Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy to the prostate.

PURPOSE: This study presents the surgical and oncological outcomes of salvage robot-assisted radical prostatectomy (RARP) after carbon ion radiotherapy at a single institution. METHODS: Patients who underwent salvage RARP for local recurrence after carbon ion radiotherapy at Kyushu University Hospital between 2020 and 2023 were included. A single surgeon performed salvage RARP with extended pelvic lymph node dissection. Clinicopathological characteristics and perioperative and postoperative outcomes were prospectively collected and electronically recorded. RESULTS: Ten cases were included. The preoperative clinical T-stage was T2, except for one case with T3a. The median console time was 171 min (range, 135-226 min). No severe perioperative or postoperative complications were noted. The pathological T-stage was T2, T3a, and T3b in four, four, and two cases, respectively. Biochemical recurrence was observed in one patient at 31.2 months after surgery. For patients with more than 1 year of follow-up, urinary continence recovery with ≤1 pad was achieved in two cases within 1 year, whereas four cases did not recover urinary continence within 1 year. CONCLUSIONS: This case series demonstrated the feasibility of salvage RARP after carbon ion radiotherapy. Although the urinary continence recovery was modest, short-term disease control was favorable.

Validation of schedules for optimal prostate-specific antigen monitoring after radical prostatectomy.

BACKGROUND: Early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is crucial for early treatment and improving survival outcomes. The optimal prostate-specific antigen (PSA) monitoring remains unclear, and several models have been proposed. We aimed to externally validate four models for optimal PSA monitoring after RP and propose modifications to improve them. METHODS: We reviewed the clinicopathological data of 896 patients who underwent robot-assisted RP between 2009 and 2022. We examined all PSA values and estimated the PSA value for four monitoring schedules at each time point in the virtual follow-up. We defined the ideal PSA for BCR detection between 0.2 and 0.4 ng/mL. RESULTS: During the median follow-up of 21.4 months, 128 (14.3%) patients presented BCR. The original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model detected BCR in 14 (10.9%), three (2.3%), 12 (9.4%), and 11 (8.6%) patients with PSA >0.4 ng/mL. Most patients experienced BCR detected with PSA >0.4 ng/mL during the first year postoperative. The modification of interval within 6 months postoperative avoided BCR detection with PSA >0.4 ng/mL within the first year postoperative in 8/9 (88.9%), 1/2 (50.0%), 5/6 (83.3%), and 4/4 (100%) for the original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model, respectively. CONCLUSION: We validated four models for PSA monitoring after RP to detect BCR and suggested modifications to avoid detections out of the desired range of PSA. These modifications could help to establish an optimal PSA monitoring schedule after RP.

Improved urinary continence recovery after robot-assisted radical prostatectomy with lateral pelvic fascia preservation.

The novel technique of lateral pelvic fascia preservation (LPFP) in robot-assisted radical prostatectomy (RARP) has been reported to improve urinary continence recovery. We aimed to investigate surgical and oncological outcomes after RARP using the LPFP technique and compare them with conventional RARP. This study included patients who underwent RARP with and without the LPFP technique. Time to urinary continence recovery was compared between the LPFP and non-LPFP groups using univariate, multivariate, and propensity-score matched analysis. Perioperative and postoperative outcomes were compared between the two groups using univariate analysis. We included 139 patients who underwent RARP, 68 in the LPFP group and 71 in the non-LPFP group. The LPFP technique was associated with a shorter time to urinary continence recovery, a shorter operative time and lower estimated blood loss. Surgical and oncological outcomes, including complications, pathological T-stage, surgical margin status, and biochemical recurrence-free survival, were comparable between the two groups. This study demonstrated that the LPFP technique improves urinary continence recovery and operative times without compromising surgical and oncological outcomes. The use of this technique in patients with clinically localized prostate cancer is recommended.

Reconstruction After Hemimandibulectomy With a Plate and Soft-Tissue Free Flap Followed by a Titanium Mesh and Particulate Cancellous Bone and Marrow Harvested From Bilateral Posterior Ilia: A Case Report.

A particulate cancellous bone and marrow (PCBM) graft combined with titanium (Ti-) mesh tray has become one of the most popular mandibular reconstruction methods. The technique has been applied to the mandibular discontinuity defects after segmental mandibulectomy. To the best of our knowledge, there are no reports on using the technique after hemimandibulectomy, during which a wide mandibular resection, including the condyle, is performed. Here, we first report a case of mandibular reconstruction after hemimandibulectomy, using a plate and soft-tissue free flap, followed by a Ti-mesh and PCBM harvested from the bilateral posterior ilia, which was successful. This case report first revealed how bone resorption occurred clinically in mandibular reconstruction using PCBM and Ti-mesh tray after hemimandibulectomy. We also revealed the high predictability of the mandibular reconstruction using PCBM and Ti-mesh tray after hemimandibulectomy. Our report also provides a guiding principle to overcome the limitation of mandibular reconstruction using PCBM and Ti-mesh tray after hemimandibulectomy. However, our manuscript has limited evidence, being a case report.

