Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation.

Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer.

REST is a major negative regulator of endocrine differentiation during pancreas organogenesis.

Multiple transcription factors have been shown to promote pancreatic ß-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced ß-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.

10-GHz-clock time-multiplexed non-degenerate optical parametric oscillator network with a variable planar lightwave circuit interferometer.

A coherent XY machine (CXYM) is a physical spin simulator that can simulate the XY model by mapping XY spins onto the continuous phases of non-degenerate optical parametric oscillators (NOPOs). Here, we demonstrated a large-scale CXYM with >47,000 spins by generating 10-GHz-clock time-multiplexed NOPO pulses via four-wave mixing in a highly nonlinear fiber inside a fiber ring cavity. By implementing a unidirectional coupling from the ith pulse to the (i + 1)th pulse with a variable 1-pulse delay planar lightwave circuit interferometer, we successfully controlled the effective temperature of a one-dimensional XY spin network within two orders of magnitude.

Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation.

Inhibitors of Mek1/2 and Gsk3ß, known as 2i, enhance the derivation of embryonic stem (ES) cells and promote ground-state pluripotency in rodents. Here we show that the derivation of female mouse ES cells in the presence of 2i and leukaemia inhibitory factor (2i/L ES cells) results in a widespread loss of DNA methylation, including a massive erasure of genomic imprints. Despite this global loss of DNA methylation, early-passage 2i/L ES cells efficiently differentiate into somatic cells, and this process requires genome-wide de novo DNA methylation. However, the majority of imprinting control regions (ICRs) remain unmethylated in 2i/L-ES-cell-derived differentiated cells. Consistently, 2i/L ES cells exhibit impaired autonomous embryonic and placental development by tetraploid embryo complementation or nuclear transplantation. We identified the derivation conditions of female ES cells that display 2i/L-ES-cell-like transcriptional signatures while preserving gamete-derived DNA methylation and autonomous developmental potential. Upon prolonged culture, however, female ES cells exhibited ICR demethylation regardless of culture conditions. Our results provide insights into the derivation of female ES cells reminiscent of the inner cell mass of preimplantation embryos.

Complementary role of Indocyanine green video angiography, dual-image video angiography and flow-800.

BACKGROUND: Visualization of cerebral vessels, their branches and the surrounding structures are essential during cerebrovascular surgery. Indocyanine green dye-based video angiography is a commonly used technique in cerebrovascular surgery. This paper aims to analyze the real-time imaging of ICG-AG, DIVA, and the use of ICG-VA with Flow 800 to compare their usefulness in surgery. METHODS: Intraoperative real-time identification of vascular and surrounding structures in twenty nine anterior circulation aneurysms and three posterior circulation aneurysm clipping, one STA-MCA bypass, and two carotid endarterectomies were performed in patients using ICG-VA alone, DIVA, ICG-VA with Flow 800 to analyze and compare each of these methods in details. RESULTS: ICG-VA and DIVA couldn't visualize perforators in twenty-three cases of cerebral aneurysms clipping when used alone. Compared to that by adding Flow 800 perforators were easily visualized. In three cases, occlusion of perforators after clip application was visualized by DIVA and solved by repositioning surgical clips. In one STA-MCA bypass surgery, adequate blood flow to cortical branches of MCA (M4) from STA branches was assessed with ICG-VA, DIVA, and the use of ICG-VA with Flow 800 color mapping. ICG-VA, DIVA, and Flow 800 observed the lack of blood flow and fluttering atherosclerotic plaques in carotid endarterectomy. In one case of basilar tip aneurysm, we used ICG-VA with Flow 800; the intensity diagram drawn after determining regions of interest showed that there was no flow within the aneurysm sac after clipping. CONCLUSION: In real-time surgery, a multimodal approach using ICG-VA, DIVA, and ICG-VA with Flow 800 colour mapping can serve as useful tools for better visualization of vascular and surrounding structures. The benefits of flow 800 color mapping, such as determining regions of interest, intensity diagrams, and color-coded images, outweigh the advantages over the ICG-VA and DIVA in the visualization of critical vascular anatomy in humans during surgical procedures.

The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of ß-catenin signaling pathway.

