Search

New clinical issues have been raised through an interval of 7 years from the previous version (2016). In this study, we update the "Clinical Practice Guidelines for tuberous sclerosis complex‐associated renal angiomyolipoma" as a 2023 version under guidance by the Japanese Urological Association. The present guidelines were cooperatively prepared by the Japanese Urological Association and Japanese Society of Tuberous Sclerosis Complex; committee members belonging to one of the two societies or specializing in the treatment of this disease were selected to prepare the guidelines in accordance with the "Guidance for preparing treatment guidelines" published by Minds (2020 version). The "Introduction" consisted of four sections, "Background Questions (BQ)" consisted of four sections, "Clinical Questions (CQ)" consisted of three sections, and "Future Questions (FQ)" consisted of three sections (total: 14 sections). Concerning CQ, an agreement was confirmed through voting by the committee members based on the direction and strength of recommendation, accuracy of evidence, and recommendation comments. The present guidelines were updated based on the current evidence. We hope that the guidelines will provide guiding principles for the treatment of tuberous sclerosis complex‐associated renal angiomyolipoma to many urologists, becoming a foundation for subsequent updating. [ABSTRACT FROM AUTHOR]

Background: We previously established a patient‐derived xenograft (PDX) model, patient‐derived organoids (PDOs), and PDX‐derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2‐positive SDC. Methods: The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice. Results: The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice. Conclusion: For the first time, we demonstrated the efficacy of anti‐HER2 therapy in HER2‐positive SDC using preclinical models of SDC PDX and PDXO. [ABSTRACT FROM AUTHOR]

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient‐derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient‐derived or PDX‐derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX‐derived organoid cells were evaluated for the presence of MYB‐mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC‐derived organoids were successfully generated in three‐dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short‐term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short‐term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC‐derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC. What's new? The biological underpinnings of salivary adenoid cystic carcinoma (ACC) remain largely unknown, owing to a lack of preclinical model systems. In this study, the authors describe the successful generation of human salivary ACC cell lines from organoid culture and the subsequent development of an in vivo salivary ACC mouse model. The orthotopic xenograft mouse model was established efficiently from ACC organoid cells from patient‐derived xenografts (PDX). Short‐term cultures of PDX‐derived ACC organoid cells further were amenable for in vitro drug‐sensitive studies with several agents. This novel approach could be useful for investigating personalized therapies for patients with salivary ACC. [ABSTRACT FROM AUTHOR]

Background: Transoral surgery (TOS) has been widely applied for early T‐stage head and neck cancer (HNC). The resection is performed with a minimum safety margin for function preservation under a limited surgical field; therefore, it is difficult to have a strong conviction about the complete resection. This study aims to evaluate the completeness of the initial TOS procedure; possibility of primary control by TOS alone; and predictive factors in patients with early T‐stage laryngeal, oropharyngeal, and hypopharyngeal cancer. Methods: Patients were treated by TOS at the primary site with or without neck dissection. The patients were divided into two groups based on the pathological evaluation of their surgical specimens: the control (observation) group, in that the resection was considered complete and the intervention (second‐look procedure) group, in that incomplete tumor resection was suspected. The predictive factors for the possibility and/or limitations of complete resection by TOS were then analyzed. Results: The study enrolled 26 and 25 patients in the control and intervention group, respectively. The success rate for single resection was 66% and the predictive factor was tumor depth obtained by enhanced computed tomography (CT) examination (odds ratio, 7.870, P = .0243). The success rate for definitive therapy by TOS alone was 83% and the predictive factor was poor differentiation observed on pathological examination (odds ratio, 6.800, P = .0248). Conclusions: TOS has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for TOS is advantageous for accurate treatment selection in patients with early T‐stage HNC. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effects and utility of intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. Methods We investigated a total of 26 patients with tuberous sclerosis complex who had angiomyolipoma ≥4 cm in diameter. For each patient, we analyzed the reduction in the size of the angiomyolipoma, the change in size after everolimus withdrawal, the size reduction rate on everolimus readministration and adverse events caused by everolimus. The volume of angiomyolipoma was measured using abdominal computed tomography or magnetic resonance imaging. Adverse events were evaluated according to CTCAE v4.0-JCOG. Results The average size reduction rate of angiomyolipoma in the initial treatment with everolimus was 67%. Eight patients (31%) did not have enlarged angiomyolipoma after everolimus withdrawal. The other 18 patients (69%) restarted everolimus treatment because of enlargement of the angiomyolipoma. The average size reduction rate of angiomyolipoma in the everolimus retreatment group was 61%, which was equivalent to the rate for the initial treatment. There were fewer adverse events during everolimus retreatment than in the initial treatment. Conclusions This is the first report regarding intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. This treatment is effective for tumor control and adverse event management. This beneficial treatment option for patients can minimize the drug dosage and the occurrence of adverse events. [ABSTRACT FROM AUTHOR]

Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next-generation sequencing using a target-enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16-related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele-specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV-HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus-associated carcinogenesis of HPV-HNSCC. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the efficacy and toxicity profiles of everolimus in Japanese patients with renal angiomyolipoma associated with tuberous sclerosis complex. Methods Patients with a 4-cm or larger angiomyolipoma meeting the diagnostic criteria of tuberous sclerosis complex were selected as participants of our investigation. In each case, we assessed tuberous sclerosis complex-associated symptoms, the treatment effect and adverse events. The treatment effect was evaluated by measuring the tumor volume reduction rate using abdominal computed tomography or magneitc resonance imaging. Adverse events were investigated using CTCAE v4.0- JCOG. The dose of everolimus was set at 10 mg once a day for adults. For childhood angiomyolipoma, everolimus administration was initiated at a dose of 5 mg once a day. Blood everolimus level was measured, and the dose was adjusted to maintain this within a range of 5-15 ng/ mL. Results The angiomyolipoma volume decreased in 46 of 47 cases, and the mean reduction rate for all cases was 60% in 12 months. The angiomyolipoma volume markedly decreased in the first 3 months, and the size leveled off after 6 months. The main adverse events related to everolimus treatment were stomatitis (91%) and irregular menstruation (65%). Grade 3 or severer adverse events were noted in three cases (6%). All patients developed some adverse events in the first 6 months. The incidence markedly decreased to 40-50% after 13 months. Conclusion The tumor volume-reducing effect of everolimus in a Japanese population was equivalent to or higher than that in Western populations. A wide variety of everolimus treatment-related adverse events can be observed, but most cases are very mild. Special attention should be given to stomatitis, irregular menstruation and interstitial lung disease as adverse events. [ABSTRACT FROM AUTHOR]

ABSTRACT Cam deformity could lead to suboptimal articulation by causing secondary femoroacetabular impingement after periacetabular osteotomy; however, the inherent femoral head-neck morphology in dysplastic hips and the effect of an additional osteoarthritic deformity have not been well described. We compared femoral head-neck morphology using three-dimensional imaging of normal and dysplastic hips in pre/early (Tönnis grade 0 and 1) and advanced stage osteoarthritis (Tönnis grade 2). Using computed tomography, we measured the circumferential α-angle and head-neck offset ratio in 68 dysplastic hips and 24 normal hips. Locations of the head-neck junction were represented by the clock position. In the pre/early group, the α-angle was significantly larger at the anterosuperior and inferior aspects (1, 2, and 5-7 o'clock) and head-neck offset ratio was smaller at the anterosuperior aspect (2 o'clock) than in the control group. The α-angle was significantly larger at the anterior aspects (1-4 o'clock) in the advanced group than in the pre/early group. The maximum α-angle was most commonly found at 2 o'clock (60%, 41/68 hips) in dysplastic hips. The prevalence of cam deformity (maximum α-angle >55°) was 4.2% (1/24 hips) in the control group, 22% (11/50 hips) in the pre/early group, and 50% (9/18 hips) in the advanced group. Cam deformity, inherent in the pre/early group, was found with relatively high frequency. The higher prevalence in the advanced group reflected degeneration-modified changes. When performing periacetabular osteotomy, preoperative radiographic assessments should include the femoral head-neck junction to prevent secondary femoroacetabular impingement, especially in patients with advanced stage osteoarthritis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1613-1619, 2016. [ABSTRACT FROM AUTHOR]

Background: A 9-year-old boy was admitted to Jikei University Hospital complaining of gradual enlarging of the left scrotal contents. Methods/Results: Physical examination was significant for bilateral descended testicles. No abnormalities were detected in the testicles or along the spermatic cords. Scrotal ultrasound showed that hyperechoic shadows were recognized in the central area of the left testicle. Subsequent testicular biopsy and histopathological examination showed intratubular malignant germ cells in tile testicular tubules. One week later, left orchiectomy was performed. Conclusions: Histopathological evaluation revealed gonadoblastoma. Gonadoblastoma, a rare gonadal neoplasm, is composed of germ cells and sex cord derivatives and usually occurs in phenotypically female patients with gonadal dysgenesis. To date, only three cases of gonadoblastoma have been reported in anatomically normal male patients with scrotal testicles. We report on a case of gonadoblastoma unaccompanied by a germ cell rumor in a physically normal male. [ABSTRACT FROM AUTHOR]