The efficacy of lumbar erector spinae plane block for postoperative analgesia management in patients undergoing lumbar unilateral bi-portal endoscopic surgery: a prospective randomized controlled trial.

BACKGROUND: The efficacy and reliability of erector spinae plane block (ESPB) in posterior open lumbar spine surgery has been demonstrated; however, few randomized controlled trials of lumbar ESPB (L-ESPB) in lumbar unilateral bi-portal endoscopic (UBE) surgery have been reported. METHODS: A total of 120 patients, aged 18 to 65 (who underwent elective lumbar UBE surgery under general anesthesia and exhibited an American Society of Anesthesiologists physical status of I to III) were randomly assigned in a 1:1 ratio to the ESPB group and the Control group. Ultrasound(US)-guided unilateral single-shot 0.25% ropivacaine L-ESPB was performed in the ESPB group, but not in the control group. Postoperative analgesic strategy for all patients: patient controlled intravenous analgesia (PCIA, diluted and dosed with fentanyl alone) was initiated immediately after surgery combined with oral compound codeine phosphate and ibuprofen sustained release tablets (1 tablet containing ibuprofen 200 mg and codeine 13 mg, 1 tablet/q12h) commenced 6 h postoperatively. We collected and compared patient-centred correlates intraoperatively and 48 h postoperatively. The primary outcomes were intraoperative and postoperative opioid consumption and postoperative quality of recovery-15 (QoR-15) scores. RESULTS: Compared to the control group (n = 56), the ESPB group (n = 58) significantly reduced intraoperative remifentanil consumption (estimated median difference - 280 mcg, 95% confidence interval [CI] - 360 to - 200, p < 0.001, power = 100%); significantly reduced fentanyl consumption at 24 h postoperatively (estimated median difference - 80mcg, 95%[CI] - 128 to - 32, p = 0.001, power = 90%); and significantly enhanced the QoR-15 score at 24 h postoperatively (estimated median difference 11, 95%[CI] 8 to 14, p < 0.001, power = 100%). Compared to the control group, the ESPB group enhanced the resting numeric rating scale (NRS) score up to 8 h postoperatively, and the active movement NRS score up to 4 h postoperatively. The incidence of postoperative nausea and vomiting (PONV) (p = 0.015, power = 70%), abdominal distension (p = 0.024, power = 64%), and muscular calf vein thrombosis (MCVT) (p = 0.033, power = 58%) was lower in the ESPB group than in the control group. Moreover, the occurrence of L-ESPB related adverse reactions was not found herein. CONCLUSION: US-guided L-ESPB reduces intraoperative and 24 h postoperative opioid consumption and improves patients' QoR-15 scores at 24 h postoperatively. L-ESPB can be safely and effectively utilized in lumbar UBE surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200061908 , date of registration: 10/07/2022. Registry URL.

Fabrication of water/oil-resistant paper by nanocellulose stabilized Pickering emulsion and chitosan.

Developing plastic/fluorine/silicon-free and degradable water/oil-resistant coatings for paper-based packaging materials to replace disposable plastic products is a very effective way to solve the problem of 'white pollution' or microplastics pollution. A novel water/oil-resistant coating was developed by alkyl ketene dimer (AKD)-based Pickering emulsion and chitosan in this work. Cellulose nanofibrils (CNF) were used as a stabilizing solid for AKD emulsion, with the addition of chitosan as an oil-resistance agent. The coating provides excellent hydrophobicity, water/oil resistance as well as good barrier properties. The water contact angle was as high as 130° and the minimum Cobb60 value was 5.7 g/m2, which was attributed to the hydrophobicity of AKD. In addition, the kit rating reached maximum 12/12 at coating weight of 8.26 g/m2 and the water vapor transmittance rate (WVTR) was reduced to 153.4 g/(m2⋅day) at the coating weight of 10.50 g/m2. The tensile strength of the paper was increased from 28.1 to 43.6 MPa after coating. Overall, this coating can effectively improve the performance of paper-based materials, which may play an important role in the process of replacing disposable plastic packaging with paper-based materials.

POEMS syndrome with undetectable M-protein: a case report and literature review.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria. CASE PRESENTATION: We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone. CONCLUSIONS: Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.

Quantitative proteomic analysis of HER2 protein expression in PDAC tumors.

Metastatic pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 11%, necessitating identification of novel treatment paradigms. Tumor tissue specimens from patients with PDAC, breast cancer, and other solid tumor malignancies were collected and tumor cells were enriched using laser microdissection (LMD). Reverse phase protein array (RPPA) analysis was performed on enriched tumor cell lysates to quantify a 32-protein/phosphoprotein biomarker panel comprising known anticancer drug targets and/or cancer-related total and phosphorylated proteins, including HER2Total, HER2Y1248, and HER3Y1289. RPPA analysis revealed significant levels of HER2Total in PDAC patients at abundances comparable to HER2-positive (IHC 3+) and HER2-low (IHC 1+ /2+ , FISH-) breast cancer tissues, for which HER2 screening is routinely performed. These data support a critical unmet need for routine clinical evaluation of HER2 expression in PDAC patients and examination of the utility of HER2-directed antibody-drug conjugates in these patients.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC).

PURPOSE: Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy. METHODS AND MATERIALS: Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy × 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2). RESULTS: The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%). CONCLUSIONS: PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant.

Background and Aims: In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach: We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan-Meier method, and correlative studies were calculated using chi-square or Fisher's exact test. Results: Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094-0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%. Conclusions: An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.

