Analysis of respiratory-induced motion trajectories of individual liver segments in patients with hepatocellular carcinoma.

PURPOSE: To analyze the respiratory-induced motion trajectories of each liver segment for hepatocellular carcinoma (HCC) to derive a more accurate internal margin and optimize treatment protocol selection. MATERIALS AND METHODS: Ten-phase-gated four-dimensional computed tomography (4DCT) scans of 14 patients with HCC were analyzed. For each patient, eight representative regions of interest (ROI) were delineated on each liver segment in all 10 phases. The coordinates of the center of gravity of each ROI were obtained for each phase, and then the respiratory motion in the left-right (LR), anteroposterior (AP), and craniocaudal (CC) directions was analyzed. Two sets of motion in each direction were also compared in terms of only two extreme phases and all 10 phases. RESULTS: Motion of less than 5 mm was detected in 12 (86%) and 10 patients (71%) in the LR and AP directions, respectively, while none in the CC direction. Motion was largest in the CC direction with a maximal value of 19.5 mm, with significant differences between liver segment 7 (S7) and other segments: S1 (p < 0.036), S2 (p < 0.041), S3 (p < 0.016), S4 (p < 0.041), and S5 (p < 0.027). Of the 112 segments, hysteresis >1 mm was observed in 4 (4%), 2 (2%), and 15 (13%) in the LR, AP, and CC directions, respectively, with a maximal value of 5.0 mm in the CC direction. CONCLUSION: A significant amount of respiratory motion was detected in the CC direction, especially in S7, and S8. Despite the small effect of hysteresis, it can be observed specifically in the right lobe. Therefore, caution is required when using 4DCT to determine IM using only end-inspiration and end-expiration. Understanding the respiratory motion in individual liver segments can be helpful when selecting an appropriate treatment protocol.

Effectiveness of prehabilitation during neoadjuvant therapy for patients with esophageal or gastroesophageal junction cancer: a systematic review.

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation's effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55-76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT.

Dosimetric effect of six degrees of freedom couch top with rotational setup error corrections in proton therapy.

PURPOSE: To investigate the dosimetric effect of six degrees of freedom (6DoF) couch top with rotational corrections in proton therapy (PT). METHODS: The water equivalent thickness (WET) was measured using a proton beam with a 6DoF couch top and patient immobilization base plate (PIBP) placed in front of a motorized water phantom. The accuracy verification was performed with the beam axis set perpendicular to the 6DoF couch top and tilted in 10° steps from 10° to 30°. Up to 3° rotational correction may be added during the actual treatment to correct the rotational setup error on our system. The measured and calculated values using the treatment planning system were compared. Additionally, the effect of the 3° difference was evaluated using actual measurements concerning each angle on the proton beam range. RESULTS: The WET of the 6DoF couch top and PIBP were 8.5 ± 0.1 mm and 6.8 ± 0.1 mm, respectively. The calculation and the actual measurement at each angle agreed within 0.2 mm at the maximum. A maximum difference of approximately 0.6 mm was confirmed when tilted at 3° following 30° with the 6DoF couch top plus PIBP. CONCLUSIONS: The dosimetric effect of the 6DoF couch top with rotational corrections in PT differs depending on the incidence angle on the couch top, and it increased with the increased oblique angle of incidence. However, the effect on the range was as small as 0.6 mm at the maximum. The amount of rotational correction, the angle of incidence of the beam, and the effect of rotational corrections on the proton beam range may differ depending on the structure of the couch top. Therefore, sufficient prior confirmation, and subsequent periodical quality assurance management are important.

Validity of the 30-Second Chair-Stand Test to Assess Exercise Tolerance and Clinical Outcomes in Patients with Esophageal Cancer: A Retrospective Study with Reference to 6-Minute Walk Test Results.

This retrospective study aimed to investigate the validity of a 30-sec chair stand test (CS-30) as a simple test to assess exercise tolerance and clinical outcomes in 53 Japanese patients with esophageal cancer. There was a strong correlation between the results of CS-30 and the 6-min walk test (6MWT), the gold standard for assessing exercise tolerance (r=0.759). Furthermore, fewer patients whose CS-30 score was greater than 16 (the cutoff value defined based on 6MWT) experienced pneumonia in their postoperative course. These results suggest that exercise tolerance could be assessed using CS-30, and its cutoff value may be useful in predicting postoperative pneumonia risk.

The combined intervention of neuromuscular electrical stimulation and nutrition therapy: A scoping review.