Association between the duration of antibiotic prophylaxis and surgical site infection after orthognathic surgery in Japan.

PURPOSE: This study aimed to evaluate the risk factors for surgical site infection (SSI) after orthognathic surgery, focusing on the duration of prophylactic antibiotic administration in Japan. STUDY DESIGN: The study included 181 patients who underwent orthognathic surgery at the Department of Oral and Maxillofacial Surgery of Yamagata University Hospital between 2012 and 2021. The clinical parameters of SSI were retrospectively investigated using patient charts. Logistic regression analysis was used to estimate the odds ratios (ORs) with 95% confidence intervals (CIs) for risk factors for SSI after orthognathic surgery. RESULTS: Nineteen patients (10.5%) were complicated with SSI. Male sex (OR, 3.638; 95% CI, 1.316-10.058) and an antibiotic prophylaxis duration ≤3 days (OR, 12.718; 95% CI, 1.639-98.673) were independent risk factors for SSI after orthognathic surgery. CONCLUSION: Extended-term antibiotic prophylaxis was more effective for prevention of SSI after orthognathic surgery than short-term in this study.

Effect of HLA genotype on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer.

The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.

Clinical impact of HSD3B1 polymorphism by metastatic volume and somatic HSD3B1 alterations in advanced prostate cancer.

This study aimed to investigate the significance of HSD3B1 gene status including germline polymorphism and somatic alterations in prostate cancer. Patients with prostate cancer treated with androgen-deprivation therapy, as well as tissues from metastatic prostate cancer, were included. Genomic DNA was extracted from cancer tissues and whole blood samples, and HSD3B1 (rs1047303, 1245C) was genotyped by Sanger sequencing. The association of HSD3B1 genotype with progression-free survival according to metastatic volume was examined. Copy number alteration and gene expression of HSD3B1 were examined in prostate cancer cells and public datasets. Among 194 patients, 121 and 73 patients were categorized into low- and high-volume diseases respectively. In multivariate analysis, the adrenal-permissive genotype (AC/CC) was significantly associated with increased risk of progression compared with the adrenal-restrictive genotype (AA) in low volume, but not high-volume diseases. Somatic mutation in HSD3B1 was detected at least in two cases of castration-resistant prostate cancer tissues. HSD3B1 amplification and overexpression were detected in castration-resistant prostate cancer cells and tissues. The current findings suggest that both germline and somatic alterations of HSD3B1 may cooperatively promote castration resistance in prostate cancer and HSD3B1 as a promising biomarker for precision medicine, warranting further investigations.

Differential diagnosis of lung cancer and benign lung lesion using salivary metabolites: A preliminary study.

BACKGROUND: Saliva is often used as a biomarker for the diagnosis of some oral and systematic diseases, owing to the non-invasive attribute of the fluid. In this study, we aimed to identify salivary biomarkers for distinguishing lung cancer (LC) from benign lung lesion (BLL). MATERIALS AND METHODS: Unstimulated saliva samples were collected from 41 patients with LC and 21 with BLL. Salivary metabolites were comprehensively analyzed using capillary electrophoresis mass spectrometry. To differentiate between patients with LCs and BLLs, the discriminatory ability of each biomarker was assessed. Furthermore, a multiple logistic regression (MLR) model was developed for evaluating discriminatory ability of each salivary metabolite. RESULTS: The profiles of 10 salivary metabolites were remarkably different between the LC and BLL samples. Among them, the concentration of salivary tryptophan was significantly lower in the samples from patients with LC than in those from patients with BLL, and the area under the curve (AUC) for discriminating patients with LC from those with BLL was 0.663 (95% confidence interval [CI] = 0.516-0.810, p = 0.036). Furthermore, from the MLR model developed using these metabolites, diethanolamine, cytosine, lysine, and tyrosine, were selected using the back-selection regression method. The MLR model based on these four metabolites had a high discriminatory ability for patients with LC and those with BLL (AUC = 0.729, 95% CI = 0.598-0.861, p = 0.003). CONCLUSION: The four salivary metabolites can serve as potential non-invasive biomarkers for distinguishing LC from BLL.

Differential Impact of TGFB1 Variation by Metastatic Status in Androgen-Deprivation Therapy for Prostate Cancer.

