The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum.

The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae. Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.

The effect of arterial spin labeling MR angiography (ASL-MRA) in visualizing the branches of external carotid artery.

This study aimed to assess the performance of arterial-spin labeling MRA (ASL-MRA) for visualizing the external carotid artery (ECA) branches in comparison with time-of-flight MRA (TOF-MRA) and CT angiography (CTA). We retrospectively selected 31 consecutive patients, who underwent both MRAs and CTA, prior to the intra-arterial chemoradiotherapy (IACRT) for head and neck cancer. Four patients underwent IACRT bilaterally, so we analyzed 35 ECAs. Pseudo-continuous, three-dimensional ASL using a turbo field echo sequence was acquired. For the TOF-MRA and CTA, clinically used parameters were applied. Two observers evaluated each ECA branch with reference to the angiogram at the IACRT, using five-point scale, in consensus. Friedman test for multiple comparisons was applied. ASL-MRA and CTA better visualized the superior thyroid, lingual, facial, submental, transverse facial, and internal maxillary arteries (IMAs) better than TOF-MRA (p < 0.05). In addition, CTA was superior to ASL-MRA in visualizing only submental artery among these arteries (p = 0.0005). Alternatively, the ASL-MRA was superior for visualizing the middle meningeal artery (MMA) and IMA, compared to the CTA (p = 0.0001 and 0.0007, respectively). ASL-MRA was superior to the TOF-MRA and similar to the CTA in visualizing most of ECA branches. Furthermore, ASL-MRA can better visualize the periphery of MMA and IMA than CTA.

Cone-beam computed tomography-guided online adaptive radiotherapy for pharyngeal cancer with whole neck irradiation: dose-volume histogram analysis between adapted and scheduled plans.

The present study aimed to evaluate whether an adapted plan with Ethos™ could be used for pharyngeal cancer. Ten patients with pharyngeal cancer who underwent chemoradiotherapy with available daily cone-beam computed tomography (CBCT) data were included. Simulated treatments were generated on the Ethos™ treatment emulator using CBCTs every four to five fractions for two plans: adapted and scheduled. The simulated treatments were divided into three groups: early (first-second week), middle (third-fourth week), and late (fifth-seventh week) periods. Dose-volume histogram parameters were compared for each period between the adapted and scheduled plans in terms of the planning target volume (PTV) (D98%, D95%, D50% and D2%), spinal cord (Dmax and D1cc), brainstem (Dmax) and ipsilateral and contralateral parotid glands (Dmedian and Dmean). The PTV D98%, D95% and D2% of the adapted plan were significantly higher than those of the scheduled plans in all periods, except for D98% in the late period. The adapted plan significantly reduced the spinal cord Dmax and D1cc compared with the scheduled plan in all periods. Ipsilateral and contralateral parotid glands Dmean of the adapted plan were lower than those of scheduled plan in the late period. In conclusion, the present study revealed that the adapted plans could maintain PTV coverage while reducing the doses to organs at risk in each period compared with scheduled plans.

Development of Pericardial Fat Count Images Using a Combination of Three Different Deep-Learning Models: Image Translation Model From Chest Radiograph Image to Projection Image of Three-Dimensional Computed Tomography.

RATIONALE AND OBJECTIVES: Pericardial fat (PF)-the thoracic visceral fat surrounding the heart-promotes the development of coronary artery disease by inducing inflammation of the coronary arteries. To evaluate PF, we generated pericardial fat count images (PFCIs) from chest radiographs (CXRs) using a dedicated deep-learning model. MATERIALS AND METHODS: We reviewed data of 269 consecutive patients who underwent coronary computed tomography (CT). We excluded patients with metal implants, pleural effusion, history of thoracic surgery, or malignancy. Thus, the data of 191 patients were used. We generated PFCIs from the projection of three-dimensional CT images, wherein fat accumulation was represented by a high pixel value. Three different deep-learning models, including CycleGAN were combined in the proposed method to generate PFCIs from CXRs. A single CycleGAN-based model was used to generate PFCIs from CXRs for comparison with the proposed method. To evaluate the image quality of the generated PFCIs, structural similarity index measure (SSIM), mean squared error (MSE), and mean absolute error (MAE) of (i) the PFCI generated using the proposed method and (ii) the PFCI generated using the single model were compared. RESULTS: The mean SSIM, MSE, and MAE were 8.56 × 10-1, 1.28 × 10-2, and 3.57 × 10-2, respectively, for the proposed model, and 7.62 × 10-1, 1.98 × 10-2, and 5.04 × 10-2, respectively, for the single CycleGAN-based model. CONCLUSION: PFCIs generated from CXRs with the proposed model showed better performance than those generated with the single model. The evaluation of PF without CT may be possible using the proposed method.

