Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: a single-arm, phase II trial.

BACKGROUND: Two cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes. METHODS: Locally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy. RESULTS: Forty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles (P = 0.03). The most common treatment-related adverse events were grades 1-2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year disease-free survival and overall survival rates were both 97.6%, and the 2-year disease-free survival and overall survival rates were 92.3% and 97.6%, respectively. Three patients experienced disease recurrence or metastasis ranging from 12.5 to 25.8 months after surgery, and one patient died 6 months after surgery due to cardiovascular disease. Neither programmed death-ligand 1 expression nor tumor mutational burden was associated with pathological response. An increased infiltration of CD56dim natural killer cells in the pretreatment tumor was correlated with better pathological response in the primary tumor. CONCLUSIONS: It seems probable that intensive cycles of neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine increased tumor regression and improved survival outcomes. Randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings. Trial registration Chinese Clinical Trial Registry, ChiCTR2000029807, Registered February 14, 2020, https://www.chictr.org.cn/showproj.aspx?proj=49459 .

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients Treated with Definitive Chemoradiotherapy for Locally Advanced Oesophageal Squamous Cell Carcinoma.

Background: The neutrophil-to-lymphocyte ratio (NLR) has been shown to have prognostic value in several common cancers. This study aimed to investigate the prognostic value of NLR in patients with advanced oesophageal squamous cell carcinoma (ESCC) after definitive chemoradiotherapy (dCRT). Methods: A retrospective analysis was performed on 158 patients with advanced ESCC who received dCRT from January 2012 to December 2018. The NLR for different treatment stages was calculated based on laboratory test results. The Kaplan-Meier (KM) method and Cox proportional regression model were used to analyse the relationship between NLR and overall survival (OS). Results: The mean NLR of 158 patients with ESCC was 3.403 ± 2.479. The pre-treatment NLR cut-off was 4.839, and patients were divided into the low NLR group (NLR < 4.839) and the high NLR group (NLR ≥ 4.839). NLR in patients with ESCC was related to N stage (P < 0.05). The KM analysis showed that the median OS of all enrolled patients was 29.3 months, the median OS periods of patients in the high and low NLR groups were 15.6 and 35.8 months, respectively, and the OS of the low NLR group was better than that of the high NLR group (P < 0.001). In the multivariate analysis, NLR was an independent prognostic factor that affects the prognosis of patients with ESCC receiving dCRT. Furthermore, patients who maintained a high NLR before and after treatment showed worse clinical outcomes than the other groups. Conclusion: Our findings suggest that NLR can effectively assess the prognosis of patients with advanced ESCC undergoing dCRT.

Are more courses of immunochemotherapy beneficial for the short-term outcome of locally advanced esophageal squamous cell carcinoma?

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and neoadjuvant immunochemotherapy have shown promising results in esophageal carcinoma. However, it is still unclear whether more courses of immunochemotherapy are therapeutically better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC received three courses of camrelizumab plus nab-paclitaxel and capecitabine before undergoing surgery. Additionally, patients received safety, computed tomography (CT), and endoscopy (with endoscopic ultrasonography and mucosal biopsy) assessments before and in the second and third courses of treatment. We used the CT and endoscopic assessment results from the second and third courses for comparison. RESULTS: From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-Programmed cell death-1 (PD-1) therapy and radical surgical resection. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with that of the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, with increased CT and endoscopy T (clinical T stage) downstaging rates by 16.3% and 25.9%, N (clincial N stage) downstaging rates by 7.0% and 11.1%, and objective response rates (ORRs) by 13.6% and 22.0%, respectively. CONCLUSIONS: Regardless of downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs.

The efficacy and safety of asleep and awake subthalamic deep brain stimulation for Parkinson's disease patients: A 1-year follow-up.

Introduction: Traditional DBS is usually conducted under local anesthesia (LA) which is intolerable to some patients, DBS under general anesthesia (GA) was opted to extended surgical indication. This study aimed to compare the efficacy and safety of bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease (PD) under asleep and awake anesthesia state in 1-year postoperative follow-up. Methods: Twenty-one PD patients were assigned to asleep group and 25 patients to awake group. Patients received bilateral STN-DBS under different anesthesia state. The PD participants were interviewed and assessed preoperatively and at 1-year postoperative follow-up. Results: At 1-year follow-up, compared surgical coordinate in two groups, the left-side Y of asleep group showed more posterior than awake group (Y was-2.39 ± 0.23 in asleep group, -1.46 ± 0.22 in awake group, p = 0.007). Compared with preoperative OFF MED state, MDS-UPDRS III scores in OFF MED/OFF STIM state remained unchanged, while in OFF MED/ON STIM state were significantly improved in awake and asleep groups, yet without significant difference. Compared with preoperative ON MED state, MDS-UPDRS III scores in ON MED/OFF STIM, and ON MED/ON STIM state remained unchanged in both groups. In non-motor outcomes, PSQI, HAMD, and HAMA score significantly improved in asleep group compared to awake group at 1-year follow-up (PSQI, HAMD, and HAMA score in 1-year follow-up were 9.81 ± 4.43; 10.00 ± 5.80; 5.71 ± 4.75 in awake group, 6.64 ± 4.14; 5.32 ± 3.78; 3.76 ± 3.87 in asleep group, p = 0.009; 0.008; 0.015, respectively), while there was no significant difference in PDQ-39, NMSS, ESS, PDSS score, and cognitive function. Anesthesia methods was significantly associated with improvement of HAMA and HAMD score (p = 0.029; 0.002, respectively). No difference in LEDD, stimulation parameters and adverse events was observed between two groups. Discussion: Asleep STN-DBS may be considered a good alternative method for PD patients. It is largely consistent with awake STN-DBS in motor symptoms and safety. Yet, it showed higher improvement in terms of mood and sleep compared to awake group at 1-year follow-up.