Transforming growth factor-ß1 (TGF-ß1) plays a dual role in cancer, acting as a tumor suppressor in the early stage of cancer development and as a tumor promoter in the later stage of cancer progression in various cancers. In this study, we investigated the association between genetic polymorphisms in TGFB1 and clinicopathological characteristics or oncological outcome in prostate cancer cases treated with androgen-deprivation therapy (ADT) according to metastasis status. Japanese male patients with hormone-sensitive prostate cancer treated with ADT from 1993 to 2005 were included in this study. Genomic DNA was obtained from whole blood samples, and genotyping of TGFB1 (rs2241716 and rs4803455) was performed by PCR-based technique. No significant association between genetic polymorphisms in TGFB1 (rs2241716 and rs4803455) and clinicopathological parameters or prognosis was observed in patients with non-metastatic disease. In patients with metastatic disease, Gleason score in CT/TT carriers (rs2241716) and CA/AA carriers (rs4803455) was unfavorable compared with CC carriers. In addition, the CT/TT alleles in rs2241716 (hazard ratio, 1.82; 95% confidence interval, 1.12-2.94; P = 0.015) and the CA/AA alleles in rs4803455 (hazard ratio, 1.75; 95% confidence interval, 1.03-2.98; P = 0.040) were associated with a higher risk of progression during ADT compared with the CC allele in patients with metastatic disease. TGFB1 genetic variations were associated with adverse characteristics and progression risk in ADT among patients with metastatic disease, but not those with non-metastatic disease, supporting a distinct role of TGF-ß signaling between non-metastatic and metastatic prostate cancer.

Prognostic impact of prior local therapy in castration-resistant prostate cancer.

OBJECTIVE: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). METHODS: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. RESULTS: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. CONCLUSIONS: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

Lavencidin, a polyene macrolide antibiotic from Streptomyces lavendulae FRI-5.

In our screening program for new biologically active compounds, a new polyene macrolide, lavencidin (1), along with known compound RKGS-A2215A (2), was isolated from the fermentation broth of Streptomyces lavendulae FRI-5 by changing the composition of liquid medium normally used for the strain. Their structures were elucidated by spectral methods (high-resolution fast-atom bombardment mass spectrometry (HRFABMS) and nuclear magnetic resonance (NMR)). Compound 1 includes a conjugated pentaene moiety together with six hydroxy groups and a carboxylic acid as a side chain. Lavencidin (1) showed moderate growth-inhibitory activity against yeast and was cytotoxic against human cancer cell lines with low-micromolar IC50 values.

Identification of Salivary Proteomic Biomarkers for Oral Cancer Screening.

BACKGROUND/AIM: The current study aimed to identify biomarkers for differentiating between patients with oral cancer (OC) and healthy controls (HCs) on the basis of the comprehensive proteomic analyses of saliva samples by using liquid chromatography-mass spectrometry (LC-MS/MS). PATIENTS AND METHODS: Unstimulated saliva samples were collected from 39 patients with OC and from 31 HCs. Proteins in the saliva were comprehensively analyzed using LC-MS/MS. To differentiate between patients with OC and HCs, a multiple logistic regression model was developed for evaluating the discriminatory ability of a combination of multiple markers. RESULTS: A total of 23 proteins were significantly differentially expressed between the patients with OC and the HCs. Six out of the 23 proteins, namely α-2-macroglobulin-like protein 1, cornulin, hemoglobin subunit ß, Ig k chain V-II region Vk167, kininogen-1 and transmembrane protease serine 11D, were selected using the forward-selection method and applied to the multiple logistic regression model. The area under the curve for discriminating between patients with OC and HCs was 0.957 when the combination of the six metabolites was used (95% confidence interval=0.915-0.998; p<0.001). Furthermore, these candidate proteins did not show a stage-specific difference. CONCLUSION: The results of the current study showed that six salivary proteins are potential non-invasive biomarkers for OC screening.

Genomic characteristics revealed by targeted exon sequencing of testicular germ cell tumors in Japanese men.

OBJECTIVE: To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men. METHODS: We analyzed the somatic missense mutation profile of testicular germ cell tumors among 21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next-generation sequencing of 409 cancer-related genes covering 1.23 Mb of the genome. RESULTS: We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR,PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT-PI3K-AKT pathway was detected in 27.3% of detected mutations. CONCLUSIONS: The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.

Gene amplification of YB-1 in castration-resistant prostate cancer in association with aberrant androgen receptor expression.

Although Y-box binding protein-1 (YB-1) is known to be overexpressed in prostate cancer, especially castration-resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB-1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB-1 amplification for the YB-1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB-1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB-1 was increased in CRPC tissues compared with treatment-naïve tissues. Furthermore, YB-1 and phosphorylated YB-1 levels were associated with AR and AR V7 expression levels. Finally, YB-1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB-1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB-1 is a promising therapeutic target in CRPC.