Clinical outcomes and failure patterns after postoperative radiotherapy for oral cavity squamous cell carcinoma.

PURPOSE: This study aimed to assess recurrence patterns and identify the optimal dose and target volumes of postoperative radiotherapy (PORT) in patients with oral cavity squamous cell carcinoma (OSCC). METHODS: Data of 111 patients who received PORT for OSCC between January 2010 and April 2020 were retrospectively reviewed. The median age was 68 years (range 19-88). PORT was administered as initial treatment to 63 patients and as salvage treatment for recurrent tumors to 48 patients. The median prescribed dose was 60 Gy (range 50-66) administered in 30 fractions (range 25-33). RESULTS: Median follow-up time was 73 months (range 24-147). Overall survival (OS), progression-free survival (PFS), local control (LC), and locoregional control (LRC) at 3 years were 55.6%, 45.6%, 74.6%, and 63.1%, respectively. There were no significant differences in OS, PFS, LC, and LRC between the initially diagnosed and postoperative recurrent cases. Of 22 patients (20%) who developed regional nodal recurrences, 17 (15%) and 11 (10%) had in-field and out-of-field recurrences, respectively. Of 105 patients who received irradiation to the primary tumor bed, 24 (23%) developed recurrence at the primary site. The PFS and LC rates were significantly worse in patients receiving ≤ 56 Gy to the primary site than those receiving > 56 Gy (p = 0.016 and p = 0.032, respectively). CONCLUSION: PORT was effective for postoperative recurrences as well as for initially diagnosed oral cavity cancer. Doses greater than 56 Gy to the primary site may be required in PORT for OSCC.

Clinical course of longer than five years after definitive radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: This study aimed to reveal the long-term outcomes and late toxicities (> 5 years) after definitive intensity-modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Data from 43 patients (median age, 55 years; range, 17-72 years) with NPC who underwent definitive IMRT between 2001 and 2018 were analyzed. All patients were alive and disease-free 5 years after IMRT. A total dose of 70 (range, 66-70) Gy was delivered in 35 (33-35) fractions with concurrent cisplatin chemotherapy. RESULTS: The median follow-up duration was 119 (range, 61.5-242.1) months. Three patients developed locoregional failure at 79, 92, and 149 months after IMRT, respectively. Of these, 2 patients died of disease progression at 136 and 153 months after IMRT. One patient died of aspiration pneumonia 141 months after IMRT, despite salvage of the recurrent tumor by re-irradiation. In addition, one patient died of aspiration pneumonia 62 months after the IMRT. Thus, the 10-year overall survival, progression-free survival, and locoregional control rates were 98%, 92%, and 94%, respectively. Grade ≥ 2 and ≥ 3 late toxicities were observed in 28 (65%) and 9 (21%) patients, respectively. Nine second primary cancers, including five tongue cancers and two external auditory canal carcinomas, were observed in seven (16%) patients. CONCLUSION: Late recurrences, severe late toxicities, and second primary cancers were observed > 5 years after IMRT. A long-term follow-up of > 5 years is needed in patients with NPC.

Actinorhodin Biosynthesis Terminates with an Unprecedented Biaryl Coupling Reaction.