Eight-year follow-up outcome of subthalamic deep brain stimulation for Parkinson's disease: Maintenance of therapeutic efficacy with a relatively low levodopa dosage and stimulation intensity.

AIMS: This follow-up study aimed to examine the 8-year efficacy and safety of subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD) in southern China. METHODS: The follow-up data of 10 patients with PD undergoing STN-DBS were analyzed. Motor symptoms were assessed before and 1, 3, 5, and 8 years after the surgery with stimulation-on in both off-medication (off-med) and on-medication (on-med) status using the Unified Parkinson's disease Rating Scale Part III. The quality of life was assessed using the 39-item Parkinson's Disease Questionnaire. The sleep, cognition, and emotion were evaluated using a series of nonmotor scales. Levodopa equivalent daily dose (LEDD) and stimulation parameters were recorded at each follow-up. RESULTS: The motor symptoms were improved by 50.9%, 37.7%, 36.7%, and 37.3% in 1, 3, 5, and 8 years, respectively, in the off-med / stimulation-on status compared with the baseline. The quality of life improved by 39.7% and 56.1% in 1 and 3 years, respectively, but declined to the preoperative level thereafter. The sleep, cognition, and emotion were mostly unchanged. LEDD reduced from 708.1 ± 172.5 mg to 330 ± 207.8 mg in 8 years. The stimulation parameters, including amplitude, pulse width, and frequency, were 2.77 ± 0.49 V, 71.3 ± 12.8 µs, and 121.5 ± 21 Hz, respectively, in 8 years. CONCLUSION: Long-term therapeutic efficacy of STN-DBS could be achieved even with relatively low stimulation intensity and medication dosage for PD patients in southern China. Motor improvement and medication reduction were maintained through the 8-year follow-up, but improvement in quality of life lasted for only 3 years. No definite changes was found in nonmotor symptoms after STN-DBS.

Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its role in the preoperative setting. The aim of this study was to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC. METHODS: Patients diagnosed with locally advanced ESCC were retrospectively included if they had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. In addition, pathological response and the relationship between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also investigated. RESULTS: Twelve patients were included and they all received three courses of preoperative treatment with camrelizumab plus nab-paclitaxel/S1. No grade 3 or higher toxicities occurred. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response (pCR) and five with a major pathological response (MPR). Neither programmed death-ligand 1 (PD-L1) expression nor TMB was correlated with treatment response. TIME analysis revealed that a higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor, while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes (LNs). CONCLUSIONS: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation.

Search for clinical predictors of good glycemic control in patients starting or intensifying oral hypoglycemic pharmacological therapy: A multicenter prospective cohort study.

AIMS: Our aim was to search for clinical predictors of good glycemic control in patients starting or intensifying oral hypoglycemic pharmacological therapy. METHODS: A multicenter, prospective cohort of 499 diabetic subjects was enrolled in this study: patients with newly diagnosed diabetes (NDM group) or poor glycemic control with oral antidiabetic drugs (OADs) (PDM group). All subjects then started or intensified OADs therapy and followed up for 91 days. Glycemic control was determined according to HbA1c at day 91 with HbA1c <7% considered good. RESULTS: The proportions of patients with good glycemic control after follow up for 91 days were 66.9% and 34.8% in NDM group and PDM group respectively. Logistic regression analysis showed that the change in GA at 28 days was the only predictor of good glycemic control in NDM patients (OR = 1.630, 95% CI 1.300-2.044, P < 0.001). In PDM patients, changes in GA at 28 days, CPI, baseline HbA1c, diabetic duration, and BMI were all independent predictors of good glycemic control (All P < 0.05). CONCLUSIONS: GA decline is a good predictor of future success in newly diagnosed patients. In patients intensifying therapy, beside GA decline, other individualized clinical characteristics should also be considered.

