oncological outcomes and could potentially reduce the need for long-term ADT.

Treatment Results of High-dose-rate Brachytherapy and External Beam Radiation With Long-term Androgen Deprivation Therapy for Patients With Metastatic Prostate Cancer.

BACKGROUND/AIM: A recent clinical trial indicated the usefulness of local radiation therapy of the prostate in patients with low-volume metastatic prostate cancer. High-dose-rate brachytherapy (HDR-BT) is used mainly for high-risk, localized, and locally advanced cases. However, few studies exist on the efficacy of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer. PATIENTS AND METHODS: We conducted a retrospective analysis of 39 patients diagnosed with regional lymph node metastasis and/or a limited number of metastases who underwent HDR-BT and EBRT with long-term androgen deprivation therapy. We utilized Cox's proportional hazards models to identify predictors of oncological outcomes. Treatment outcomes, including biochemical recurrence-free survival (BCRFS), clinical progression-free survival (CPFS), and castration-resistant prostate cancer-free survival (CRPCFS), were compared according to the clinical stage. RESULTS: The median follow-up duration was 49 months (range=23-136 months). The 5-year BCRFS, CPFS, CRPCFS, and cancer-specific survival rates were 62.2%, 67.2%, 83.2%, and 93.4%, respectively. Based on Kaplan-Meier analysis, N1M0 and N0-1M1b showed favorable outcomes compared with N1M1a. Multivariate analysis revealed that N1M1a prostate cancer was an independent risk factor for poor BCRFS, CPFS, and CRPCFS. CONCLUSION: HDR-BT and EBRT with androgen deprivation therapy is a feasible approach for patients with newly diagnosed regional and low-metastatic-burden prostate cancer. However, in our cohort M1a prostate cancer had significantly inferior outcomes. A well-controlled prospective study is imperative to confirm our results.

The prognostic significance of the clinical T stage and Grade Group in patients with locally advanced prostate cancer treated via high-dose-rate brachytherapy and external beam radiation.

BACKGROUND: Although the optimal management of locally advanced prostate cancer (PCa) remains unclear, local definitive therapy, thus combined radiotherapy and androgen deprivation, is one option. We evaluated the long-term outcomes of patients with locally advanced PCa who underwent high-dose-rate brachytherapy (HDR-BT) and external beam radiation therapy (EBRT). METHODS: We retrospectively analyzed 173 patients with locally advanced PCa (cT3a-4N0-1M0) who underwent HDR-BT and EBRT. We employed Cox's proportional hazards models to identify pre-treatment predictors of oncological outcomes. Treatment outcomes (biochemical recurrence-free survival [BCRFS], clinical progression-free survival [CPFS], and castration-resistant prostate cancer-free survival [CRPCFS] were compared according to the combination of the pre-treatment predictors. RESULTS: The 5-year BCRFS, CPFS, and CRPCFS rates were 78.5, 91.7, and 94.4% respectively; there were two PCa deaths. Multivariate analysis revealed that the clinical T stage (cT3b and cT4) and Grade Group (GG) 5 status were independent risk factors for poor BCRFS, CPFS, and CRPCFS. In the GG ≤ 4 group, the Kaplan-Meier curves for BCRFS, CPFS, and CRPCFS revealed excellent outcomes. However, in the GG5 group, patients with cT3b and cT4 PCa evidenced significantly poorer oncological outcomes than those with cT3a PCa. CONCLUSION: The clinical T stage and GG status were significantly prognostic of oncological outcomes in patients with locally advanced PCa. In patients of GG ≤ 4 PCa, HDR-BT was effective even in patients with cT3b or cT4 PCa. However, in patients with GG5 PCa, careful monitoring is essential, particularly of patients with cT3b or cT4 PCa.

Endoplasmic Reticulum Stress is Involved in the Protective Effect of Sivelestat Sodium Hydrate (ONO-5046) in Spinal Cord Ischemia-Reperfusion Injury.