A plethora of dimeric natural products exist with diverse chemical structures and biological activities. A major strategy for dimerization is aryl coupling catalyzed by cytochrome P450 or laccase. Actinorhodin (ACT) from Streptomyces coelicolor A3(2) has a dimeric pyranonaphthoquinone structure connected by a C-C bond. In this study, we identified an NmrA-family dimerizing enzyme, ActVA-ORF4, and a cofactor-independent oxidase, ActVA-ORF3, both involved in the last step of ACT biosynthesis. ActVA-ORF4 is a unique NAD(P)H-dependent enzyme that catalyzes the intermolecular C-C bond formation using 8-hydroxydihydrokalafungin (DHK-OH) as the sole substrate. On the other hand, ActVA-ORF3 was found to be a quinone-forming enzyme that produces the coupling substrate, DHK-OH and the final product, ACT. Consequently, the functional assignment of all essential enzymes in the biosynthesis of ACT, one of the best-known model natural products, has been completed.

Unusual Photoisomerization Pathway in a Near-Infrared Light Absorbing Enzymerhodopsin.

Microbial and animal rhodopsins possess retinal chromophores which capture light and normally photoisomerize from all-trans to 13-cis and from 11-cis to all-trans-retinal, respectively. Here, we show that a near-infrared light-absorbing enzymerhodopsin from Obelidium mucronatum (OmNeoR) contains the all-trans form in the dark but isomerizes into the 7-cis form upon illumination. The photoproduct (λmax = 372 nm; P372) possesses a deprotonated Schiff base, and the system exhibits a bistable nature. The photochemistry of OmNeoR was arrested at <270 K, indicating the presence of a potential barrier in the excited state. Formation of P372 is accompanied by protonation changes of protonated carboxylic acids and peptide backbone changes of an α-helix. Photoisomerization from the all-trans to 7-cis retinal conformation rarely occurs in any solvent and protein environments; thus, the present study reports on a novel photochemistry mediated by a microbial rhodopsin, leading from the all-trans to 7-cis form selectively.

Organs-at-risk dose constraints in head and neck intensity-modulated radiation therapy using a dataset from a multi-institutional clinical trial (JCOG1015A1).

BACKGROUND: JCOG1015A1 is an ancillary research study to determine the organ-specific dose constraints in head and neck carcinoma treated with intensity-modulated radiation therapy (IMRT) using data from JCOG1015. METHODS: Individual patient data and dose-volume histograms of organs at risk (OAR) were collected from 74 patients with nasopharyngeal carcinoma treated with IMRT who enrolled in JCOG1015. The incidence of late toxicities was evaluated using the cumulative incidence method or prevalence proportion. ROC analysis was used to estimate the optimal DVH cut-off value that predicted toxicities. RESULTS: The 5-year cumulative incidences of Grade (G) 1 myelitis, ≥ G1 central nervous system (CNS) necrosis, G2 optic nerve disorder, ≥ G2 dysphagia, ≥ G2 laryngeal edema, ≥ G2 hearing impaired, ≥ G2 middle ear inflammation, and ≥ G1 hypothyroidism were 10%, 5%, 2%, 11%, 5%, 26%, 34%, and 34%, respectively. Significant associations between DVH parameters and incidences of toxicities were observed in the brainstem for myelitis (D1cc ≥ 55.8 Gy), in the brain for CNS necrosis (D1cc ≥ 72.1 Gy), in the eyeball for optic nerve disorder (Dmax ≥ 36.6 Gy), and in the ipsilateral inner ear for hearing impaired (Dmean ≥ 44 Gy). The optic nerve, pharyngeal constrictor muscle (PCM), and thyroid showed tendencies between DVH parameters and toxicity incidence. The prevalence proportion of G2 xerostomia at 2 years was 17 versus 6% (contralateral parotid gland Dmean ≥ 25.8 Gy vs less). CONCLUSIONS: The dose constraint criteria were appropriate for most OAR in this study, although more strict dose constraints might be necessary for the inner ear, PCM, and brainstem.

Block-Iterative Reconstruction from Dynamically Selected Sparse Projection Views Using Extended Power-Divergence Measure.