Salivary Metabolomics for Prognosis of Oral Squamous Cell Carcinoma.

This study aimed to identify salivary metabolomic biomarkers for predicting the prognosis of oral squamous cell carcinoma (OSCC) based on comprehensive metabolomic analyses. Quantified metabolomics data of unstimulated saliva samples collected from patients with OSCC (n = 72) were randomly divided into the training (n = 35) and validation groups (n = 37). The training data were used to develop a Cox proportional hazards regression model for identifying significant metabolites as prognostic factors for overall survival (OS) and disease-free survival. Moreover, the validation group was used to develop another Cox proportional hazards regression model using the previously identified metabolites. There were no significant between-group differences in the participants' characteristics, including age, sex, and the median follow-up periods (55 months [range: 3-100] vs. 43 months [range: 0-97]). The concentrations of 5-hydroxylysine (p = 0.009) and 3-methylhistidine (p = 0.012) were identified as significant prognostic factors for OS in the training group. Among them, the concentration of 3-methylhistidine was a significant prognostic factor for OS in the validation group (p = 0.048). Our findings revealed that salivary 3-methylhistidine is a prognostic factor for OS in patients with OSCC.

Nucleophilic Arylation of Halopurines Facilitated by Brønsted Acid in Fluoroalcohol.

Various aryl-substituted purine derivatives were synthesized through the direct arylation of halopurines with aromatic compounds, facilitated by the combination of triflic acid and fluoroalcohol. This metal-free method is complementary to conventional coupling reactions using metal catalysts and reagents for the syntheses of aryl-substituted purine analogues.

Synthesis of Uracil-Iodonium(III) Salts for Practical Utilization as Nucleobase Synthetic Modules.

Iodonium(III) salts bearing uracil moieties have recently appeared in the literature, but their structural scope and utilization are limited because of their hygroscopic characteristics. In this study, we describe our detailed investigations for synthesizing a series of uracil iodonium(III) salts derived with various structural motifs and counterions. These new compounds have been utilized as attractive synthetic modules in constructing functionalized nucleobase and nucleosides.

Identification of biosynthetic genes for the ß-carboline alkaloid kitasetaline and production of the fluorinated derivatives by heterologous expression.

ß-Carboline alkaloids exhibit a broad spectrum of pharmacological and biological activities and are widely distributed in nature. Genetic information on the biosynthetic mechanism of ß-carboline alkaloids has not been accumulated in bacteria, because there are only a few reports on the microbial ß-carboline compounds. We previously isolated kitasetaline, a mercapturic acid derivative of a ß-carboline compound, from the genetically modified Kitasatospora setae strain and found a plausible biosynthetic gene cluster for kitasetaline. Here, we identified and characterized three kitasetaline (ksl) biosynthetic genes for the formation of the ß-carboline core structure and a gene encoding mycothiol-S-conjugate amidase for the modification of the N-acetylcysteine moiety by using heterologous expression. The proposed model of kitasetaline biosynthesis shows unique enzymatic systems for ß-carboline alkaloids. In addition, feeding fluorotryptophan to the heterologous Streptomyces hosts expressing the ksl genes led to the generation of unnatural ß-carboline alkaloids exerting novel/potentiated bioactivities.

Selective carboxylation of reactive benzylic C-H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system.

An oxidation system comprising phenyliodine(III) diacetate (PIDA) and iodosobenzene with inorganic bromide, i.e., sodium bromide, in an organic solvent led to the direct introduction of carboxylic acids into benzylic C-H bonds under mild conditions. The unique radical species, generated by the homolytic cleavage of the labile I(III)-Br bond of the in situ-formed bromo-λ3-iodane, initiated benzylic carboxylation with a high degree of selectivity for the secondary benzylic position.

Engineered production of kitasetalic acid, a new tetrahydro-ß-carboline with the ability to suppress glucose-regulated protein synthesis.

ß-Carboline alkaloids and related compounds show a broad spectrum of biological activities. We previously identified new members of the ß-carboline alkaloid family by using an engineered Kitasatospora setae strain and a heterologous Streptomyces host expressing the plausible biosynthetic genes, including the hypothetical gene kse_70640 (kslB). Here, we elucidated the chemical structure of a new tetrahydro-ß-carboline compound (named kitasetalic acid) that appeared in a heterologous Streptomyces host expressing the kslB gene alone. Kitasetalic acid suppressed the expression of glucose-regulated protein 78 (GRP78) without inducing cell death. This is the first report to show that a tetrahydro-ß-carboline compound regulates the expression of the GRP78 protein in cancer cell lines.