BACKGROUND & AIMS: Neuromuscular electrical stimulation (NMES) is a safe and appropriate complement to voluntary resistance training for muscle weakness. However, its feasibility and effectiveness in combination with nutritional therapy remains unclear. This scoping review aimed to summarize the evidence on combined interventions for individuals with or at risk of sarcopenia for guiding future relevant research. METHODS: A systematic electronic search was conducted using the following databases and registry: MEDLINE, CINAHL, Web of Science, PEDro, and ClinicalTrials. gov. Two independent reviewers summarized the characteristics, effectiveness, and feasibility of the combined intervention and the risk of bias in the literature. RESULTS: Nine RCTs and four non-RCTs involving 802 participants were eligible. A diverse group of participants were included: older adults with sarcopenic obesity, patients in intensive care, and patients with cancer. Evidence-based interventions combining NMES and nutritional therapy were tailored to each patient's underlying disease. Although most studies were of low to moderate quality, it can be suggested that combined interventions may be feasible and effective for increasing skeletal muscle mass. CONCLUSION: This scoping review demonstrates the potential of combined interventions as a new sarcopenia treatment strategy and highlights the need to examine the effects in high-quality RCTs with larger sample sizes.

Protocol for a randomised, placebo-controlled, double-blinded clinical trial on the effect of oestrogen replacement on physical performance to muscle resistance exercise for older women with osteoarthritis of knee joint: the EPOK trial.

BACKGROUND: Knee osteoarthritis (KOA) is highly prevalent in older women, and previous studies suggest the involvement of hormonal factors play a role in the pathogenesis of osteoarthritis. KOA causes musculoskeletal impairment, resulting in decreased physical activity, muscle mass, and strength, which leads to sarcopenia and further increases the burden on healthcare systems. Oestrogen replacement therapy (ERT) improves joint pain and muscle performance in early menopausal women. Muscle resistance exercise (MRE) is a non-pharmacological method that preserves the physical functions of patients with KOA. However, data on short-term oestrogen administration combined with MRE in postmenopausal women, especially in those aged > 65 years, are limited. Therefore, this study presents a protocol of a trial aimed to examine the synergistic effect of ERT and MRE on lower-limb physical performance in older women with KOA. METHODS: We will conduct a double-blinded, randomised placebo-controlled trial in 80 Japanese women aged > 65 years living independently with knee pain. The participants will be randomly categorised into two groups: (1) 12-week MRE programme with transdermal oestrogen gel containing 0.54 mg oestradiol per push and (2) 12-week MRE programme with placebo gel. The primary outcome measured using the 30-s chair stand test, and secondary outcomes (body composition, lower-limb muscle strength, physical performance, self-reported measure of knee pain, and quality of life) will be measured at baseline, 3 months, and 12 months, and these outcomes will be analysed based on the intention-to-treat. DISCUSSION: The EPOK trial is the first study to focus on the efficacy of ERT on MRE among women aged > 65 years with KOA. This trial will provide an effective MRE to prevent KOA-induced lower-limb muscle weakness, confirming the benefit of short-term oestrogen administration. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs061210062. Registered 17th December 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs061210062 .

Effectiveness of early exercise on reducing skeletal muscle loss during preoperative neoadjuvant chemotherapy for esophageal cancer.

PURPOSE: To investigate if early exercise can help prevent skeletal muscle loss and improve the clinical outcomes of esophageal cancer patients receiving preoperative neoadjuvant chemotherapy (NAC). METHODS: This was a single-center, retrospective observational cohort study of 110 patients with advanced esophageal cancer. We analyzed the effect of early exercise on the risk of skeletal muscle loss (defined as > 2.98%) during NAC and the subsequent clinical outcomes. Patients in the early exercise group (n = 71) started exercise therapy 8 days earlier than those the late exercise group (n = 39). RESULTS: The median age of the patients was 65.4 years, the mean BMI was 21.1 kg/m2, and 92 (84%) of the 110 patients were men. Skeletal muscle loss occurred in 34% and 67% of the early and late exercise groups, respectively (p < 0.001). There was a lower risk of surgical site infection in the early exercise group (1% vs 16%, p = 0.021). Multivariate analysis revealed that early exercise reduced the risk of skeletal muscle loss (OR = 0.25, 95% CI 0.09-0.65, p = 0.006). CONCLUSIONS: Our results suggest that early exercise reduces the risk of both skeletal muscle loss during NAC and subsequent surgical site infection in patients with esophageal cancer.