Iterative reconstruction of density pixel images from measured projections in computed tomography has attracted considerable attention. The ordered-subsets algorithm is an acceleration scheme that uses subsets of projections in a previously decided order. Several methods have been proposed to improve the convergence rate by permuting the order of the projections. However, they do not incorporate object information, such as shape, into the selection process. We propose a block-iterative reconstruction from sparse projection views with the dynamic selection of subsets based on an estimating function constructed by an extended power-divergence measure for decreasing the objective function as much as possible. We give a unified proposition for the inequality related to the difference between objective functions caused by one iteration as the theoretical basis of the proposed optimization strategy. Through the theory and numerical experiments, we show that nonuniform and sparse use of projection views leads to a reconstruction of higher-quality images and that an ordered subset is not the most effective for block-iterative reconstruction. The two-parameter class of extended power-divergence measures is the key to estimating an effective decrease in the objective function and plays a significant role in constructing a robust algorithm against noise.

Characterization of stereospecific enoyl reductase ActVI-ORF2 for pyran ring formation in the actinorhodin biosynthesis of Streptomyces coelicolor A3(2).

Actinorhodin (ACT) is a benzoisochromanequinone antibiotic produced by Streptomyces coelicolor A3(2), which has served as a favored model organism for comprehensive studies of antibiotic biosynthesis and its regulation. (S)-DNPA undergoes various modifications as an intermediate in the ACT biosynthetic pathway, including enoyl reduction to DDHK. It has been suggested that actVI-ORF2 encodes an enoyl reductase (ER). However, its function has not been characterized in vitro. In this study, biochemical analysis of recombinant ActVI-ORF2 revealed that (S)-DNPA is converted to DDHK in a stereospecific manner with NADPH acting as a cofactor. (R)-DNPA was also reduced to 3-epi-DDHK with the comparable efficacy as (S)-DNPA, suggesting that the stereospecificity of ActVI-ORF2 was not affected by the stereochemistry at the C-3 of DNPA. ActVI-ORF2 is a new example of a discrete ER, which is distantly related to known ERs according to phylogenetic analysis.

epi-Aszonalenin B from Aspergillus novofumigatus inhibits NF-κB activity induced by ZFTA-RELA fusion protein that drives ependymoma.

Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA.

Therapeutic efficacy of selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin for fixed bulky nodal disease in head and neck cancer of unknown primary.

PURPOSE: Fixed bulky nodal disease in patients with head and neck cancer of unknown primary (HNCUP) remains difficult to treat. This retrospective study evaluated the therapeutic efficacy of selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin for fixed bulky nodal disease in HNCUP. METHODS: Data from seven consecutive patients with fixed bulky nodal disease in HNCUP who had undergone selective intra-arterial chemoradiotherapy were analyzed. Whole pharyngeal mucosa and all bilateral nodal areas were irradiated (total dose 50 Gy), and bulky nodal lesions were provided an additional 20 Gy. Intra-arterial chemotherapy used a combination of nedaplatin (80 mg/m2) and docetaxel (60 mg/m2). Outcome measures were local control, disease-free survival, overall survival, and adverse events. Statistical analyses were performed using the Kaplan-Meier method. RESULTS: Median follow-up period was 24 months (range 9-64). All patients had extracapsular extension (N3b) on imaging and clinical findings. Symptoms due to bulky disease were neck discomfort (100%), tumor bleeding (43%), tracheal obstruction (14%), and carotid sinus syndrome (28%). Median value for maximum diameter of cervical disease was 84 mm (range 70-107), and 3-year local control, disease-free survival, and overall survival rates were 100, 54, and 64%, respectively. Symptoms due to bulky disease disappeared in all patients after intra-arterial chemoradiotherapy. Grade 4 leukopenia occurred in two patients (28%) as an acute adverse event. No other serious acute adverse events were observed. CONCLUSION: Selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin can potentially achieve both favorable local control and survival in in HNCUP with fixed bulky nodal disease.

Therapeutic efficacy of selective intraarterial chemoradiotherapy with docetaxel and nedaplatin for human papilloma virus-negative oropharyngeal cancer.

