Genome editing iPSC to purposing enhancement of induce CD8 killer T cell function for regenerative immunotherapy.

In recent years, immunotherapy has become a standard cancer therapy, joining surgery, chemotherapy, and radiation therapy. This therapeutic approach involves the use of patient-derived antigen-specific T cells or genetically modified T cells engineered with chimeric antigen receptors (CAR) or T cell receptors (TCR) that specifically target cancer antigens. However, T cells require ex vivo stimulation for proliferation when used in therapy, and the resulting "exhaustion," which is characterized by a diminished proliferation capacity and anti-tumor activity, poses a significant challenge. As a solution, we reported "rejuvenated" CD8 + T cells that possess high proliferation capacity from induced pluripotent stem cells (iPSCs) in 2013. This review discusses the status and future developments in immunotherapy using iPSC-derived T cells, drawing insights from our research to overcome the exhaustion associated with antigen-specific T cell therapy.

Arteriovenous fistula in a renal allograft with gross hematuria and subsequent acute kidney injury due to urinary tract obstruction: a case report.

BACKGROUND: Arteriovenous fistula (AVF) due to renal allograft biopsy is mechanical trauma resulting from the penetration of small arteries and veins by a core needle. Most AVFs are reported to resolve asymptomatically and spontaneously. This report presents a patient with acute kidney injury (AKI) due to urinary tract obstruction caused by a bleeding AVF in a renal allograft. CASE PRESENTATION: A 22-year-old Japanese woman who underwent living-donor kidney transplantation (KT) at 3 years due to end-stage renal disease caused by focal segmental glomerulosclerosis (FSGS) presented with a renal transplant AVF (gourd-shaped; 42 × 19 × 20 mm). The AVF was unexpectedly discovered by ultrasound before a surveillance biopsy at 10 years after KT. The patient had a history of recurrent FSGS, had undergone several renal allograft biopsies after KT, and did not experience symptoms or growth of the AVF for years. Nineteen years after KT, the patient developed AKI with sudden, asymptomatic, gross hematuria and anuria. Plain computed tomography revealed a hematoma in the pelvis of the renal allograft and bladder tamponade. The AVF was successfully treated by coil embolization. Hemodialysis was performed for AKI, and graft function was gradually recovered. CONCLUSIONS: Unexpected bleeding from a renal transplant AVF may lead to transplant dysfunction. Angiographic embolization against the ruptured renal transplant AVF may prevent rebleeding and rescue the renal allograft.

Variants in HOXB13, G132E and F127C, Are Associated With Prostate Cancer Risk in Japanese Men.

BACKGROUND/AIM: Several studies have reported on the relationship between HOXB13 variants and an increased prostate cancer (PC) risk. To our knowledge there are not many studies on HOXB13 mutations in Japanese patients with prostate cancer, and there many issues remain uninvestigated. We herein clarified the association between HOXB13 genetic variants and PC risk in a Japanese population. PATIENTS AND METHODS: PC patients were diagnosed at the Gunma University Hospital and affiliated hospitals from 1994 to 2016. Sanger sequencing was performed on the coding regions of the HOXB13 gene in 152 familial PC (FPC) patients. Genotyping was performed on single nucleotide variants (SNVs) found in Sanger sequencing in 230 FPC patients from 152 pedigrees and 197 sporadic PC (SPC) patients and 144 controls. Allelic frequency and clinical data for each variant were studied in cases and controls. RESULTS: G132E and F127C were identified in FPC patients. The frequencies of G132E and F127C were significantly higher compared to the control group (p=0.039). In three families, seven PC patients shared the G132E variant, within second-to-third-degree relatives. It was not possible to clarify to pathogenicity of each SNV alone. CONCLUSION: We found two significant variants of the HOXB13 gene, G132E, F127C by analyzing and comparing gene samples from PC and non-PC patients. Furthermore, the HOXB13 G132E variant was found significantly increased in the FPC group.

Improved Arterial Preservation Achieved by Combined Use of Indocyanine Green Angiography and Doppler Detector During Microsurgical Subinguinal Varicocelectomy.

Objectives: The microsurgical approach is considered the most reliable procedure in varicocelectomy. However, as there are difficulties in identifying the spermatic artery at the peripheral level, we had introduced intraoperative indocyanine green angiography (ICGA) for identification of arteries. In this study, we further investigated the usefulness of intraoperative ICGA in combination with an ordinary Doppler detector in microsurgical subinguinal varicocelectomy. Methods: A total of 140 men who underwent microsurgical subinguinal varicocelectomy at Gunma University Hospital were included. An operating microscope equipped with a near-infrared charge-coupled device was used for intraoperative ICGA. After exposing the vessels, arteries were identified using endoscopic vision only or with assistance of Doppler detector or ICGA, or of both. The number of preserved arteries was compared among the groups. Results: ICGA clearly visualized the internal spermatic arteries in all cases, allowing the surgeon to perform real-time identification and isolation of the spermatic artery intraoperatively. The use of ICGA or Doppler detector significantly increased the number of preserved arteries compared to the microscope-only operation from 1.11 to 1.75 (p < 0.05) and 1.57 (p < 0.05), respectively. The additional use of ICGA with Doppler detector further increased the number of preserved arteries to 2.41 (p < 0.05). Conclusions: Intraoperative ICGA facilitated safe and quick microsurgical subinguinal varicocelectomy by enabling visualization of thin spermatic cord blood vessels. Improved preservation of thin arteries, which is essential for patients with infertility, can be achieved with the combined use of ICGA and ordinary Doppler detector.

