Clinical efficacy and performance evaluation of a bendable remote robot system for a bone tumour surgery: A pilot animal study.

BACKGROUND: Traditional open surgery for bone tumours sometimes has as a consequence an excessive removal of healthy bone tissue because of the limitations of rigid surgical instruments, increasing infection risk and recovery time. METHODS: We propose a remote robot with a 4.5-mm diameter bendable end-effector, offering four degrees of freedom for accessing the inside of the bone and performing tumour debridement. The preclinical studies evaluated the effectiveness, clinical scenario, and usability across 12 total surgeries-six phantom surgeries and six bovine bone surgeries. Evaluation criteria included skin incision size, bone window size, surgical time, removal rate, and conversion to open surgery. RESULTS: Preclinical studies demonstrated that the robotic approach requires significantly smaller incision size and procedure times than traditional open curettage. CONCLUSION: This study validated the performance of the proposed system by assessing its preclinical effectiveness and optimising surgical methods using human phantom and bovine bone tumour models.

Supporting Life Adjustment in Patients With Lung Cancer Through a Comprehensive Care Program: Protocol for a Controlled Before-and-After Trial.

BACKGROUND: Lung cancer diagnosis affects an individual's quality of life as well as physical and emotional functioning. Information on survivorship care tends to be introduced at the end of treatment, but early intervention may affect posttreatment adjustment. However, to the best of our knowledge, no study has explored the effect of early information intervention on the return to work, family, and societal roles of lung cancer survivors. OBJECTIVE: We report the study protocol of a comprehensive care prehabilitation intervention designed to facilitate lung cancer survivors' psychological adjustment after treatment. METHODS: A comprehensive care program was developed based on a literature review and a qualitative study of patients with lung cancer and health professionals. The Lung Cancer Comprehensive Care Program consists of educational videos and follow-up visits by a family medicine physician. To prevent contamination, the control group received routine education, whereas the intervention group received routine care and intervention. Both groups completed questionnaires before surgery (T0) and at 1-month (T1), 6-month (T2), and 1-year (T3) follow-up visits after surgery. The primary outcome was survivors' psychological adjustment to cancer 6 months after pulmonary resection. RESULTS: The historical control group (n=441) was recruited from September 8, 2021, to April 20, 2022, and the intervention group (n=350) was recruited from April 22, 2022, to October 17, 2022. All statistical analyses will be performed upon completion of the study. CONCLUSIONS: This study examined the effectiveness of an intervention that provided general and tailored informational support to lung cancer survivors, ranging from before to the end of treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05078918; https://clinicaltrials.gov/ct2/show/NCT05078918. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54707.

Conditional Survival of Patients Who Underwent Curative Resection for Esophageal Squamous Cell Carcinoma.

OBJECTIVE: To analyze conditional survival estimates of patients with esophageal cancer who underwent curative resection. SUMMARY BACKGROUND DATA: Conditional survival reflects dynamic prognosis updated to the current status and is a more relevant indicator for current healthcare and life decisions. METHODS: This study included 1883 patients who underwent complete resection for esophageal squamous cell carcinoma at a tertiary cancer center from 1994 to 2016. We calculated 5-year (5Y) conditional overall survival (COS), conditional recurrence-free survival (CRFS), and conditional relative survival (CRS) estimates from diagnosis to 5 years of survival. RESULTS: The 5Y COS, CRFS, and CRS increased from 63.7%, 65.2%, and 70.2% at diagnosis to 75.8%, 91.9%, and 86.4 at 5 years after diagnosis, respectively. While there were large differences with different stages (stage I, II, III) at diagnosis (81.2%, 64.9%, and 37.3% for COS; 85.1, 65.1%, and 67.9% for CRFS; 89.2%, 72.1%, and 41.1% for CRS), the gap decreased with time; rates were similar after 5 years (77.1%, 75.7%, and 72.6% for COS; 91.7%, 90.6%, and 94.5% for CRFS, and 89.3%, 85.4%, and 78.3% in CRS, respectively). The 5Y COS, CRFS, and CRS were persistently lower in older patients even after 5 years. CONCLUSIONS: Conditional survival estimates generally increase over time, and the largest improvements were observed for patients with advanced stage. Availability of updated prognosis at various time points allows clinicians to better guide their patients. Our results also imply substantial residual risk of recurrence and sustained excess mortality compared to the general population even after 5 years.