OBJECTIVE: Human papilloma virus-negative oropharyngeal cancer has not achieved satisfactory outcomes compared with those of human papilloma virus-positive oropharyngeal cancer. This study evaluated the therapeutic efficacy of selective intraarterial chemoradiotherapy with the docetaxel and nedaplatin regimen for human papilloma virus-negative oropharyngeal cancer. METHODS: Twenty-two consecutive patients with human papilloma virus-negative oropharyngeal cancer who had undergone selective intraarterial chemoradiotherapy were retrospectively analyzed. The primary tumor and whole neck were irradiated (50 Gy). Subsequently, the primary site and metastatic lymph nodes were boosted by 20 Gy. The intraarterial chemotherapy regimen comprised a combination of nedaplatin (80 mg/m2) and docetaxel (60 mg/m2), which was initially administered at the start of radiotherapy and was given every 4 weeks for three sessions. Each intraarterial dose of an anticancer agent was determined according to the percentage of the tumor volume supplied by the target artery to the total tumor volume, which was intraoperatively measured via cone-beam computed tomography. The outcome measures were locoregional control, disease-free survival, and overall survival rates and adverse events. Statistical analyses were performed using the Kaplan-Meier method. RESULTS: The median follow-up period was 59 (range, 15-103) months. The T stage was T1/T2 in 5 patients (23%), T3 in 5 patients (23%), and T4 in 12 patients (54%). Cervical lymph node metastasis was staged as ≥N2c in 7 (32%) patients. Complete response was achieved in all patients at the first imaging examination after intraarterial chemoradiotherapy. The 5-year locoregional control, disease-free survival, and overall survival rates were 96% (95% confidence interval, 0.72-0.99), 91% (95% confidence interval, 0.68-0.98), and 100% (95% confidence interval, not available), respectively. Regarding serious acute adverse events, grade 4 laryngeal edema and leukopenia were observed in 1 (5%) and 11 patients (50%), respectively. No other serious acute adverse events were observed. CONCLUSION: Selective intraarterial chemoradiotherapy with docetaxel and nedaplatin has the potential to achieve favorable locoregional control, disease-free survival, and overall survival rates in human papilloma virus-negative oropharyngeal cancer.

Small dose of oral gastrografin for computed tomography-based image-guided brachytherapy in patients with uterine cervical cancer.

Oral administration of a water-soluble iodine contrast agent (gastrografin) was reported to assist in the appropriate contouring of the small intestine on computed tomography (CT)-based radiotherapy (RT) planning. The efficacy and optimal dose of gastrografin in CT-based image-guided brachytherapy (IGBT) for cervical cancer remain unknown. This study aimed to investigate the efficacy of pretreatment oral administration of gastrografin at a small dose of 50 ml in CT-based IGBT for cervical cancer. A total of 422 sessions in 137 patients who underwent CT-based IGBT with 50 ml of oral gastrografin (concentration, 3% or 4%) were analyzed. Preparation of gastrografin was judged as effective when the small intestine was contrast-enhanced at the area where the small intestine was in contact with the uterus/adnexa. About 287 out of 422 sessions (68%) were judged as effective with gastrografin preparation. The 135 ineffective sessions were considered as follows: (i) the contrast enhancement of the small intestine was not confirmed (n = 36), (ii) the small intestine was not in contact with the uterus/adnexa despite the confirmation of the contrast enhancement of the small intestine (n = 34), and (iii) gastrografin was absent in the small intestine at the area in contact with the uterus/adnexa, even when gastrografin was observed in the small intestine at the area not in contact with the uterus/adnexa (n = 65). In conclusion, pretreatment oral administration of a small dose gastrografin achieved moderate efficacy for accurate contouring of the small intestine close to the uterus/adnexa in CT-based IGBT for cervical cancer.

Patterns of recurrence after low-dose postoperative radiotherapy for head and neck squamous cell carcinoma.