Dosimetric impact of simulated changes in large bowel content during proton therapy with simultaneous integrated boost for locally advanced pancreatic cancer.

PURPOSE: To investigate the dosimetric impact of changes in the large bowel content during proton therapy (PT) with simultaneous integrated boost (SIB) for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Fifteen patients with LAPC were included in this study. The SIB method was performed using five fields according to our standard protocol. A total dose of 67.5 Gy(relative biological effectiveness [RBE]) was prescribed in 25 fractions using the SIB method. A dose of 45 Gy(RBE) was prescribed for the entire planning target volume (PTV) by using four main fields. The remaining 22.5 Gy(RBE) was prescribed to the PTV excluding for the gastrointestinal tract using one subfield. Five simulated doses were obtained by the forward dose calculations with the Hounsfield units (HU) override to the large bowel to 50, 0, -100, -500, and -1000, respectively. The dose-volume indices in each plan were compared using the 50 HU plan as a reference. RESULTS: At D98 of the clinical target volume (CTV) and spinal cord-D2cc , when the density of the large bowel was close to that of gas, there were significant differences compared to the reference plan (p < 0.05). By contrast, no significant difference was observed in stomach-D2cc duodenum-D2cc , small bowel-D2cc , kidneys-V18 , and liver-Dmean under any of the conditions. There were no cases in which the dose constraint of organs at risk, specified by our institution, was exceeded. CONCLUSION: Density change in the large bowel was revealed to significantly affect the doses of the CTV and spinal cord during PT with SIB for LAPC. For beam arrangement, it is important to select a gantry angle that prevents the large bowel from passing as much as possible. If this is unavoidable, it is important to carefully observe the gas image on the beam path during daily image guidance and to provide adaptive re-planning as needed.

Conventional Trabeculotomy versus Gonioscopy-Assisted Transluminal Trabeculotomy: A Retrospective Cohort Study.

BACKGROUND: Conventional trabeculotomy (CT) is performed in an ab-externo manner with at most 120 degrees of incision area of Schlemm's canal (SC). Recently, gonioscopy-assisted transluminal trabeculotomy (GATT), which makes possible a 360-degree incision area of SC in an ab-interno manner, is introduced. The purpose of this study was to compare surgical outcomes for CT and GATT with and without simultaneous phacoemulsification over 24 months and to identify factors associated with surgical success. RESULTS: Patients' baseline characteristics were not significantly different between two groups. The surgical success rate in CT and GATT with phacoemulsification groups were 40.4% and 96.6% and were significantly higher in the GATT group than in the CT group (p < 0.001). However, the surgical success rate in CT and GATT without phacoemulsification groups were 40.8% and 54.2%, and there were no significant differences between two groups without phacoemulsification (p = 0.55). Similarly, the postoperative IOP was significantly lower in the GATT group than in the CT group only in eyes with simultaneous phacoemulsification. There were no significant differences in the numbers of glaucoma medications between the two groups. Additional glaucoma surgery was needed in 13.2% and 25.9% of patients in the GATT and CT groups, respectively (p = 0.157). The multivariate logistic regression analysis revealed that the surgical success of trabeculotomy was significantly associated with combined phacoemulsification and the type of glaucoma surgery (GATT). CONCLUSION: Although both groups without phacoemulsification had a similar surgical success and IOP-lowering effect, GATT combined with phacoemulsification had a higher surgical success rate and a greater IOP-lowering effect compared with combined CT and phacoemulsification. Multivariate logistic regression analysis showed that the factors associated with higher surgical success at one year and two years postoperatively were the combined phacoemulsification procedure and the GATT.

An uncertainty metric to evaluate deformation vector fields for dose accumulation in radiotherapy.

BACKGROUND AND PURPOSE: In adaptive radiotherapy, deformable image registration (DIR) is used to propagate delineations of tumors and organs into a new therapy plan and to calculate the accumulated total dose. Many DIR accuracy metrics have been proposed. An alternative proposed here could be a local uncertainty (LU) metric for DIR results. MATERIALS AND METHODS: The LU represented the uncertainty of each DIR position and was focused on deformation evaluation in uniformly-dense regions. Four cases demonstrated LU calculations: two head and neck cancer cases, a lung cancer case, and a prostate cancer case. Each underwent two CT examinations for radiotherapy planning. RESULTS: LU maps were calculated from each DIR of the clinical cases. Reduced fat regions had LUs of 4.6 ±â€¯0.9 mm, 4.8 ±â€¯1.0 mm, and 4.5 ±â€¯0.7 mm, while the shrunken left parotid gland had a LU of 4.1 ±â€¯0.8 mm and the shrunken lung tumor had a LU of 3.7 ±â€¯0.7 mm. The bowels in the pelvic region had a LU of 10.2 ±â€¯3.7 mm. LU histograms for the cases were similar and 99% of the voxels had a LU < 3 mm. CONCLUSIONS: LU is a new uncertainty metric for DIR that was demonstrated for clinical cases. It had a tolerance of <3 mm.