Previous studies have shown that phosphorylation of the retinoid X receptor-α (RXRα) is associated with the development of hepatocellular carcinoma (HCC). However, these findings were revealed using HCC cell lines that express phosphorylated-RXRα (p-RXRα) proteins; therefore, it remains unclear whether p-RXRα affects hepatocarcinogenesis in vivo. Therefore, to investigate the biological function of p-RXRα in vivo, we developed a doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress the phosphomimetic mutant form of RXRα, T82D/S260D, in a doxycycline-dependent manner. We found that the development of liver tumors, especially high-grade adenoma and HCC, was enhanced in diethylnitrosamine (DEN)-treated T82D/S260D-inducible mice. Moreover, the increased incidence of liver tumors in the transgenic mice was attributable to the promotion of cell cycle progression. Interestingly, the expression of ß-catenin protein and its target gene cyclin D1 was elevated in the liver tumors of DEN-treated T82D/S260D-inducible mice, concurrent with increased cytoplasmic and nuclear ß-catenin protein expression, indicating its stabilization and transcriptional activation. These results indicate that p-RXRα promotes DEN-induced hepatocarcinogenesis in mice through the activation of the ß-catenin signaling pathway, suggesting that p-RXRα may serve as a possible therapeutic target for HCC.

Generation of mice for evaluating endogenous p16Ink4a protein expression.

The cyclin-dependent kinase inhibitor p16Ink4a plays a central role in cellular senescence in vitro. Although previous studies suggested cellular senescence is integrated in the systemic mechanisms of organismal aging, the localization and the dynamics of p16Ink4a in tissues remain poorly understood, which hinders uncovering the role of p16Ink4a under the in vivo context. One of the reasons is due to the lack of reliable reagents; as we also demonstrate here that commonly used antibodies raised against human p16INK4A barely recognize its murine ortholog. Here we generated a mouse model, in which the endogenous p16Ink4a is HA-tagged at its N-terminus, to explore the protein expression of p16Ink4a at the organismal level. p16Ink4a was induced at the protein level along the course of senescence in primary embryonic fibroblasts derived from the mice, consistently to its transcriptional level. Remarkably, however, p16Ink4a was not detected in the tissues of the mice exposed to pro-senescence conditions including genotoxic stress and activation of oncogenic signaling pathways, indicating that there is only subtle p16Ink4a proteins induced. These results in our mouse model highlight the need for caution in evaluating p16Ink4a protein expression in vivo.

YAP1/TAZ activity maintains vascular integrity and organismal survival.

Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.

Microwave focal therapy of prostate cancer: a non-clinical study and exploratory clinical trial.

OBJECTIVE: To examine the safety and efficacy of microwave tissue coagulation (MTC) for prostate cancer and assess its use in lesion-targeted focal therapy in a non-clinical study and a clinical phase II trial. METHODS: In the non-clinical study using Microtaze® -AFM-712 (Alfresa Pharma Corporation, Osaka, Japan) with an MTC needle, MTC was performed using a transperineal approach to targeted canine prostatic tissue under real-time ultrasonography guidance. Using various MTC output and irradiation time combinations, the targeted and surrounding tissues (rectum, bladder and fat) were examined to confirm the extent of coagulative necrosis or potential cell death, and to compare intra-operative ultrasonography and pathology findings. The exploratory clinical trial was conducted to examine the safety and efficacy of MTC. Five selected patients underwent transperineal MTC to clinically single lesion magnetic resonance imaging (MRI)-visible lesions with Gleason score 3 + 4 or 4 + 4. Prostate-specific antigen (PSA), MRI and Expanded Prostate Cancer Index Composite questionnaire findings were compared before and 6 months after surgery. RESULTS: The region of coagulative necrosis was predictable by monitoring of ultrasonically visible vaporization; thus, by placing the MTC needle at a certain distance, we were able to perform a safe procedure without adverse events affecting the surrounding organs. Based on the non-clinical study, which used various combinations of output and irradiation time, MTC with 30-W output for 60-s irradiation was selected for the prostate. Based on the predictable necrosis, the therapeutic plan (where to place the MTC needle to achieve complete ablation of the target and how many sessions) was strictly determined per patient. There were no serious adverse events in any patient and only temporary urinary symptoms related to MTC therapy were observed. Furthermore, post-treatment satisfaction was very high. All preoperative MRI-visible lesions disappeared, and PSA decreased by 55% 6 months after surgery. CONCLUSION: Microwave tissue coagulation may be an option for lesion-targeted focal therapy for prostate cancer.

Multisystem Inflammatory Syndrome in Adults after Mild SARS-CoV-2 Infection, Japan.

In Japan, a 51-year-old man had minimally symptomatic severe acute respiratory syndrome coronavirus 2 infection. Multisystem inflammatory syndrome was diagnosed ≈5 weeks later; characteristics included severe inflammation, cardiac dysfunction, and IgG positivity. Clinicians should obtain detailed history and examine IgG levels for cases of inflammatory disease with unexplained cardiac decompensation.