Risk of Postoperative Gastrointestinal Bleeding and Its Associated Factors: A Nationwide Population-Based Study in Korea.

Postoperative gastrointestinal bleeding (PGIB) is a serious complication with expensive medical costs and a high mortality rate. This study aims to analyze the incidence of PGIB and its associated factors, including its relationship with postoperative analgesic use. Patients aged ≥20 years who received various kinds of surgery from 2013 to 2017 were included (n = 1,319,807). PGIB was defined by admission with ICD-10 codes of gastrointestinal bleeding plus transfusion within 2 months after surgery. A total of 3505 (0.27%) subjects had PGIB, and the incidence was much higher for those who underwent major gastrointestinal and major cardiovascular surgery (1.9% for both), followed by major head and neck (0.7%), major genitourinary (0.5%), and orthopedic surgery (0.45%). On multivariate analysis, older age, male sex, lower income, comorbidities, peptic ulcer disease, and congestive heart failure were associated with a higher risk of gastrointestinal bleeding. Among analgesics, steroid use was associated with increased postoperative bleeding risk (adjusted OR: 1.36, 95% CI: 1.25-1.48). Acetaminophen/nonsteroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors, anticonvulsants, antidepressants, and opioids were not associated with increased risk. PGIB is considerable for major surgeries, and its risk should be considered, especially for patients with older age and comorbidities and use of steroids.

Conditional relative survival and competing mortality in patients who underwent surgery for lung cancer: A nationwide cohort study.

We aimed to investigate the conditional relative survival (CRS) and competing mortality in patients who underwent surgery for newly diagnosed lung cancer. Using a nationwide population-based database, we calculated 5-year CRS on 1 to 5 years survival after surgery. These rates were reported according to age, sex, socioeconomic status, comorbidities and treatment received. We also estimated cause-specific mortality with the consideration of competing risk. We identified 34 349 patients newly diagnosed with primary lung cancer from 2007 to 2013. The 5-year CRS after surgery was 71.7% at baseline improving steadily to 85.4% by 5 years, suggesting evidence of persistent excess mortality risk. Throughout the period, lung cancer was the most common cause of death, contributing to 83.6% mortality 1 year after surgery and 66.3% 5 years after surgery. Other causes of death included cardiovascular disease and respiratory disease, which increased continuously with time after surgery. CRS rates for patients with lung cancer improved over time but did not reach the level of the general population even 5 years after surgery. Although the main cause of death continues to be lung cancer, death from noncancer causes increased with time after surgery. Evidence-based decisions could be made on the dynamic risk profiles of the patients.

AAV-Mediated Combination Gene Therapy for Neuropathic Pain: GAD65, GDNF, and IL-10.

Neuropathic pain is a chronic pain state characterized by nerve damage, inflammation, and nociceptive neuron hyperactivity. As the underlying pathophysiology is complex, a more effective therapy for neuropathic pain would be one that targets multiple elements. Here, we generated recombinant adeno-associated viruses (AAVs) encoding three therapeutic genes, namely, glutamate decarboxylase 65, glial cell-derived neurotrophic factor, and interleukin-10, with various combinations. The efficacy for pain relief was evaluated in a rat spared nerve injury model of neuropathic pain. The maximal analgesic effect was achieved when the AAVs expressing all three genes were administered to rats with neuropathic pain. The combination of two virus constructs expressing the three genes was named KLS-2031 and evaluated as a potential novel therapeutic for neuropathic pain. Single transforaminal epidural injections of KLS-2031 into the intervertebral foramen to target the appropriate dorsal root ganglion produced notable long-term analgesic effects in female and male rats. Furthermore, KLS-2031 mitigated the neuroinflammation, neuronal cell death, and dorsal root ganglion hyperexcitability induced by the spared nerve injury. These results suggest that KLS-2031 represents a promising therapeutic option for refractory neuropathic pain.