In toto extraction of spontaneous conjunctival cysts without incision under slit-lamp microscopic view.

OBJECTIVE: We describe a technique for the in toto extraction of spontaneous conjunctival cysts without incision under slit-lamp microscopic view. DESIGN: Interventional case series. PARTICIPANTS: Eleven eyes of 11 patients. METHODS: This was a multicentre study. Selection criterion was symptomatic conjunctival spontaneous cysts. Topical anaesthesia was applied, and the conjunctival cyst was extracted with a 26-gauge × 0.5-inch needle attached to a 1-mL disposable syringe. The bevel of the needle was oriented toward the surgeon, and it was inserted into the conjunctival cyst. The surgeon then pulled the plunger to produce negative pressure and sucked the fluid from the cyst. After the fluid was drained, the negative pressure also sucked the inner walls of the cysts into the needle tip. The surgeon slowly pulled the needle tip from the subconjunctival space. In most cases, a stump of the cyst remained at the entry site; it was grasped with forceps and totally extracted. RESULTS: This technique was used on 11 eyes that were followed for 23.2 months. The conjunctival cysts were extracted in toto from all eyes, and a recurrence was observed in 1 eye during the follow-up period. In the 1 eye, a small residual cyst recurred, and it was extracted by the same technique. CONCLUSIONS: This method of extracting conjunctival cysts is indicated for spontaneous conjunctival cysts that are considered to be free from adhesion to the surrounding tissue. It is an easy and minimally invasive method of extraction under a slit-lamp microscope without incision.

Epidemiological evaluation of YAG capsulotomy incidence for posterior capsule opacification in various intraocular lenses in Japanese eyes.

BACKGROUND AND OBJECTIVE: We investigated the yttrium aluminum garnet (YAG) capsulotomy rates in various intraocular lenses (IOLs). STUDY DESIGN/PATIENTS AND METHODS: We retrospectively analyzed 23,440 eyes implanted with either MA60BM, MA60AC, VA-60BB, CeeOnEdge, Clariflex, Technis Z9002, SI-40NB, or UV26T IOLs. We calculated the YAG capsulotomy rates at 1, 3, 5, and 10 years post lens implantation. RESULTS: YAG capsulotomy rates at 3 years postimplantation for the eight groups of IOLs were, respectively, 3.7%, 3.9%, 23.7%, 3.4%, 4.5%, 4.7%, 10.4%, and 21.0%. YAG capsulotomy rates at 10 years postimplantation for the MA60BM and SI-40NB IOLs were, respectively, 9.1% and 15% (P<0.05). The average YAG rates for all sharp-edged and round-edged IOLs at 5 years postimplantation were, respectively, 5.2%±0.7% and 25.6%±9.0% (P<0.05). CONCLUSION: In all studied IOLs, posterior capsule opacification prevention seemed to be associated with the posterior optic sharp-edge design. Round-edged silicone IOLs may also retard posterior capsule opacification formation, though not as much as sharp-edged IOLs. As the follow-up period progressed, round-edged silicone IOLs showed significantly higher YAG rates than sharp-edged IOLs.

A case with transient refractive change after removal of pituitary tumor.

BACKGROUND: Refractive change can be caused by systemic illnesses such as Lupus erythematosus, thyroid deficiency, and diabetes mellitus. However, refractive change after pituitary tumor removal has so far not been reported. CASE PRESENTATION: A 62-year-old woman presented with blurred near vision 10 days after trans-sphenoidal surgery (TSS) for a pituitary tumor. Around the same time, she experienced intercurrent hyponatremia. The corrected visual acuity of both eyes was 20/20, the spherical equivalent of the right eye was -2.125 diopters, and of the left eye was -2.0 diopters before TSS. However, 11 days after TSS, the spherical equivalent of the right eye changed to -0.75 diopters, and that of left eye changed to -1.125 diopters without hyperglycemia. There were no changes in the corrected visual acuity during the follow-up. CONCLUSION: We demonstrated a case with transient refractive change after TSS. The following mechanism is proposed: Hyponatremia induced by the pituitary tumor removal causes an osmotic change in the aqueous humor with lens swelling. This case report is a reminder to both ophthalmologists and neurosurgeons that ophthalmological factors such as lens thickness and axial length should be taken into account when conducting preoperative examinations especially for patients undergoing TSS.