Polaron Masses in CH_{3}NH_{3}PbX_{3} Perovskites Determined by Landau Level Spectroscopy in Low Magnetic Fields.

We investigate the electron-phonon coupling in CH_{3}NH_{3}PbX_{3} lead halide perovskites through the observation of Landau levels and high-order excitons at weak magnetic fields, where the cyclotron energy is significantly smaller than the longitudinal optical phonon energy. The reduced masses of the carriers and the exciton binding energies obtained from these data are clearly influenced by polaron formation. We analyze the field-dependent polaronic and excitonic properties, and show that they can be quantitatively reproduced by the Fröhlich large polaron model.

Moving away from systematic biopsies: image-guided prostate biopsy (in-bore biopsy, cognitive fusion biopsy, MRUS fusion biopsy) -literature review.

OBJECTIVE: To compare the detection rate of clinically significant cancer (CSCa) by magnetic resonance imaging-targeted biopsy (MRI-TB) with that by standard systematic biopsy (SB) and to evaluate the role of MRI-TB as a replacement from SB in men at clinical risk of prostate cancer. METHODS: The non-systematic literature was searched for peer-reviewed English-language articles using PubMed, including the prospective paired studies, where the index test was MRI-TB and the comparator text was SB. Also the randomized clinical trials (RCTs) are included if one arm was MRI-TB and another arm was SB. RESULTS: Eighteen prospective studies used both MRI-TB and TRUS-SB, and eight RCT received one of the tests for prostate cancer detection. In most prospective trials to compare MRI-TB vs. SB, there was no significant difference in any cancer detection rate; however, MRI-TB detected more men with CSCa and fewer men with CISCa than SB. CONCLUSION: MRI-TB is superior to SB in detection of CSCa. Since some significant cancer was detected by SB only, a combination of SB with the TB technique would avoid the underdiagnosis of CSCa.

Impact of prostate-specific antigen screening on tumor size in patients with prostate cancer in a super-aging district in Kyoto, Japan.

BACKGROUND: Population-based prostate-specific antigen (PSA) screening is effective for reducing prostate cancer (PCa)-related mortality rates. In this study, we assessed biopsy-proven maximum cancer core length (MCCL) and maximum cancer diameter on magnetic resonance imaging (MRI; MCDM) in prostate biopsy and multiparametric MRI (mp-MRI) by PCa detection. METHODS: We retrospectively assessed 214 male PCa patients and 187 PCa patients with Prostate Imaging Reporting and Data System version 2 (PI-RADS) category 3-5 lesions in pre-biopsy mp-MRI and targeted biopsy characteristics. The mean biopsy-proven MCCL and MCDM were compared among three PSA screening groups, namely the population-based PSA screening (PBS), opportunistic PSA screening (OPS), and symptomatic outpatient PSA examination (SOP) groups. RESULTS: The median age and PSA value of the 214 participants were 75 years and 7.9 ng/mL, respectively. In the PBS, OPS, and SOP groups, the median ages were 73, 76, and 76 years, respectively (p = 0.046); PSA values were 7.2, 9.5, and 11.5 ng/mL, respectively (p < 0.001); and biopsy-proven MCCL and MCDM were significantly increased to 7, 10, and 14 mm (p < 0.001) and to 11, 15, and 17 mm (p < 0.001), respectively. In the 187 PCa patients with PI-RADS category 3-5 lesions on mp-MRI, MCDM were 11, 14, and 17 mm (p < 0.001), respectively. CONCLUSIONS: The biopsy-proven MCCL and MCDM were significantly smaller in the PBS and OPS groups than in the SOP group, which suggests that PSA screening detected PCa earlier than in symptomatic patients. PSA screening with MRI could objectively lead to earlier diagnosis based on tumor size.

Elucidating Influence of Mg- and Cu-Doping on Electrochemical Properties of O3-Nax [Fe,Mn]O2 for Na-Ion Batteries.

Although O3-NaFe1/2 Mn1/2 O2 delivers a large capacity of over 150 mAh g-1 in an aprotic Na cell, its moist-air stability and cycle stability are unsatisfactory for practical use. Slightly Na-deficient O3-Na5/6 Fe1/2 Mn1/2 O2 (O3-Na5/6 FeMn) and O3-Na5/6 Fe1/3 Mn1/2 Me1/6 O2 (Me = Mg or Cu, O3-FeMnMe) are newly synthesized. The Cu and Mg doping provides higher moist-air stability. O3-Na5/6 FeMn, O3-FeMnCu, and O3-FeMnMg deliver first discharge capacities of 193, 176, and 196 mAh g-1 , respectively. Despite partial replacement of Fe with redox inactive Mg, oxide ions in O3-FeMnMg participate in the redox reaction more apparently than O3-Na5/6 FeMn. X-ray diffraction studies unveil the formation of a P-O intergrowth phase during charging up to >4.0 V.