Voltage adjustment improves rigidity and tremor in Parkinson's disease patients receiving deep brain stimulation.

Deep brain stimulation of the subthalamic nucleus is recognized as the most effective treatment for moderate and advanced Parkinson's disease. Programming of the stimulation parameters is important for maintaining the efficacy of deep brain stimulation. Voltage is considered to be the most effective programming parameter. The present study is a retrospective analysis of six patients with Parkinson's disease (four men and two women, aged 37-65 years), who underwent bilateral deep brain stimulation of the subthalamic nucleus at the First Affiliated Hospital of Sun Yat-sen University, China, and who subsequently adjusted only the stimulation voltage. We evaluated motor symptom severity using the Unified Parkinson's Disease Rating Scale Part III, symptom progression using the Hoehn and Yahr scale, and the levodopa equivalent daily dose, before surgery and 1 and 2 years after surgery. The 2-year follow-up results show that rigidity and tremor improved, and clinical symptoms were reduced, while pulse width was maintained at 60 µs and frequency at 130 Hz. Voltage adjustment alone is particularly suitable for patients who cannot tolerate multiparameter program adjustment. Levodopa equivalent daily dose was markedly reduced 1 and 2 years after surgery compared with baseline. Our results confirm that rigidity, tremor and bradykinesia can be best alleviated by voltage adjustment. The trial was registered at ClinicalTrials.gov (identifier: NCT01934881).

Early versus Late Application of Subthalamic deep brain Stimulation to Parkinson's disease patients with motor complications (ELASS): protocol of a multicentre, prospective and observational study.

INTRODUCTION: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical treatment for Parkinson's disease (PD). However, there is currently no consensus on the best timing for this surgery. The aim of our study is to compare the therapeutic efficacy of bilateral STN DBS in patients with PD with early and late motor complications. METHODS AND ANALYSIS: 200 patients with PD will be enrolled in this multicentre, prospective, observational study, and will be followed up for 4 years. Patients with PD who meet the criteria for STN DBS surgery will be allocated to either the early stimulation group or the late stimulation group based on the duration of their motor complications. The primary outcome will be changes in quality of life from baseline to 4 years, measured using the 39-item Parkinson's Disease Questionnaire Summary Index. The secondary outcomes include changes in motor function measured using Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, self-reported experiences of daily living measured using MDS-UPDRS Part I B and Part II, good 'on' time recorded by the patients using a diary and safety profile of both groups. ETHICS AND DISSEMINATION: The study received ethical approval from the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. The results of this study will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT01922388; Pre-results.

Glycated albumin is superior to glycated hemoglobin for glycemic control assessment at an early stage of diabetes treatment: A multicenter, prospective study.

AIMS: This study was to determine whether serum glycated albumin (GA) was a better indicator of glycemic control than hemoglobin A1c (HbA1c) when starting a new treatment regimen for type 2 diabetes. METHODS: Newly diagnosed type 2 diabetes patients, or patients who had poor glycemic control with oral hypoglycemic agents, were enrolled at 10 hospitals in Beijing. Serum GA, HbA1c, fasting blood glucose (FBG), and C-peptide were assayed on Days 0, 14, 28, and 91 after treatment. RESULTS: Four hundred ninety-nine patients were enrolled. Mean FBG, GA and HbA1c decreased significantly in patients at Days 14, 28, and 91. In patients with improved glycemic control, the reduction of GA and HbA1c levels was 10.5±13.3% vs. 5.1±5.4% on Day 14, 16.0±13.4% vs. 9.0±7.0% on Day 28, and 18.0±16.7% vs. 18.3±9.4% on Day 91, respectively, compared with baseline values. Changes in GA on Day 14, 28 and 91 were all closely correlated with changes in HbA1c on Day 91. Change in GA on Day 14 was correlated with treatment effectiveness evaluated by HbA1c on Day 91. CONCLUSIONS: GA may be a useful marker for assessing glycemic control at an early stage of new diabetes treatment and assist in guiding adjustments to treatment and therapy.

[Effects of free fatty acids on insulin signaling proteins in rat islet cells].

AIM: To investigate whether free fatty acid impair insulin signaling proteins to inhibit insulin action in rat islet cells. METHODS: After rat islet cells were incubated with palmitate (0.25 mmol/L) or oleate (0.125 mmol/L) for 12 hours, 24 hours and 36 hours, western bolt was used to assess the protein abundance of cPKCalpha, Grb2 and FERK2. RESULTS: The protein content of cPKCalpha were significantly upregulated and the protein abundance of Grb2 and ERK2 was decreased comparing with control in rat islet cells after incubated with free fatty acids. CONCLUSIONS: Free fatty acids may inhibit insulin activity in rat islet cells through up-regulating the expression of cPKCalpha or down-regulating the expression of Grb2 and ERK2.