The Improved Antigen Uptake and Presentation of Dendritic Cells Using Cell-Penetrating D-octaarginine-Linked PNVA-co-AA as a Novel Dendritic Cell-Based Vaccine.

Cancer immunotherapy using antigen-pulsed dendritic cells can induce strong cellular immune responses by priming cytotoxic T lymphocytes. In this study, we pulsed tumor cell lysates with VP-R8, a cell-penetrating D-octaarginine-linked co-polymer of N-vinylacetamide and acrylic acid (PNVA-co-AA), into the DC2.4 murine dendritic cell line to improve antigen uptake and then determined the anti-tumor effect in tumor-bearing mice. DC2.4 cells were pulsed with the cell lysate of EL4, a murine lymphoma cell line, and VP-R8 to generate the DC2.4 vaccine. For the in vivo study, DC2.4 cells pulsed with EL4 lysate and VP-R8 were subcutaneously injected into the inguinal lymph node to investigate the anti-tumor effect against EL4 and EL4-specific T cell immune responses. VP-R8 significantly improved antigen uptake into DC2.4 compared to conventional keyhole limpet hemocyanin (p < 0.05). The expression of MHC class I, MHC class II, and CD86 in DC2.4 cells significantly increased after pulsing tumor lysates with VP-R8 compared to other treatments (p < 0.05). The intra-lymph node injection of DC2.4 pulsed with both VP-R8 and EL4 lysate significantly decreased tumor growth compared to DC2.4 pulsed with KLH and lysates (p < 0.05) and induced tumor-infiltrating CD8T cells. The DC2.4 vaccine also remarkably increased the population of IFN-gamma-producing T cells and CTL activity against EL4 cells. In conclusion, we demonstrated that VP-R8 markedly enhances the efficiency of dendritic cell-based vaccines in priming robust anti-tumor immunity, suggesting its potential as a beneficial additive for dendritic cell-based immunotherapy.

Therapeutic outcome of combination therapy using immune-checkpoint inhibitors and tyrosine kinase inhibitors for metastatic non-clear-cell renal cell carcinoma.

INTRODUCTION: We aimed to clarify the therapeutic outcome of combination therapy using immune-checkpoint inhibitors (ICIs) and/or tyrosine kinase inhibitors (TKIs) for meta-static non-clear-cell renal cell carcinoma (nccRCC). METHODS: We have been retrospectively investigating the therapeutic efficacy and prognosis in 36 patients with metastatic nccRCC undergoing combination therapy using two ICIs, ipilimumab plus nivolumab (ICI-ICI), and ICI plus TKI (ICI-TKI), at Kobe University and affiliated institutions since 2018. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse event (AE) were compared. RESULTS: The first-line regimen was ICI-ICI in 26 cases and ICI-TKI in 10 cases. The ORRs in the ICI-ICI and ICI-TKI groups were 34.6 and 30.0%, respectively (p=0.9433). The 50% PFS for the ICI-TKI group was 9.7 months, significantly longer than that for the ICI-ICI group (4.6 months, p=0.0499), and there was no significant difference in OS between groups (p=0.3984). There was no significant difference in the occurrence rate of AE for below grade 2 (p=0.8535), nor above grade 3 (p=0.3786) between the ICI-ICI and ICI-TKI groups. CONCLUSIONS: From our analysis of real-world data, a better outcome of PFS was expected in the ICI-TKI group compared with that in the ICI-ICI group, while there was no significant difference in OS or ORR.

Robot-assisted laparoscopic pyeloplasty in the management of lower pole ureteropelvic junction obstruction in a patient with an incomplete duplicated collecting system.

Introduction: The performance of robot-assisted laparoscopic pyeloplasty has recently been increasing in frequency. However, patients with duplicated renal pelvises and ureters can present challenges. Case presentation: A 71-year-old woman presented with flank pain and was diagnosed with ureteropelvic junction obstruction with an incomplete duplicated collecting system. Preoperative imaging did not reveal the details of the stenosis. Therefore, three reconstructive procedures were prepared: The Anderson-Hynes procedure, end-to-side pyeloureterostomy, and upper pole ureter to lower pole pyeloplasty with the Anderson-Hynes procedure for the lower pole. These procedures were determined by the length of the intact ureter and the presence of crossed vessels. During the surgery, the crossing vein was severed, allowing successful reconstruction with Anderson-Hynes anastomosis. Conclusion: Preoperative evaluation and preparation of multiple surgical techniques are crucial in robot-assisted laparoscopic pyeloplasty for incomplete duplicated collecting systems.