Higher expression of phosphodiesterase type 5 in the anterior fibromuscular stroma of the human prostate.

PURPOSE: To examine phosphodiesterase type 5 (PDE5) expression in the anterior fibromuscular stroma (AFMS) of the prostate. Although PDE5 expression was identified in the human prostate, differences in PDE5 expression in intra-prostatic regions are unknown. The AFMS in the prostate has peculiar innervations that could contribute to voiding function. Here, we examined regional differences in PDE5 expression in the prostate with special reference to the AFMS. METHODS: A total 18 human prostate and bladder specimens were obtained. Tissue specimens were processed by hematoxylin-eosin (H&E) staining and immunohistochemistry for PDE5. Immunoreactivity with PDE5 was evaluated using computer-assisted image analysis in the following regions: the AFMS, bladder neck, stromal hyperplasia in the transition zone, glandular hyperplasia in the transition zone (TZ gland), and the peripheral zone (PZ). The correlation between PDE5 expression in the AFMS and clinical data was analysed. RESULTS: Image analysis revealed that the median ratio of the PDE5-immunoreactive area to smooth muscle area by H&E staining was 74.7% in the AFMS. There was significantly higher PDE5 expression in the AFMS than in the TZ gland (p = 0.034) and PZ (p = 0.002). PDE5 expression in the AFMS was not significantly correlated with age, prostate volume, transition zone volume, or transition zone index. However, older men had a tendency to have higher PDE5 expression in the AFMS. CONCLUSIONS: We found higher PDE5 expression in the AFMS compared with other prostatic regions, which suggested that the AFMS is a target region of PDE5 inhibitors in the prostate.

RNA-binding protein Ptbp1 regulates alternative splicing and transcriptome in spermatogonia and maintains spermatogenesis in concert with Nanos3.

PTBP1, a well-conserved RNA-binding protein, regulates cellular development by tuning posttranscriptional mRNA modification such as alternative splicing (AS) or mRNA stabilization. We previously revealed that the loss of Ptbp1 in spermatogonia causes the dysregulation of spermatogenesis, but the molecular mechanisms by which PTBP1 regulates spermatogonium homeostasis are unclear. In this study, changes of AS or transcriptome in Ptbp1-knockout (KO) germline stem cells (GSC), an in vitro model of proliferating spermatogonia, was determined by next generation sequencing. We identified more than 200 differentially expressed genes, as well as 85 genes with altered AS due to the loss of PTBP1. Surprisingly, no differentially expressed genes overlapped with different AS genes in Ptbp1-KO GSC. In addition, we observed that the mRNA expression of Nanos3, an essential gene for normal spermatogenesis, was significantly decreased in Ptbp1-KO spermatogonia. We also revealed that PTBP1 protein binds to Nanos3 mRNA in spermatogonia. Furthermore, Nanos3+/-;Ptbp1+/- mice exhibited abnormal spermatogenesis, which resembled the effects of germ cell-specific Ptbp1 KO, whereas no significant abnormality was observed in mice heterozygous for either gene alone. These data implied that PTBP1 regulates alternative splicing and transcriptome in spermatogonia under different molecular pathways, and contributes spermatogenesis, at least in part, in concert with NANOS3.

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior.

The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an ApcMin/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion.

Magnetic resonance imaging-guided targeted prostate biopsy: Comparison between computer-software-based fusion versus cognitive fusion technique in biopsy-naïve patients.

OBJECTIVE: To compare magnetic resonance imaging-guided cognitive fusion-targeted biopsies versus computer-software-based fusion-targeted biopsies in prostate biopsy-naïve patients. METHODS: This was a retrospective review of 298 consecutive patients, in which suspected clinically significant prostate cancer lesions were detected on pre-biopsy magnetic resonance imaging, and cognitive fusion-targeted biopsies or software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies was carried out. The positivity rates of any cancer and clinically significant prostate cancer, Gleason score, and maximum cancer core length were compared between the cognitive fusion-targeted biopsies and software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies groups. RESULTS: The any-cancer positivity rate was 79.6% (90/113 patients) in the cognitive fusion-targeted biopsies group and 84.8% (157/185 patients) in the software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies group (P = 0.516), and the clinically significant prostate cancer positivity rate was 72.5% (82/113 patients) in the cognitive fusion-targeted biopsies group and 75.7% (140/185 patients) in the software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies group (P = 0.498). Among the patients in which the largest lesion diameter on magnetic resonance imaging was ≤5.0 mm, the clinically significant prostate cancer positivity rate was 39.2% (11/28 patients) in the cognitive fusion-targeted biopsies group and 66.6% (24/36 patients) in the software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies group (P = 0.043). The median maximum cancer core length was 7.5 mm (0.25-16 mm) in the cognitive fusion-targeted biopsies group and 8 mm (0.2-19 mm) in the software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies group (P = 0.040). CONCLUSIONS: Software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies offers a greater detection rate for smaller targeted lesions and also superior ability to sample greater cancer core length compared with cognitive fusion-targeted biopsies. The present results suggest that software-guided magnetic resonance imaging-ultrasound fusion-targeted biopsies might improve biopsy outcomes compared with cognitive fusion-targeted biopsies.

