Palliative Treatment of Leptomeningeal Carcinomatosis From Renal Cell Carcinoma With Local CyberKnife Radiotherapy and Systemic Pazopanib Therapy: A Case Report.

Leptomeningeal carcinomatosis (LMC) from renal cell carcinoma (RCC) is rare. There is no established treatment strategy for LMC, and the prognosis is extremely poor. We describe a case of LMC from RCC treated with local CyberKnife radiotherapy (CKR) and systemic therapy with pazopanib. The patient was a 63-year-old man with brain metastases from right RCC. Surgery and CKR were performed for the brain metastases, and the lesions were subsequently controlled. The patient developed isolated lesions in the pituitary stalk, right internal auditory canal, left ventricular choroid plexus (CP), left facial nerve, and medulla oblongata after the surgery and CKR for brain metastases. We diagnosed LMC and treated the patient with systemic therapy with pazopanib. We performed local therapy with CKR for lesions of the pituitary stalk, right internal auditory canal, left facial nerve, and medulla oblongata. The CP lesion was not treated with CKR because the lesion tended to shrink after systemic therapy with pazopanib. There were no symptoms due to LMC until the end of life and no adverse events due to CKR. Ten years and five months after the nephrectomy for RCC, one year and four months after the initial CKR for brain metastases, and nine months after the diagnosis of LMC, the patient died due to pleural effusion from lung metastases. Our case suggests that CKR combined with pazopanib may be effective as a palliative treatment for LMC from RCC.

The clock gene Bmal1 controls inflammatory mediators in rheumatoid arthritis fibroblast-like synoviocytes.

OBJECT: To clarify the involvement of clock genes in the production of inflammatory mediators from RA-FLS, we examined the role of Bmal1, one of the master clock genes. METHODS: RA-FLSs were stimulated with IL-1ß (0, 20 ng/mL), IL-6 (0, 20 ng/mL), IL-17 (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expression of Bmal1, MMP-3, CCL2, IL-6, IL-7 and IL-15 by qPCR and immunofluorescence staining. After silencing Bmal1, RA-FLSs were stimulated with IL-1ß (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expressions of inflammatory mediators; MMP-3, CCL2, IL-6 and IL-15 by qPCR, ELISA and immunofluorescence staining. RESULTS: Bmal1 expressions were increased by IL-1ß, TNF-α and IFN-γ stimulations. Under stimulations with TNF-α, IL-1ß, and IFN-γ, mRNA and protein expressions of MMP-3, CCL2 and IL-6 were suppressed by siBmal1. CONCLUSION: Results indicate that Bmal1 contributes the production of MMP-3, CCL2, and IL-6 from RA-FLS, implying Bmal1 is involved in the pathogenesis of RA by regulating the inflammation.

Efficacy of the Addition of Robot-assisted Radical Cystectomy with Extracorporeal Urinary Diversion after an Enhanced Recovery Protocol.

PURPOSE: It is unclear if robotic radical cystectomy with extracorporeal urinary diversion (eRARC) provides additional benefit when performed along with enhanced recovery after surgery (ERAS). We assessed the additional efficacy of eRARC in terms of perioperative outcomes. MATERIALS AND METHODS: We retrospectively assessed 143 patients undergoing radical cystectomy with urinary diversion between June 2010 and December 2021 at a single center. The patients were assigned to three groups: open radical cystectomy (ORC) with conventional recovery after surgery (CRAS) [Group A], ORC with ERAS [Group B], and eRARC with ERAS [Group C]. A propensity score-matched analysis was performed to evaluate how ERAS and eRARC affected outcomes respectively. Meanwhile, multivariable analysis was used to detect the predictors of prolonged length of hospital stay (LOS). RESULTS: The median LOS was shorter after ERAS and eRARC. In the propensity score-matched analysis, ERAS was linked to a significantly shorter median LOS (28.0 vs. 20.0 days, P < .001), but eRARC was not associated with a shorter LOS (19.0 vs. 17.5 days, P = .21). Neither ERAS nor eRARC were connected with a reduce in complication rate. Following multivariable analysis, ERAS was found to be independently associated with shorter LOS (OR=0.23, P < .001), but eRARC demonstrated no such correlation (OR=0.29, P = .096). CONCLUSION: ERAS had strong association with shorter LOS, although eRARC did not contribute to additional efficacy. Neither ERAS nor eRARC decreased the complication rate.

Tocilizumab suppresses NF-kappa B activation via toll-like receptor 9 signaling by reducing cell-free DNA in rheumatoid arthritis.

Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA.

[ADOPTION OF ENHANCED RECOVERY AFTER SURGERY (ERAS) PROTOCOL FOR THE MANAGEMENT OF PATIENTS UNDERGOING RADICAL CYSTECTOMY IN JAPAN].