The impact of primary region resection on the therapeutic outcome of combination regimens for metastatic renal cell carcinoma.

The present study aimed to clarify the relationship between the therapeutic outcome of combination regimens, including immune checkpoint inhibitors (ICIs) and/or tyrosine kinase inhibitors (TKIs), and cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). The present study retrospectively assessed the association between treatment efficacy and prognosis with or without CN, and the timing of CN in 151 patients treated with combination regimens for mRCC who were categorized as intermediate/poor risk. The first-line regimens included the ICI-ICI and ICI-TKI regimens in 98 and 53 cases, respectively. In patients with recurrence after radical surgery (n=66), the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 33.6 months and not reached (NR) (P=0.4032), respectively, and the 50% OS times were 53.7 months and NR (P=0.6886), respectively. Among the 38 patients with metastasis from the initial diagnosis who underwent upfront CN, the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 10.5 and 8.2 months (P=0.5806), respectively, and the 50% OS times were NR and 15.8 months (P=0.0587), respectively. Among the 51 patients who did not receive upfront CN, the 50% PFS time of the ICI-TKI group was significantly higher than that in the ICI-ICI group (4.1 months and NR, respectively; P=0.0210), and the 50% OS times were 29.8 months and NR (P=0.7343), respectively. In conclusion, according to the analysis of real-world data, good therapeutic efficacy can be achieved with any regimen in patients with recurrence after radical surgery. In addition, improved results could be achieved through treatment with ICI-TKI in patients without upfront CN.

An oral cancer vaccine using Bifidobacterium vector augments combination of anti-PD-1 and anti-CTLA-4 antibodies in mouse renal cell carcinoma model.

Recently, immune checkpoint inhibitor (ICI) based combination therapies, including anti-PD-1 antibody, nivolumab with anti-CTLA-4 antibody, and ipilimumab have become the primary treatment option for metastatic or unresectable renal cell carcinoma (RCC). However, despite the combination of two ICIs, 60-70% of patients are still resistant to first-line cancer immunotherapy. In the present study, undertook combination immunotherapy for RCC using an oral cancer vaccine (Bifidobacterium longum displaying WT1 tumor associated antigen (B. longum 420)) with anti-PD-1 and anti-CTLA-4 antibodies in a mouse syngeneic model of RCC to explore possible synergistic effects. We found that B. longum 420 significantly improved the survival of mice bearing RCC tumors treated by anti-PD-1 and anti-CTLA-4 antibodies compared to the mice treated by the antibodies alone. This result suggests that B. longum 420 oral cancer vaccine as an adjunct to ICIs could provide a novel treatment option for RCC patients. Our microbiome analysis revealed that the proportion of Lactobacilli was significantly increased by B. longum 420. Although the detailed mechanism of action is unknown, it is possible that microbiome alteration by B. longum 420 enhances the efficacy of the ICIs.

A recombinant adenovirus vector containing the synNotch receptor gene for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is known as the most difficult molecular subtype of breast cancer to treat. Recent studies revealed that cancer stem cells (CSCs) play a critical role in TNBC recurrence and metastasis. In this study, we developed a recombinant replication-deficient adenoviral vector (Ad-CD44-N-HIF-3α4), which contains a gene encoding a synthetic Notch (synNotch) receptor composed of the extracellular domain of CD44 (CD44-ECD) and the hypoxia-inducible factor (HIF)-3α4 connected by the Notch core regulatory region. CD44 is a transmembrane glycoprotein and known as a CSC marker in breast cancer and other malignancies. HIF-3α4 is a dominant-negative regulator of HIF-1α and HIF-2α and inhibits hypoxia-inducing effect. Both CD44 and HIF signals contribute cancer stemness and maintaining CSCs in breast cancer. The CD44-ECD in the synNotch receptor acts as the CD44 decoy receptor, and after a ligand such as a hyaluronic acid binds to the CD44-ECD, HIF-3α4 is released from the Notch core domain. We performed an in vivo study using a mouse xenograft model of MDA-MB-231, a highly invasive TNBC cell, and confirmed the significant antitumor activity of the intratumoral injections of Ad-CD44-N-HIF3α4. Our findings in this study warrant the further development of Ad-CD44-N-HIF3α4 for the treatment of patients with TNBC.