Immunogenicity and immunomodulatory effects of the human chondrocytes, hChonJ.

BACKGROUND: Invossa™ (TissueGene-C) is a cell and gene therapy for osteoarthritis. It is composed of primary human chondrocytes (hChonJ cells) and irradiated human chondrocytes modified to express TGF-ß1 (hChonJb#7 cells). The hChonJ cells were isolated from a polydactyly donor, and TGF-ß1 cDNA was delivered to the cells, generating hChonJb#7 cells. Since the cells are allogeneic, the concern of immune response against cells has been raised. In this study, we investigated the immunogenicity of allogenic human chondrocyte, hChonJ cells. METHODS: The immunological properties of hChonJ cells were investigated through the analysis of surface marker expression and the effect on allogeneic T cell proliferation. Flow cytometry and RT-PCR analysis were performed to analyze the surface marker expression related to immune response, such as major histocompatibility complex (MHC) class I, class II, T cell co-stimulatory molecules and T cell co-inhibitory molecules. A mixed lymphocyte reaction (MLR) was conducted to evaluate how allogeneic T cells would respond to hChonJ cells. RESULTS: We observed that hChonJ cells did not express MHC class II and T cell co-stimulatory molecules, but expressed T cell co-inhibitory molecule PD-L2. IFN-γ treatment induced the expression of PD-L1, and up-regulated the expression of PD-L2. Also, we observed that hChonJ cells did not stimulate T cell proliferation from a MHC-mismatched donor. Further, they could suppress the proliferation of activated T cells. We also observed that the blockade of PD-L1 and/or PD-L2 with specific neutralizing antibody could lead to the restoration of allo-reactive T cell proliferation. CONCLUSIONS: We showed that hChonJ cells were not immunogenic but immunosuppressive, and that this phenomenon was mediated by co-inhibitory molecules PD-L1 and PD-L2 on hChonJ cells in a contact-dependent manner.

The effects of a single intravenous injection of novel activin A/BMP-2 (AB204) on toxicity and the respiratory and central nervous systems.

The purpose of this study was to determine the effects of a single intravenous injection of a novel osteoinductive material, activin A/BMP-2 (AB204), to rodents on toxicity and their respiratory functions and central nervous system (CNS). A single intravenous injection of AB204 was given to Sprague-Dawley (SD) rats in doses of 0, 0.625, 2.5 and 10 mg/kg to observe the mortality rate, the general symptoms for 14 days. The experimental groups were also given 0.2, 0.4 and 0.8 mg/kg of AB204, respectively, and the respiration rate, the tidal volume and the minute volume were measured for 240 min. The experimental groups of imprinting control region (ICR) mice were given a single intravenous injection of 0.2, 0.4 and 0.8 mg/kg of AB204, respectively. Their body temperature was taken and general behaviors were observed to evaluate the effect of AB204 on the CNS for 240 min. The study on toxicity of a single intravenous injection found no death or abnormal symptoms, abnormal findings from autopsy, or abnormal body weight gain or loss in all the experimental groups. No abnormal variation associated with the test substance was observed in the respiration rate, the tidal volume, the minute volume, body temperature or the general behaviors. On the basis of these results, the approximate lethal dose of AB204 for a single intravenous injection exceeds 10 mg/kg for SD rats and a single intravenous injection of ≤0.8 mg/kg AB204 has no effect on their respiratory system for SD rat and no effect on their CNS for ICR mice.