Phosphorylation status of Fas-associated death domain protein is associated with biochemical recurrence after radical prostatectomy.

OBJECTIVE: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. MATERIALS AND METHODS: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. RESULTS: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. CONCLUSION: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone-naive patients who have undergone radical prostatectomy.

Heme oxygenase-1 promotes angiogenesis in urothelial carcinoma of the urinary bladder.

Angiogenesis is necessary for the growth, invasion, and metastasis of solid tumors. Previous studies have shown that heme oxygenase-1 (HO-1) plays an important role in angiogenesis in both normal and cancerous cells, such as vascular endothelial cells and pancreatic cancer cells, respectively. In this study, we analyzed the role of HO-1 and other angiogenic factors in urothelial carcinoma of the bladder. Specifically, we used real-time reverse transcription polymerase chain reaction (PCR) and Western blotting to investigate the upregulation of 7 angiogenic factors, namely, HO-1, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, HIF-2α, cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) under hypoxic conditions in the T24 urothelial carcinoma cell line. We also used enzyme-linked immunosorbent assay (ELISA) to measure the amount of VEGF secreted into the growth media. In addition, we administered an HO-1 inhibitor, zinc protoporphyrin IX, to mice with subcutaneous T24 tumors to assess the modulation of angiogenesis in solid tumors in vivo. We also performed immunohistochemical analyses of 23 primary bladder cancer specimens with high-grade tumors infiltrating into the stroma (pT1) for expression of HO-1, VEGF, HIF-1α, HIF-2α, COX-2, and CD31. Image analysis of CD31 staining was performed to estimate microvessel density (MVD), a measure of angiogenesis. Hypoxic conditions induced upregulation of HO-1, VEGF, HIF-1α, HIF-2α, and COX-2 in T24 cells and increased VEGF secretion, which could be suppressed by zinc protoporphyrin IX. In vivo, inhibition of HO-1 decreased tumor growth and MVD by suppressing angiogenic factors, particularly VEGF and HIF-1α. In clinical specimens of bladder cancer, high expression of HO-1 was correlated with high expression of HIF-1α (P=0.027) and high MVD (P=0.005), but not with VEGF expression (P=0.19). In conclusion, since overexpression of HO-1 promotes angiogenesis in urothelial carcinoma cells, HO-1 inhibitors could be used as novel therapeutics for urothelial carcinoma of the urinary bladder.

[A case of solitary fibrous malignant tumor with multiple metastases].

An 80-year-old woman visited her family physician because of back pain. A chest X-ray film showed a mass in the left middle lung field. She was referred to our hospital for further examinations. A computed tomography-guided lung biopsy revealed a solitary fibrous tumor, and a whole body examination demonstrated multiple metastases, including in the spine, ribs, femurs and pubis. Considering her age, chemotherapy was not given, but we administered radiotherapy for the metastatic lesions. Subsequently detected metastases of the left orbit, liver, scapula and humerus were also then irradiated, but she died 11 months after the initial diagnosis due to the complication of bacterial pneumonia. A case of a solitary malignant fibrous tumor with multiple metastases was reported.

Clinical significance of heme oxygenase-1 expression in non-muscle-invasive bladder cancer.

INTRODUCTION: In several malignant diseases, elevated heme oxygenase-1 (HO-1) is associated with progression or resistance to chemotherapy. We evaluated the clinical significance of HO-1 expression in non-muscle-invasive bladder cancer. PATIENTS AND METHODS: We examined 109 patients with non-muscle-invasive bladder cancer. The immunoexpression of HO-1, p53, and Ki-67 was analyzed using paraffin-embedded tissue from transurethral resection in comparison with the clinicopathological variables. RESULTS: Positive expression of HO-1 was found in 66 of 109 tumors (61%), and the positivity of HO-1 correlated significantly with high tumor grade and the altered expression patterns of p53 and Ki-67. In our analysis of 16 cases treated by intravesical administration of anthracyclines, the positive expression of HO-1 correlated with poor disease-free survival (p = 0.015). In in vitro experiments using urothelial cancer cell lines, HO-1 upregulation was observed by exposure to doxorubicin. Moreover, siRNA-mediated suppression of HO-1 upregulation sensitized the urothelial cancer cells to doxorubicin. CONCLUSIONS: Our findings suggested that resistance against anthracyclines correlated with HO-1 and expression analysis of HO-1 may be a useful predictive marker for intravesical administration of anthracyclines.