Treatment outcome after sequential chemotherapy with cisplatin-etoposide, amrubicin and nogitecan in patients with treatment-related pure small-cell neuroendocrine prostate cancer.

OBJECTIVE: This study retrospectively reviewed the clinical characteristics and treatment outcomes of patients with histologically diagnosed treatment-related pure small-cell neuroendocrine prostate cancer. METHODS: We retrospectively evaluated data for 13 patients with treatment-related neuroendocrine prostate cancer who were diagnosed between May 2015 and February 2022. Standardized systemic therapies of etoposide plus cisplatin (or carboplatin), amrubicin and nogitecan were selected as sequential treatments. Cancer-specific survival and progression-free survival were evaluated as the primary endpoint. The Cox proportional hazards model was used to evaluate the relationships between treatment regimens, clinical variables, cancer-specific survival and progression-free survival. RESULTS: The median cancer-specific survival after diagnosis for all patients was 22.4 months (range 1.3-33.4 months). The median progression-free survival was 9.3 months after first-line etoposide plus cisplatin (or carboplatin) treatment (n = 13); 4.2 months after second-line amrubicin treatment (n = 4); and >15 months after third-line nogitecan treatment (n = 2). The median progression-free survival after first-line chemotherapy of the liver metastasis (-) group was 10.2 months, and that of the (+) group was 5.3 months (P = 0.015, hazard ratio = 11.6, 95% confidence interval = 1.01 - 133.7). No clinicopathological parameters were identified as significant independent predictors of cancer-specific survival in univariate analysis. CONCLUSION: Sequential chemotherapy with etoposide plus cisplatin (or carboplatin), amrubicin and nogitecan may be helpful for patients with treatment-related pure small-cell neuroendocrine prostate cancer. Early biopsy of metastases and initiation of effective therapy is essential for patients with progressive castration-resistant prostate cancer and low prostate-specific antigen.

[Two Cases of Unilateral Multifocal Renal Cell Carcinoma Treated with Robot-Assisted Partial Nephrectomy].

Recently, robot-assisted laparoscopic partial nephrectomy (RAPN) has become a commonly performed surgical treatment for small renal tumors, but for difficult cases, such as those presenting with multiple tumors, there are few institutions with experience. We herein report two cases of unilateral multifocal renal cell carcinoma that were successfully treated with RAPN. Case 1: A 65-year-oldwoman was incidentally identified to have two right kidney tumors on imaging. RAPN under cold ischemia was performed. Pathological examinations revealed both tumors to be clear cell carcinoma. Case 2: A 56-year-oldman was incidentally found to have two left kidney tumors on imaging. RAPN under zero-ischemia and warm ischemia was performed. Pathological examinations revealed both tumors to be clear cell carcinoma. In both cases, no recurrence has been observed, and the decrease that occurred in the renal function was mild during the one-and-a half year follow-up.

Association between sarcopenia based on psoas muscle index and the response to nivolumab in metastatic renal cell carcinoma: A retrospective study.

PURPOSE: Two methods are used to identify sarcopenia by calculating skeletal muscle area on computed tomography: the skeletal muscle index (SMI) and the psoas muscle index (PMI). Programmed death (PD)-1 inhibitors are helpful in treating metastatic renal cell carcinoma (mRCC). However, there remains insufficient information regarding a clear and easy-to-use biomarker for predicting the response to PD-1 inhibitors in patients with mRCC. Therefore, we investigated the influence of sarcopenia on clinical outcomes in patients with mRCC undergoing treatment with nivolumab. MATERIALS AND METHODS: This study evaluated 96 patients with RCC who received nivolumab. The SMI and PMI were calculated for each patient and normalized for stature by use of the following formulas: SMI (cm²/m²)=([skeletal muscle cross-sectional area at the level of L3]/[height]²) and PMI (cm²/m²) = ([left-right sum of the psoas muscle areas at the level of L3]/[height]²). The relationship of the clinical variables with progression-free survival and overall survival (OS) was examined using a Cox proportional hazards model. RESULTS: According to the SMI-based definition of sarcopenia, 74.0% of patients had sarcopenia. However, according to the PMI-based definition of sarcopenia, only 34.3% of patients were diagnosed with sarcopenia. Multivariate analysis identified sarcopenia based on PMI (hazard ratio [HR], 3.85; 95% confidence interval [CI], 2.04-7.26; p<0.001) and International Metastatic RCC Database Consortium poor risk status (HR, 1.90; 95% CI, 1.03-3.50; p=0.041) as significant and independent prognostic factors of OS. CONCLUSIONS: PMI-based sarcopenia is a significant prognostic factor for OS in patients with RCC who receive nivolumab therapy.