(Objectives) The Enhanced Recovery After Surgery (ERAS) protocols are standardized and multimodal perioperative care pathways designed to improve surgical outcomes by minimizing stress response and inflammation following surgery. First adopted in colorectal surgery, ERAS is now being employed in various other types of surgeries, most recently in patients undergoing radical cystectomy (RC). Implementation of ERAS protocols resulted in reductions in perioperative complication rates and length of hospital stay (LOS). However, information on the adoption of ERAS in patients undergoing RC in Japan is limited. The objective of this study was to evaluate the safety and efficacy of ERAS implemented in the Toyohashi Municipal Hospital in 2017 for the management of patients with RC. (Patients and methods) This was a retrospective study of 103 patients who underwent RC and urinary diversion from January 2012 to March 2019. Of the 103 patients, 71 underwent surgery prior to the introduction of the ERAS were allocated to the 'traditional' group, while 32 were exposed to the ERAS protocol were allocated to the 'ERAS' group. In this study, ERAS included no bowel preparation, preoperative carbohydrate loading, preoperative fluid reduction, preoperative fasting, reduced drainage use, no nasogastric intubation, and early postoperative drinking and eating. A comparative analysis was performed to evaluate LOS and postoperative complication rate (Clavien classification ≥2) after RC between the 'traditional' and 'ERAS' groups. (Results) Patient characteristics and intraoperative variables such as median age, sex, body mass index, clinical and pathological cancer stage, amount of bleeding, need for transfusion, and technique of urinary diversion did not differ between groups. However, duration of surgery was significantly shorter in the ERAS group than in the traditional group (402 min vs. 470 min; P = 0.03). Further, rate of complication was significantly lower (43.8% vs. 67.6%; P=0.03) and LOS after RC was significantly shorter (21 days vs. 28 days; P<0.001) in the ERAS group compared to the traditional group. Moreover, ERAS was an independent factor affecting shorter LOS after RC (OR, 5.22; 95% CI, 1.52-17.90; P = 0.009) in multivariate analyses. (Conclusions) It is possible that the ERAS protocol adopted in this study reduced the LOS and postoperative complication rate after RC at this site in Japan.

Efficacy of zoledronic acid in older prostate cancer patients undergoing androgen deprivation therapy.

OBJECTIVES: The purpose of this study is to evaluate the efficacy of annual zoledronic acid treatment in Japanese patients with nonmetastatic prostate cancer during androgen deprivation therapy (ADT). METHODS: This is a single institution 12-month study. Between 2016 and 2019, patients aged 70 years or older on ADT for nonmetastatic prostate cancer had bone mineral density (BMD) measured and 10-year probability of fracture calculated using fracture risk assessment tool (FRAX). Patients who showed osteopenia or had a 10-year hip fracture risk ≥ 3% or a 10-year probability of major osteoporotic fracture ≥ 20% were offered treatment with zoledronic acid 5 mg intravenously (ZA group). The patients who did not receive treatment were set as the control group. Lumbar and hip BMD were measured 6 and 12 months after treatment in the ZA group and 12 months after baseline in the control group. The yearly BMD change of both groups was compared. RESULTS: The mean ages of the ZA group (n = 26) and control group (n = 12) were 80.5 ± 9.1 and 76.1 ± 6.7 years, respectively. In the ZA group, lumbar and hip BMD changes at 12 months were +2.1% and +0.8%, respectively. In the control group, lumbar and hip BMD changes were -0.9% and -4.9%, respectively. There were statistically significant differences between the 2 groups in BMD percent changes (P < 0.05). CONCLUSIONS: Without intervention, BMD tends to continue to decrease during ADT. Our findings suggest that administration of zoledronic acid enables maintenance of BMD in the older adults.

[A CASE OF RETROPERITONEAL HEMORRHAGE CAUSED BY THE INSERTION OF A URETERAL ACCESS SHEATH. A RARE COMPLICATION ASSOCIATED WITH FLEXIBLE TRANSURETHRAL LITHOTRIPSY (fTUL)].

A 77-year-old man with a right kidney stone was admitted to our hospital. A ureteroscope was introduced into the ureter without dilation under direct vision. We then performed flexible transurethral lithotripsy (f-TUL) using a ureteral access sheath and successfully fragmented the stone and extracted almost all the stone fragments without any complications. Just 3 hours after the operation, he suddenly developed right abdominal pain with a decrease in hemoglobin. A CT scan showed a retroperitoneal hemorrhage around the lower ureter. We herein describe a rare complication associated with flexible transurethral lithotripsy.

Risk factors for late deep infection after total hip arthroplasty in patients with rheumatoid arthritis.