Inhibition of heme oxygenase-1 enhances the cytotoxic effect of gemcitabine in urothelial cancer cells.

BACKGROUND: Elevated heme oxygenase-1 (HO-1) is associated with resistance to chemo- and radiotherapy through anti-apoptotic function. The present study evaluated whether the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), enhances the cytotoxic effect of gemcitabine in urothelial carcinoma (UC). MATERIALS AND METHODS: The in vitro cytotoxic effect of combination treatment of gemcitabine and ZnPP on UC cells was examined. The in vivo growth inhibitory effects of intraperitoneal administration of gemcitabine and/or ZnPP on mouse subcutaneous tumours were examined. The apoptotic changes were analysed with the detection of DNA fragmentation and cleaved caspase-3. RESULTS: HO-1 was up-regulated by both gemcitabine and irradiation treatment in vitro. ZnPP sensitised the UC cells to both therapies. Enhanced apoptosis was induced by the ZnPP combined with gemicitabine. ZnPP enhanced the antitumour effect of gemcitabine in vivo along with decreased numbers of proliferating cells and increased numbers of apoptotic cells. CONCLUSION: These findings suggest that ZnPP combined with gemcitabine or irradiation therapy may be an effective therapeutic modality for UC patients.

Expression of thrombin-activatable fibrinolysis inhibitor (TAFI) is up-regulated by increase in intracellular cyclic AMP levels in cultured HepG2 cells.

Thrombin-activatable fibrinolysis inhibitor (TAFI), a carboxypeptidase B-like proenzyme, is predominantly biosynthesised in the liver and released into circulating plasma. Activated TAFI has a role in maintaining the balance between blood coagulation and fibrinolysis. We investigated the regulation of TAFI expression in cultured human hepatoma HepG2 cells. Stimulation of the cells with forskolin and dibutyryl cyclic AMP (DBcAMP) increased TAFI antigen levels in the cells in parallel with TAFI mRNA levels and antigen release from the cells into the conditioned medium. The elevated TAFI expression was abolished by pretreatment of the cells with KT5720, a protein kinase A (PKA) inhibitor. The promoter activity of the TAFI gene and the half-life of the TAFI transcript in DBcAMP-stimulated HepG2 cells increased to 1.5-fold and 2.0-fold, respectively, of those in the control cells. The increased promoter activity and the prolonged half-life were abolished by pretreatment of the cells with KT5720. These results suggest that an increase in intracellular cAMP levels up-regulates TAFI expression in the cells in accompaniment with an elevation of TAFI mRNA levels, and that the elevated mRNA levels are derived from both transcriptional and post-transcriptional regulations of the TAFI gene mediated by activation of the AMP/PKA signaling pathway.

Interleukin-18 prevents apoptosis via PI3K/Akt pathway in normal human keratinocytes.

Interleukin-18 (IL-18) is a pleiotropic cytokine expressed in both immune and non-immune cells. In the present study, we demonstrate an anti-apoptotic role of IL-18 in normal human neonatal foreskin epidermal keratinocytes (NHEK-F). Cultured NHEK-F spontaneously produced the active form of IL-18. Treatment of NHEK-F cells with anti-IL-18 receptor alpha-chain neutralizing antibody increased apoptosis and caspase-3 activity. Exogenous IL-18 augmented phosphorylation of Akt and activation of NF-kappaB. The promotion of Akt phosphorylation by IL-18 was abolished by LY294002, a PI3K inhibitor, but not SN50, an NF-kappaB inhibitor, indicating that IL-18 functions via the PI3K/Akt pathway and independently of NF-kappaB. In addition, IL-18 was found to augment expression of anti-apoptotic proteins, Bcl-2, XIAP and glucose regulated protein78/BiP, while anti-IL-18 receptor alpha-chain neutralizing antibody suppressed expression of Bcl-2, XIAP, glucose regulated protein94 and protein disulfide isomerase. Taken together, these results indicate that IL-18 plays an important role in keratinocyte survival.