BACKGROUND: Postoperative chemoradiotherapy is recommended for patients with head and neck squamous cell carcinoma with positive margins or extracapsular extension at high risk of recurrence. However, high-dose radiotherapy in the head and neck region often causes severe acute and late radiation-related adversities. In our institution, the radiation dose has been relatively lower than that used in Western countries to reduce radiation-related toxicities. Therefore, in this study, we examined the treatment outcomes of low-dose postoperative chemoradiotherapy. METHODS: The outcomes of 90 consecutive head and neck squamous cell carcinoma patients who received postoperative radiotherapy between June 2009 and December 2016 were retrospectively analyzed. All patients received postoperative three-dimensional conformal radiotherapy with or without concurrent systemic chemotherapy. The median patient age was 65 years. Concurrent chemoradiotherapy was administered at a total dose of 50.4 Gy in 28 fractions (daily fraction, 1.8 Gy). High-risk patients received 10.8 Gy of boost irradiation in six fractions. For radiotherapy alone, the irradiation dose was up to 54 Gy in 30 fractions and 64.8 Gy in 36 fractions for high-risk patients to increase the treatment intensity. RESULTS: The median follow-up period was 40.5 months. The 3-year locoregional control and overall survival rates were 67.5% and 82.7%, respectively. A significantly higher proportion of patients with oral cavity carcinoma experienced locoregional failure (p = 0.004). The acute adverse events were mild, and the only late adverse event was grade 3 dysphagia (n = 3). CONCLUSION: This study suggests that de-escalation of the postoperative radiation dose can potentially reduce the severe adverse events of irradiation in patients while ensuring its effectiveness. In patients with oral cavity carcinoma, it might be necessary to increase the radiation dose.

Up-front neck dissection followed by chemoradiotherapy for T1-T3 hypopharyngeal cancer with advanced nodal involvement.

BACKGROUND: The advantage of up-front neck dissection (UFND) followed by chemoradiotherapy (CRT) for hypopharyngeal cancer (HPC) with advanced neck involvement remains controversial. We aimed to determine the indications. METHODS: The data of 41 and 14 patients with stage IVA/B (T1-T3 and ≥N2a) HPC who underwent UFND followed by CRT and received CRT, respectively, were retrospectively analyzed and compared. RESULTS: The 5-year overall survival (OS) and disease-specific survival rates for the UFND and CRT groups were 61% and 52% (p = 0.1019), and 89% and 74% (p = 0.2333), respectively. Moreover, patients aged ≥70 years or those with a pulmonary disease history had a significantly poorer prognosis due to aspiration pneumonia in the UFND group. The 5-year regional control (RC) for the UFND and CRT groups were 92% and 57%, respectively (p = 0.0001). CONCLUSIONS: UFND followed by CRT was feasible with satisfactory RC. To further improve OS, aspiration pneumonia prevention is essential.

Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity.

Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3'-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT's cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.

Chemoembolization for Symptomatic Metastatic Epidural Spinal Cord Compression Refractory to Re-radiotherapy.

PURPOSE: To evaluate the efficacy of chemoembolization for inoperable metastatic epidural spinal cord compression (MESCC) refractory to re-radiotherapy. METHODS: Nineteen consecutive patients with recurrent MESCC after re-radiotherapy who had undergone chemoembolization were retrospectively analyzed. Outcome measures were pain relief rate, neurological improvement rate, objective response rate, and adverse events. MESCC degree classification was assessed using Bilsky grades. Pain assessment was performed using Numerical Rating Scale, and neurological function was evaluated using the Frankel classification. RESULTS: The median follow-up period was 7 (range 2-44) months. All participants had MESCC grade 2 or higher and had severe pain. Fifteen patients (79%) had neurological deficits, and ten had Frankel classification C and five had D. Symptoms were relieved in almost all patients the day following chemoembolization. Pain relief was achieved in 18 of 19 (95%) patients; the median decrease in Numerical Rating Scale score was 8 (range 0-10; p < 0.001). Neurological improvement was achieved in 11 of 15 patients (73%); the median increase in Frankel classification was 1 (range 0-2; p = 0.006). Ten of 19 (53%) patients showed a reduction in MESCC; the median decrease in Bilsky grade was 1 (range 0-2; p = 0.005). There was no correlation between the change in Bilsky grade and pain relief (p = 0.421). However, the decrease in Bilsky grade significantly improved neurological symptoms (p = 0.01). No serious adverse events occurred. CONCLUSION: Chemoembolization may be a useful palliative treatment modality for MESCC refractory to re-radiotherapy. LEVEL OF EVIDENCE: Level 3b, Follow up Study.