Focal salvage low-dose-rate brachytherapy for recurrent prostate cancer based on magnetic resonance imaging/transrectal ultrasound fusion biopsy technique.

OBJECTIVE: To examine the effect of permanent salvage brachytherapy in prostate cancer patients suffering recurrence after three-dimensional conformal external beam radiotherapy. METHODS: The ultra-focal (target lesion alone), hemi-lobe (within a hemi-lobe) or focused whole-gland (focusing on the lesion, but extending into the whole gland) pattern was selected based on the Gleason score for the targeted biopsy, the numbers of positive cores in the targeted and systematic biopsies, and the locations of the positive cores. Novel dosimetry criteria derived from three-dimensional cancer mapping, which was based on targeted magnetic resonance imaging/transrectal ultrasound fusion biopsies, were used in these cases. RESULTS: Permanent salvage brachytherapy was carried out in 13 patients who suffered prostate-specific antigen failure (prostate-specific antigen 2.1-6.8 ng/mL; age range 57-75 years; Gleason score ≤7 [n = 10], Gleason score ≥8 [n = 2] and Gleason score not available [n = 1]) since 2012. The targeted biopsy showed a single focus in three patients. The ultra-focal, hemi-lobe and focused whole-gland patterns were chosen in three, five and five patients, respectively. During the follow-up period (median duration 48 months), prostate-specific antigen failure occurred in zero of three, one of five and three of five of the patients treated with the ultra-focal, hemi-lobe and focused whole-gland patterns, respectively. The 4-year biochemical recurrence-free survival rate was 74%. No grade 3-4 adverse intestinal or urological events occurred. CONCLUSIONS: Targeted fusion biopsy-based three-dimensional cancer mapping should be used for permanent salvage brachytherapy treatment planning to reduce the incidence of treatment-related adverse events while maintaining good oncological outcomes.

Less nephrotoxicity of paclitaxel and ifosfamide plus nedaplatin for refractory or relapsed germ cell tumors in patients with impaired renal function.

OBJECTIVES: To determine the safety and efficacy of the combined regimen of paclitaxel and ifosfamide plus nedaplatin for patients with refractory or relapsed germ cell tumors and impaired renal function. METHODS: Of a total of 68 patients who received paclitaxel, ifosfamide and nedaplatin chemotherapy for germ cell tumors, those with an estimated glomerular filtration rate <60 mL/min/1.73 m2 before paclitaxel, ifosfamide and nedaplatin treatment were defined as having renal dysfunction. The combination chemotherapy regimen included paclitaxel (210 mg/m2 on day 1) and ifosfamide (1.2 g/m2 on days 2-6) with nedaplatin (100 mg/m2 on day 2) on a 3-week cycle. RESULTS: A total of 10 patients had renal dysfunction with a median estimated glomerular filtration rate of 49.97 mg/mL/1.73 m2 (range 31.7-57.5 mg/mL/1.73 m2 ). Paclitaxel, ifosfamide and nedaplatin chemotherapy was given as second-line therapy in four patients, third-line in four and fourth-line or later in two. Patients with impaired renal function received pretreatment of a median of 5.5 cycles of platinum-based chemotherapy (range 3-11 cycles) with a median cisplatin dose of 550 mg/m2 . The patients were given two to six cycles of paclitaxel, ifosfamide and nedaplatin chemotherapy with no dose reduction, with an overall response rate of 60%. Chemotherapy-induced kidney dysfunction was not observed in any patient with decreased renal function. Furthermore, there was no difference in the frequency of adverse events between patients with renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2 ) and those with normal renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m2 ). CONCLUSIONS: Paclitaxel, ifosfamide and nedaplatin chemotherapy can be considered a safe and effective regimen that results in less nephrotoxicity in germ cell tumor patients with renal dysfunction.