BACKGROUND: Postoperative complications of thoracoabdominal aortic aneurysm include paraplegia due to impaired blood flow in the spinal cord. Sivelestat sodium hydrate (ONO-5046), a specific neutrophil elastase inhibitor, can prevent neuropathy after ischemia-reperfusion of the spinal cord; however, the underlying mechanism remains unclear. Here, we examined whether ONO-5046 elicits its protective effects in spinal cord ischemia by affecting endoplasmic reticulum (ER) stress. METHODS: Forty-five male Japanese white rabbits (weight 2.5-3.0 kg) were assigned to three groups: a sham control group (n = 5), and two other groups (n = 20, respectively; n = 5 each time point) that were subjected to spinal cord ischemia-reperfusion for 15 min and administered saline or ONO-5046 intravenously. From 8 h to 7 d after resumption of blood flow, a neurological evaluation, histological evaluation of the spinal cord, and immunohistochemical evaluation based on the expression of GRP78 and caspase12 were performed. RESULTS: Rabbits treated with ONO-5046 had fewer functional deficits and more surviving motor neurons after ischemia than did rabbits in the saline and control groups. In rabbits treated with ONO-5046, histological findings of the spinal cord showed a high number of viable motor nerves, whereas induction of GRP78, an ER stress response-related protein, was prolonged. Furthermore, caspase12 expression was activated by excessive ER stress and was downregulated in rabbits treated with ONO-5046, as compared with that in rabbits administered saline. CONCLUSIONS: ONO-5046 exerts a protective effect on the spinal cord by relieving ER stress during spinal cord ischemia.

Comparison of Quality of Life and Injection Site Reactions After Switching from Degarelix 80 mg to 480 mg in Advanced Prostate Cancer: A Prospective Trial.

BACKGROUND/AIM: Degarelix has been widely used for prostate cancer; however, injection site reactions (ISRs) can be a clinical issue. We assessed differences in ISR intensity and patient quality of life (QOL) between degarelix 80 mg and 480 mg, a three-month formulation launched in 2020 in Japan. PATIENTS AND METHODS: We prospectively analyzed 25 patients with advanced prostate cancer. ISR intensity and patient QOL were evaluated before and after switching from degarelix 80 mg to 480 mg. A visual analogue scale (VAS) and faces rating scale (FRS) were applied to assess the ISRs. We applied a rating format from the M. D. Anderson Symptom Inventory (MDASI) to assess patient QOL. RESULTS: For degarelix 80 mg and a first dose of 480 mg, the incidence rate of ISRs was 84% and 92%, respectively (p=0.083). ISR pain on the third day after injection scored by VAS was 2.7±2.8 and 5.2±2.7, respectively (p<0.001). Other ISR findings such as redness, induration, swelling, warmth, and itching were significantly worse for degarelix 480 mg than for 80 mg. In the category of patient QOL, interference with activities of daily living such as general activity was significantly worse after degarelix 480 mg (p=0.003). However, 80% of patients were able to continue degarelix 480 mg during the nine months of follow-up. CONCLUSION: Degarelix 480 mg seems to exacerbate pain and other ISR findings, and to reduce patient QOL, compared with degarelix 80 mg. Optimal management of ISRs is essential to maintain patient QOL when using degarelix 480 mg.

Effective Blocking and Stabilizing Methods Using Synthetic Polymer on ELISA.

In ELISA, blocking reagents and stabilizers are important to improve the sensitivity and/or quantitative nature of the measurement system. Usually, biological substances such as bovine serum albumin and casein are used, but they still have problems such as lot-to-lot differences and biohazard. Here, we describe the methods using a chemically synthesized polymer, BIOLIPIDURE®, as a new blocking agent and stabilizer that can solve these problems.

l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells.

Eif2ak4, a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic ß-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l-asparaginase was identified. Although l-asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l-asparaginase. l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic ß-cells by l-asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use.