An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression.

BACKGROUND: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA velocity (PSAV) while monitoring oncologic outcomes and survival in Japanese patients. METHODS: We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients' median age was 75 ± 7.9 years (range, 53-93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA-progression-free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595). RESULTS: We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA-PFS, and OS were significantly higher compared with post docetaxel (PSA-PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1-2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA-progression (P < .05). CONCLUSIONS: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.

Efficacy of Indocyanine Green Angiography on Microsurgical Subinguinal Varicocelectomy.

OBJECTIVES: Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles related to male infertility and scrotal pain. However, the difficulty in identifying testicular arteries, which should be spared, is a limitation of this technique. To visualize and identify the testicular arteries in spermatic cord during the operation, we examined the efficacy of intraoperative indocyanine green angiography (ICGA), which is regularly used in microsurgical neurosurgery. METHODS: After the exposure of the spermatic cord blood vessels, ICG was injected intravenously under a surgical microscope for observing infrared fluorescence in patients to identify and isolate the testicular artery. RESULTS: The testicular artery was clearly identified by ICGA and was able to separate under ICGA view. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The preserved arteries were confirmed by repeated ICGA at the end of microsurgical operation. The number of arteries identified by ICGA was greater than the number detected by preoperative computed tomography angiogram. CONCLUSIONS: Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.

A CASE OF GROWING TERATOMA SYNDROME.

A 25-year-old man with a left testicular tumor underwent a high inguinal orchiectomy. Histopathological examination of the resected specimen revealed tumors of more than one histological type, mixed forms (seminoma, immature teratoma). Further evaluation revealed no metastasis (pT1N0M0S1 Stage IS).Four months after orchiectomy, alpha-fetoprotein (AFP) was elevated.CT scan revealed retroperitoneal masses of recurrent tumor. Although the AFP returned to normal level after four courses of BEP (bleomycin, etoposide and cisplatin), the retroperitoneal lymph nodes continued to grow. He underwent excision of the retroperitoneal lymph node dissection. Histopathological examination of the resected specimen revealed mature teratoma.Few reports examined about the development mechanism of growing teratoma syndrome (GTS). We considered that the development mechanism of GTS in this case is induction of differentiation. In this case report, we discuss the development mechanism of GTS based on bibliographical consideration.

[SQUAMOUS CELL CARCINOMA WITH CLOACAL EXSTROPHY: A CASE REPORT].

A 41-year-old man with a history of cloacal exstrophy presented to a local clinic with abdominal pain and bowel sounds. He was noted to have pain at the site of scarring due to cloacal exstrophy and a laceration at its center, which was stained with feces. He was referred to our department because of an enterocutaneous fistula. Skin biopsy of the neoplastic lesion at this site led to a diagnosis of squamous cell carcinoma. Computed tomography showed tumor invasion of the ileum and right inguinal lymph node enlargement. We performed tumor resection, partial enterectomy, intestinal anastomosis, abdominal wall reconstruction with a left pedicled anterolateral thigh flap, split-thickness skin grafting, and right inguinal lymph node biopsy. Histopathological examination revealed cancer growth, invasion, and pearl formation in the lymph nodes, leading to a diagnosis of abdominal squamous cell carcinoma with metastasis to the inguinal lymph nodes. The skin graft took well, and the patient was discharged. He is scheduled for right inguinal lymph node dissection at a later date.

[EFFICACY OF MICROSURGICAL SUBINGUINAL VARICOCELECTOMY USING INDOCYANINE GREEN FLUORESCENCE ANGIOGRAPHY: A PILOT STUDY].

Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles. However, the difficulty in identifying testicular arteries that should be spared is a limitation of this technique. We assessed the efficacy of intraoperative indocyanine green angiography (ICGA) during microsurgical subinguinal varicocelectomy in three pilot cases. We performed microsurgical subinguinal varicocelectomy using a surgical microscope for observing infrared fluorescence in patients with infertility or chronic pain associated with varicoceles. After the exposure of the spermatic cord blood vessels, ICG was injected intravenously to identify and isolate the testicular artery. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The testicular artery could be clearly identified by ICGA and were able to separate under ICGA. The preserved arteries were confirmed by ICGA at the end of microsurgical operation. Though, all the internal spermatic veins could be safely ligated, while sparing the testicular arteries and lymphatic vessels. Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.