Porous interbody fusion cage design via topology optimization and biomechanical performance analysis.

The porous interbody fusion cage could provide space and stable mechanical conditions for postoperative intervertebral bone ingrowth. It is considered to be an important implant in anterior cervical discectomy and internal fixation. In this study, two types of unit cells were designed using topology optimization method and introduced to the interbody fusion cage to improve the biomechanical performances of the cage. Topology optimization under two typically loading conditions was first conducted to obtain two unit cells (O-unit cell and D-unit cell) with the same volume fraction. Porous structures were developed by stacking the obtained unit cells in space, respectively. Then, porous interbody fusion cages were obtained by the Boolean intersection between the global structural layout and the porous structures. Finite element models of cervical spine were created that C5-C6 segment was fused by the designed porous cages. The range of motion (ROM) of the cervical spine, the maximum stress on the cage and the bone graft, and the stress and displacement distributions of the cage were analyzed. The results showed the ROMs of C5-C6 segment in D-unit cell and O-unit cell models were range from 0.14° to 0.25° under different loading conditions; the cage composed of the D-unit cells had a more uniform stress distribution, smaller displacement on cage, a more reasonable internal stress transfer mode (transmission along struts of the unit cell), and higher stress on the internal bone graft (0.617 MPa). In conclusion, the optimized porous cage is a promising candidate for fusion surgery, which would avoid the cage subsidence, and promote the fusion of adjacent endplates.

TKIs beyond immunotherapy predict improved survival in advanced HCC.

PURPOSE: For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response. METHODS: We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan-Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis. RESULTS: For all patients, median overall survival (mOS) was 13 months (95% CI 8-19), and median progression-free survival (mPFS) was 6 months (95% CI 4-10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s), p < 0.0001) and mOS (not met vs. 11 vs. 3 months, p < 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months p = 0.133) and mOS (17 vs. 9 months; p = 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months, p = 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (p = 0.0043). CONCLUSION: We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.

A Phase I Study of the Non-Receptor Kinase Inhibitor Bosutinib in Combination with Pemetrexed in Patients with Selected Metastatic Solid Tumors.

Src is overexpressed in various cancers, including 27% of non-small cell lung cancer NSCLC, and is correlated with poor clinical outcomes. We hypothesize that Src kinase inhibitors, including Bosutinib, may exhibit clinical synergy in combination with the antifolate drug pemetrexed. In this Phase I, dose-escalation, safety, and maximum tolerated dose (MTD)-determining study, 14 patients with advanced metastatic solid tumors that had progressed on "standard of care" chemotherapy were enrolled in a 3 + 3 dose escalation study. Oral Bosutinib was administered once daily beginning on day 1, where the first cohort started at an oral dose of 200 mg daily with pemetrexed 500 mg/m2 IV on a three-week schedule. The study's primary objective was to determine the dose-limiting toxicity (DLT), the MTD of Bosutinib in combination with pemetrexed, and the type and frequency of adverse events associated with this treatment. Twelve patients were evaluable for response, including ten patients with adenocarcinoma of the lung, one patient with metastatic adenocarcinoma of the appendix, and one patient with urothelial carcinoma. The median number of Bosutinib and pemetrexed cycles received was 4 (range, 1-4). The MTD of oral Bosutinib in this combination was 300 mg daily. Two patients (17%) had a partial response (PR), and seven patients (58%) showed stable disease (SD) as the best response after the fourth cycle (end of treatment). One patient had disease progression after the second cycle, while three patients had disease progression after the fourth cycle. The two responders and the two patients with the longest stable disease duration or stabilization of disease following progression on multiple systemic therapies demonstrated Src overexpression on immunohistochemical staining of their tumor. The median progression-free survival (PFS) was 6.89 months (95% CI (3.48, 30.85)), and the median overall survival (OS) was 11.7 months (95% CI (3.87, 30.85)). Despite the limitations of this Phase I study, there appears to be potential efficacy of this combination in previously treated patients.

Establishment of an induced pluripotent stem cell line (ZJULLi004-A) from a hypertrophic cardiomyopathy patient carrying MYBPC3/c.3764C>A mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disease characterized by left ventricular hypertrophy and a high risk of sudden death. In this study, a skin biopsy was obtained from a HCM patient harboring a heterozygous missense mutation (c.3764C>A; p.A1225D) in the myosin binding protein C3 (MYBPC3) gene. The isolated fibroblasts were reprogrammed using non-integrated Sendai viral method to establish the patient-specific induced pluripotent stem cell (iPSC) line. The established iPSC line displayed normal morphology and karyotype, expressed pluripotency markers, and can differentiate into three germ layers in vivo.

Generation of an induced pluripotent stem cell line (ZJULLi003-A) from a hypertrophic cardiomyopathy patient carrying MYH7/c.4384G > A mutation.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiovascular disease characterized by left ventricular hypertrophy and cardiomyocyte disarray. In this study, a skin biopsy was obtained from a HCM patient, who carried a missense mutation (c.4384G > A; p.E1462K) in the myosin heavy chain 7 (MYH7) gene. The skin fibroblasts were subsequently reprogrammed with a non-integrated Sendai viral method to generate a patient-specific induced pluripotent stem cell (iPSC) line. The generated iPSC line showed typical morphology and normal karyotype, expressed pluripotency markers, and was capable to differentiate into three germ layers.