The lumbosacral angle is a significant predictor for using a semi-rigid ureteroscopic approach in middle ureteral stones.

Background: Ureteroscopy for middle ureteral stones is often difficult from an anatomical view. This study aimed to evaluate the pelvic anatomy in three dimensions and investigate the relationship between the pelvic anatomy and potential semi-rigid ureteroscopic approach for treating middle ureteral stones. Methods: From a total of 967 patients who underwent ureteroscopy from December 2017 to January 2021, 124 patients who had middle ureteral stones were included in this retrospective cohort study. The pelvic transverse diameter, pelvic vertical diameter, pelvic depth, and lumbosacral angle were measured through preoperative non-contrast computed tomography to define the shape of the pelvic cavity. The relationship between the reachability of the middle ureteral stone using a semi-rigid ureteroscope and the aforementioned anatomical factors, as well as treatment outcomes, was examined retrospectively. Results: The lumbosacral angle and female sex were significant predictors of the possibility of a semi-rigid ureteroscopic approach to middle ureteral stones [odds ratio =1.08; 95% confidence interval (CI): 1.03-1.14; P=0.003, and odds ratio =3.23; 95% CI: 1.12-9.32; P=0.03, respectively]. The cutoff value of the lumbosacral angle was 149.9°, with a sensitivity of 55.1% and a specificity of 72.7%. The time to reach the stone was longer in the lumbosacral angle <150° group than in the lumbosacral angle ≥150° group (P=0.049). Conclusions: In this study, gradual lumbosacral angle and female sex are positive predictors of the reachability of the middle ureteral stone with a semi-rigid ureteroscope.

Efficacy of preoperative cine magnetic resonance imaging in evaluation of adhesion of renal cancer thrombus to inferior vena cava wall.

OBJECTIVE: In renal cell carcinoma with inferior vena cava (IVC) thrombus, adhesion to, or invasion into, the IVC wall will often increase the level of surgical difficulty and even necessitate resection of the IVC. It will generally be difficult to perform an accurate preoperative assessment using the standard imaging modalities of contrast-enhanced computed tomography and standard magnetic resonance imaging (MRI). Cine MRI is an MRI sequence that captures motion to produce detailed information on both the anatomy and the dynamic motion. In the present study, we evaluated the accuracy of preoperative cine MRI for determining the need for IVC wall resection, with validation of the imaging findings according to the intraoperative findings. METHODS: A total of 15 patients who had undergone radical nephrectomy and tumor thrombectomy from May 2018 to April 2020 met the inclusion criteria. The primary outcome of interest was the need for IVC resection because of adhesion or invasion of a venous tumor thrombus. Cine MRI was used to evaluate the blood flow between the tumor thrombus and the IVC wall and the presence of tumor thrombus mobility during free respiration. The sensitivity and specificity were calculated for preoperative cine MRI for determining the need for IVC wall resection. The Fisher exact test was used to determine the association between intraoperative IVC wall resection and the cine MRI findings. Furthermore, receiver operating characteristic curves and the area under the curve were used to compare the accuracy of conventional MRI and cine MRI. RESULTS: Of the 15 patients, 8 (53.3%) had undergone IVC resection. We found that the absence of both dynamic blood flow and tumor thrombus mobility on cine MRI could reliably predict for IVC resection with 100% (95% confidence interval, 51.8%-100%) sensitivity and 85.7% (95% confidence interval, 42.1%-1.00%) specificity. The area under the receiver operating characteristic curve was 0.821 for conventional MRI and 0.929 for cine MRI. CONCLUSIONS: In the preoperative setting, cine MRI could be a helpful examination modality to predict for the need for IVC wall resection for patients with renal cell carcinoma with venous tumor thrombus.

Is the membranous urethral length related to postoperative urinary incontinence after holmium laser enucleation of the prostate?