Effect of a Single Injection of Basic Fibroblast Growth Factor into the Vocal Folds: A 36-Month Clinical Study.

OBJECTIVE: A single injection of basic fibroblast growth factor (bFGF) into the vocal folds of patients with glottal insufficiency has been shown to be effective for a few years. However, the long-term therapeutic effect of a single injection of bFGF into the vocal folds has yet to be demonstrated. In this study, the therapeutic effect of a single injection of bFGF into the vocal folds was investigated over several years by monitoring patients for 36 months following this treatment. METHODS: Nineteen patients with glottal insufficiency received injections of bFGF diluted to 20 µg/mL in the superficial layer of the lamina propria of the bilateral vocal folds. The following parameters were evaluated at preinjection baseline and 6, 12, 18, 24, and 36 months later, and statistical comparisons were performed. The parameters evaluated were: the Grade, Rough, Breathy, Asthenic, and Strained (GRBAS) scale score; maximum phonation time; acoustic analysis; and glottal wave analysis (GWA) and kymograph edge analysis (KEA) using high-speed digital imaging (HSDI). The amplitude perturbation quotient (APQ) and period perturbation quotient (PPQ) were measured by acoustic analysis. The mean minimum glottal area during vocalization and mean minimum distance between the vocal folds were measured by GWA. The amplitudes of the bilateral vocal folds were measured by KEA. RESULTS: Postinjection, the GRBAS scale score decreased from 6 months after injection, and maximum phonation time was prolonged. The mean minimum glottal area during vocalization and the mean minimum distance between the vocal folds calculated by GWA of HSDI decreased significantly after 6 months. These effects persisted until 36 months postinjection. APQ and PPQ derived from acoustic analysis tended to decrease, but not significantly. There was no clear change in the amplitudes of the bilateral vocal folds calculated by KEA of HSDI before and after injection. CONCLUSIONS: These results suggest that the effects of a single injection of bFGF into the vocal folds persist for 36 months.

Development of a Novel Evaluation Method for Endoscopic Ultrasound-Guided Fine-Needle Biopsy in Pancreatic Diseases Using Artificial Intelligence.

We aimed to develop a new artificial intelligence (AI)-based method for evaluating endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) specimens in pancreatic diseases using deep learning and contrastive learning. We analysed a total of 173 specimens from 96 patients who underwent EUS-FNB with a 22 G Franseen needle for pancreatic diseases. In the initial study, the deep learning method based on stereomicroscopic images of 98 EUS-FNB specimens from 63 patients showed an accuracy of 71.8% for predicting the histological diagnosis, which was lower than that of macroscopic on-site evaluation (MOSE) performed by EUS experts (81.6%). Then, we used image analysis software to mark the core tissues in the photomicrographs of EUS-FNB specimens after haematoxylin and eosin staining and verified whether the diagnostic performance could be improved by applying contrastive learning for the features of the stereomicroscopic images and stained images. The sensitivity, specificity, and accuracy of MOSE were 88.97%, 53.5%, and 83.24%, respectively, while those of the AI-based diagnostic method using contrastive learning were 90.34%, 53.5%, and 84.39%, respectively. The AI-based evaluation method using contrastive learning was comparable to MOSE performed by EUS experts and can be a novel objective evaluation method for EUS-FNB.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Double common bile duct associated with pancreaticobiliary maljunction.

A 45-year-old female was admitted to the hospital with a diagnosis of acute pancreatitis. A computed tomography scan showed two extrahepatic bile ducts. Magnetic resonance cholangiopancreatography suggested a stone in one of the bile ducts. Endoscopic retrograde cholangiopancreatography revealed two extrahepatic bile ducts joining at the hilum of the liver accompanied with pancreaticobiliary maljunction. Sphincterotomy was performed and a protein plug was drained from the bile duct. Several treatment options were discussed, and the patient was treated with laparoscopic cholecystectomy without extrahepatic bile duct resection and planned to be followed up considering the risk of carcinogenesis in the bile ducts.