The toxicological evaluation of repetitive 2- and 4-week intravenous injection of Activin A/BMP-2 chimera (AB204) into rats.

The subchronic (28-days) toxicity of an Activin A/BMP-2 chimera (AB204) was assessed in rats. Sprague-Dawley rats received repetitive intravenous injection of AB204 in doses of 0, 0.25 and 0.5 mg/kg for two weeks and in doses of 0, 0.08, 0.16 and 0.32 mg/kg/day for four weeks. No animal was dead and no change caused by the AB204 was observed in general symptoms, weight variation, and food and water intake as well as blood test and autopsy findings. In conclusion, the no observed adverse effects level (NOAEL) of the AB204 on rats was determined to be 0.32 mg/kg/day.

Sulforaphane inhibition of TPA-mediated PDCD4 downregulation contributes to suppression of c-Jun and induction of p21-dependent Nrf2 expression.

Programmed cell death 4 (PDCD4) is a bona fide tumor suppressor protein and plays a critical role in controlling the rate of protein synthesis. Here, we show that TPA selectively activated the S6K1 and ERK1/2 kinases, contributing to PDCD4 proteolysis and Pdcd4 mRNA degradation in HepG2 cells, respectively. In addition, we observed that sulforaphane suppression of TPA-induced S6K1 and ERK1/2 activation played a critical role in attenuating PDCD4 poly-ubiquitination and Pdcd4 mRNA downregulation. Moreover, we observed that silencing Pdcd4 led to not only an increased expression of c-Jun, but also a decreased expression of p21, the latter of which contributed to suppression of Keap1-dependent Nrf2 poly-ubiquitination. Finally, we demonstrate that the expression of PDCD4, p21 and Nrf2 is higher, but that of c-Jun is lower in normal human liver tissues, compared with hepatoma tissues. Collectively, our study illustrates that attenuating the rate of PDCD4 proteolysis and Pdcd4 mRNA degradation serves as a novel anti-inflammatory and cytoprotective mechanism of sulforaphane.

Sulforaphane suppresses LPS-induced or TPA-induced downregulation of PDCD4 in RAW 264.7 cells.

Sulforaphane is a natural chemopreventive isothiocyanate and abundantly found in various cruciferous vegetables. Although chemopreventive activity of sulforaphane is well documented, the detailed biochemical mechanism(s), underlying how it regulates the protein translation process to antagonize pro-inflammatory responses are largely unclear. In the present study, we show that lipopolysaccharide (LPS) or 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment reduces cellular levels of PDCD4, and this event is mediated by affecting both transcription and proteolysis in RAW 264.7 cells. We show that LPS-mediated or TPA-mediated PDCD4 downregulation is catalyzed by the activation of intracellular Akt1 or S6K1 kinases and that sulforaphane suppresses LPS-induced or TPA-induced Akt1 or S6K1 activation, thereby resulting in the attenuation of PDCD4 downregulation in RAW 264.7 cells. We propose that sulforaphane suppression of PDCD4 downregulation serves as a novel molecular mechanism to control proliferation in response to pro-inflammatory signals.

A giant intradiploic epidermoid cyst with perforation of the dura and brain parenchymal involvement.

A patient with a long-standing intradiploic epidermoid cyst with perforation of the dura and brain parenchymal involvement is reported. A 69-year-old man, who had previously presented with a subcutaneous mass on the left frontoparietal scalp, developed a sudden grand mal seizure. Magnetic resonance imaging showed a well-defined mass in the frontoparietal scalp with destruction of the skull. Penetration of the dura allowed for communication with the intracranial structures. Surgical resection and cranioplasty were performed. There were no well-defined margins in the deep portion and the mass was subtotally removed. Histological examination showed that the cystic structure was lined by squamous epithelium containing laminated keratin material. The pathologic findings were consistent with the diagnosis of an epidermoid cyst.

The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide.

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.