OBJECTIVES: To investigate the findings of preoperative magnetic resonance imaging associated with the occurrence of transient urinary incontinence after holmium laser enucleation of the prostate. METHODS: At a single institution, 360 patients underwent holmium laser enucleation of the prostate between January 2014 and December 2018. Of those, we retrospectively evaluated 237 who underwent preoperative magnetic resonance imaging and for whom postoperative evaluations were available for >3 months after holmium laser enucleation of the prostate. We carried out preoperative magnetic resonance imaging, and measured the periurethral sphincter complex, levator ani thickness, membranous urethral length and minimal residual membranous urethral length. Logistic regression analysis was carried out to assess the variables associated with incontinence. RESULTS: Transient urinary incontinence occurred after holmium laser enucleation of the prostate in 68 patients (28.7%); 46 (67.6%) of whom recovered within 3 months. Multivariate analysis showed that the membranous urethral length was independently associated with postoperative urinary incontinence at 1 and 3 months after surgery. The operative time was also independently associated with postoperative transient urinary incontinence at 1 month after surgery. CONCLUSION: Preoperative membranous urethral length and operative time are independent predictors of transient urinary incontinence after holmium laser enucleation of the prostate. These findings should be considered by surgeons before surgery.

[THE USE OF CT-GUIDED MARKING FOR THE LAPAROSCOPIC RESECTION OF A SOLITARY RETROPERITONEAL TUMOR].

When resecting small tumors or tumors with an irregular margin, a marking technique is conducted prior to the surgery. CT-guided marking techniques are common in pulmonary surgery, but it is rarely used in abdominal or urological surgery. We performed a marking technique for a small tumor that was undetectable by ultrasound using CT guidance prior to laparoscopic resection.A 63 year-old woman, two years after total hysterectomy for uterine stromal sarcoma, underwent combined right kidney resection and retroperitoneal tumor resection for a giant recurrence. Two months after the surgery, micro recurrence was observed in the vicinity of the right intestinal psoas muscle which upon follow up, the tumor size increased to 1 cm. Surgical resection of the small recurrent tumor was planned. Since it was difficult to detect by ultrasound, preoperative CT-guided marking was performed. Retroperitoneal laparoscopic resection was performed the following day. The histopathological diagnosis was endometrial stromal sarcoma.

[A Case of IgG4-Related Disease Diagnosed by Prostate Biopsy].

A 74 year-old man presented with complaints of dysuria and miction pain. Since the prostate volume was 43.5 ml, the patient was scheduled for surgical treatment of benign prostatic hyperplasia. However, prostate cancer was suspected from the magnetic resonance imaging findings and a prostate biopsy was performed. No malignant findings were observed in the pathological results, but numerous plasma cells stained positive for IgG4. Abdominal computed tomography showed pancreatic head enlargement with surrounding inflammatory changes and elevated serum IgG4 was also observed. The patient was diagnosed with IgG4-related disease (pancreatitis/prostatitis). Dysuria improved with induction of 30 mg prednisolone. The patient no longer needed to take the α1 blocker and 5α reductase inhibitor. The international prostate symptom score and urine flow measurement indicated that the patient remained in good condition at 18 months since the start of treatment.

The Use of CT-Guided Marking for the Laparoscopic Resection of a Solitary Retroperitoneal Metastasis of Colon Cancer.

Background: CT-guided marking technique is rarely used in abdominal or urologic surgery. We developed and performed a marking technique for a small tumor, undetectable by ultrasound, using CT guidance before laparoscopic resection of the tumor. Case Presentation: A 73-year-old woman with a history of breast cancer underwent right colectomy with D3 lymph node dissection for ascending colon cancer. Five years after the operation, a solitary tumor was found in the right pararenal region of the retroperitoneal space on enhanced abdominal CT. The tumor was 20 mm in diameter and undetectable by ultrasound, so we performed a marking technique using CT guidance before the operation. Placing the patient in a prone position on the CT table, a 22-gauge needle was inserted into the Gerota's fascia percutaneously and a mixed fluid containing India ink and Iopamidol was injected para to the tumor by the radiologist. During the surgery, the marker was clearly identified and the cutting line was determined to ensure a sufficient surgical margin. The tumor was laparoscopically resected as planned. The histopathologic diagnosis was adenocarcinoma, compatible with metastasis of colon cancer. The postoperative course was uneventful and the patient remained free of disease at 10 months after surgery. Conclusion: When resecting small tumors or tumors with an irregular margin, a marking technique is conducted before the surgery. But, preoperative CT-guided marking has not been applied generally for resection of intraabdominal lesion yet. CT-guided marking can be effective when performing minimally invasive and curable surgery on small tumors. This is the first report of an effective CT-guided marking before retroperitoneal laparoscopic tumorectomy. We believe that this technique provides an important therapeutic option for small tumors that may be undetectable by ultrasound.