OBJECTIVE: Postoperative infections, a serious complication of orthopedic surgery, occur 2-4 times more frequently in patients with rheumatoid arthritis (RA) without adjustment for medication. Some studies have demonstrated a similar risk of postoperative infection following orthopedic surgery regardless of whether patients underwent tumor necrosis factor-α (TNF-α) inhibitor therapy; however, other studies have reported a higher risk with TNF-α inhibitor use. However, few reports have focused on the correlation between TNF-α inhibitor use and postoperative late infection. Therefore, we investigated the correlation between TNF-α inhibitor therapy and serious postoperative late infection in patients with RA who underwent total hip arthroplasty (THA). METHODS: Ninety-nine patients with RA who were enrolled in our institution's and Konan Kakogawa Hospital's THA registry between January 2003 and December 2012 were eligible to participate. Data collected included clinical parameters and medications, including biological drugs, disease-modifying antirheumatic drugs, and glucocorticoids. Logistic regression analysis was performed to examine the association between clinical parameters, medications, and the development of postoperative late infection. RESULTS: One risk factor was identified in the multivariate analysis. TNF inhibitor therapy was found to be significantly associated with the development of late infection after THA (biological drugs: OR: 9.5, 95% CI: 1.0-88.8; TNF inhibitor: OR: 11.7, 95% CI: 1.2-109.7). CONCLUSION: Biological drug therapy, especially TNF inhibitors, may be associated with an increased rate of late deep infection after THA. When the use of TNF-α inhibitor therapy is considered, rheumatologists must be attentive to patients after THA.

Short-term outcome of finger joint synovectomy in rheumatoid arthritis.

Rheumatoid arthritis (RA) frequently affects finger joints, and persistent synovitis is believed to cause not only bone destruction but also various deformities of the fingers in the long run. Synovectomy of the finger joints is carried out when chronic swelling of the synovium does not respond to any conservative treatment with medication and rehabilitation. In the present study the short-term results of finger joint synovectomy in RA were reviewed in 49 finger joints. The subjects were evaluated at two time points, with average follow-up periods of 14 and 62 months, and the results were compared between the two follow-up time points. In regard to results, pain relief, swelling abatement, and only a little loss of motion were observed in most fingers. Moreover, only a few patients demonstrated progression of bone destruction, suggesting that synovectomy has a retarding effect and tends to be effective especially in the early stages of the disease. In conclusion, we recommend synovectomy for finger joints in RA patients before bone changes occur, and when chronic synovitis of the finger joints does not respond to any other conservative treatment.

Prospective study of methotrexate treatment for rheumatoid arthritis treated legitimately according to the government recommended 8 mg/week dose.

Clinical squeal of the treatment of rheumatoid arthritis patients with methotrexate (MTX) according to the Japanese government recommended dose of 8 mg/week was evaluated prospectively. A total of 176 patients with active RA attending Konan Kakogawa Hospital and Kobe University Hospital were enrolled. Patients' profile at the start of study was Class 2.0 +/- 1.1 and X-ray stage 2.6 +/- 1.0. The effects of MTX treatment were evaluated by the American College of Rheumatology (ACR) core set, disease activity score of 28 joints (DAS28), and European League Against Rheumatism (EULAR) response criteria. A modified Sharp method was used to evaluate the radiographs. The improvement in the clinical signs and symptoms of the ACR core set was maintained for a 24-month period (p < 0.05). The ACR20/50/70 and DAS28 were also improved at the 12- and 24-month assessments. However, 82 of 130 patients (63.5%) were found to be nonresponders at 24 months of MTX therapy, as evaluated by EULAR response criteria. The X-ray study showed that joint destruction progressed despite the treatment. Thus, long-term MTX treatment performed in accordance with the Japanese 8 mg/week regimen appears to be favorable in terms of the signs and symptoms of RA; however, it is clearly insufficient for and cannot halt the progression of rheumatic joint destruction.

Total knee arthroplasty for rheumatoid knee with bilateral, severe flexion contracture: report of three cases.

The treatment of patients with severe flexion contracture of the rheumatoid knee, deprived of ambulation for long periods of time, is challenging. Based on three cases, we indicate the potential risks of posterior dislocation of the knee after total knee arthroplasty. In this pathological condition, surgeons must carefully select the type of implant in order to avoid this serious complication. We also emphasize the importance of working on disuse muscle atrophy of trunk (back, abdominal) and lower limbs, both of which play an integral role in ambulation. The personality of each rheumatoid patient should be carefully considered when considering surgical and rehabilitation options.

Tumor chemopreventive activity of 3-O-acylated (--)-epigallocatechins.

In order to seek promising cancer chemopreventive agents, we assessed the antitumor promoting activities of 3-O-octanoyl- or 3-O-(2-methyloctanoyl)-(--)-epigallocatechins, inhibiting markedly the activation of Epstein-Barr virus early antigen, in a two-stage mouse skin carcinogenesis assay. As a result, these derivatives inhibited a papilloma formation 1.3-1.6-fold more strongly than (--)-epigallocatechin gallate well established as anti-tumor promoter.