A new approach to overcoming resistance to immunotherapy: nanotechnology.

Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.

Timing of endoscopy for acute variceal bleeding in patients with cirrhosis (CHESS1905): A nationwide cohort study.

BACKGROUND: Endoscopy plays an important role in the management of acute variceal bleeding (AVB) in patients with cirrhosis. This study aimed at determining the optimal endoscopy timing for cirrhotic AVB. METHODS: Patients with cirrhosis with AVB across 34 university hospitals in 30 cities from February 2013 to May 2020 who underwent endoscopy within 24 hours were included in this study. Patients were divided into an urgent endoscopy group (endoscopy <6 h after admission) and an early endoscopy group (endoscopy 6-24 h after admission). Multivariable analysis was performed to identify risk factors for treatment failure. Primary outcome was the incidence of 5-day treatment failure. Secondary outcomes included in-hospital mortality, need for intensive care unit, and length of hospital stay. A propensity score matching analysis was performed. In addition, we performed an analysis, in which we compared the 5-day treatment failure incidence and the in-hospital mortality among patients with endoscopy performed at <12 hours and 12-24 hours. RESULTS: A total of 3319 patients were enrolled: 2383 in the urgent endoscopy group and 936 in the early endoscopy group. After propensity score matching, on multivariable analysis, Child-Pugh class was identified as an independent risk factor for 5-day treatment failure (HR, 1.61; 95% CI: 1.09-2.37). The incidence of 5-day treatment failure was 3.0% in the urgent endoscopy group and 2.9% in the early group ( p = 0.90). The in-hospital mortality was 1.9% in the urgent endoscopy group and 1.2% in the early endoscopy group ( p = 0.26). The incidence of need for intensive care unit was 18.2% in the urgent endoscopy group and 21.4% in the early endoscopy group ( p = 0.11). The mean length of hospital stay was 17.9 days in the urgent endoscopy group and 12.9 days in the early endoscopy group ( p < 0.05). The incidence of 5-day treatment failure in the <12-hour group was 2.3% and 2.2% in the 12-24 hours group ( p = 0.85). The in-hospital mortality was 2.2% in the <12-hour group and 0.5% in the 12-24 hours group ( p < 0.05). CONCLUSIONS: The data suggest that performance of endoscopy within 6-12 or within 24 hours of presentation among patients with cirrhosis with AVB led to similar treatment failure outcomes.

Antitumor therapy for breast cancer: Focus on tumor-associated macrophages and nanosized drug delivery systems.

BACKGROUND: In breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention. AIMS: This review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs. MATERIALS & METHODS: The existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment. RESULTS: TAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies. DISCUSSION: TAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs. CONCLUSION: TAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

Cost-effectiveness analysis of toripalimab for metastatic or recurrent triple-negative breast cancer.

Background: Toliparibizumab in combination with nab-paclitaxel (T+N) has excellent efficacy inmetastatic or recurrent triple-negative breast cancer (TNBC), but the optimal choice of sequence of therapy is unclear given the trade-offs between quality of life and cost. Cost-effectiveness analyses can quantify these tradeoffs, leading to more informed decisions. Our objective was to assess the societal cost-effectiveness of the T+N regimen for metastatic or recurrent TNBC. Methods: Clinical data were extracted from a multicenter, randomized, double-blind trial, TORCHLIGHT (NCT04085276). Patients were randomized into the T+N group or placebo plus nab-paclitaxel (P+N) group. 531 patients from 53 study locations were randomly assigned (T+N, n=353; P+N, n=178) into intend to treat (ITT) population; 200 and 100 patients, respectively had programmed death protein 1 (PD-L1) positive TNBC. A Markov model was established with a 21-day cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). Results: The cost differences were 47,538.3 CNY in ITT population (T+N, 143,725.67 CNY; P+N group, 96,187.37 CNY) and 29,258.84 CNY in PD-L1+ subgroup (T+N, 100,128.28 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs were 0.03409 in the ITT population (T+N, 0.55323 QALY; P+N, 0.51914 QALY) and 0.03409 in the PD-L1+ subgroup (T+N, 0.42327 QALY; P+N, 0.37628 QALY). The ICERs between T+N and P+N groups were 1,394,548.41 CNY/QALY in the ITT population and 622,663.98 CNY/QALY in the PD-L1+ subgroup. We also analyzed the cost-effectiveness of toripalimab could be received in the Chinese medical insurance catalog. If toripalimab could be reimbursed at an 80% rate, the cost differences were changed to 16,598.99 CNY in ITT population (T+N, 112,786.36 CNY; P+N group, 96,187.37 CNY) and 7,704.58 CNY in PD-L1+ subgroup (T+N, 78,574.03 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs remained unchanged. The ICERs between T+N and P+N groups were changed to 486,935.82 CNY/QALY in the ITT population and 163,962.96 CNY/QALY in the PD-L1+ subgroup. Sensitivity analyses indicated the stability of the model and the impact of utility. Conclusion: At current drug prices, the T+N group is not more cost-effective than the P+N group, but after incorporating toripalimab into medical insurance, the T+N group will be more cost-effective for patients with PD-L1+ metastatic or recurrent triple-negative breast cancer.

Treatment Strategies in Emergency Endoscopy for Acute Esophageal Variceal Bleeding (CHESS1905): A Nationwide Cohort Study.

Background and Aims: Emergency endoscopy is recommended for patients with acute esophageal variceal bleeding (EVB) and their prognosis has improved markedly over past decades due to the increased specialization of endoscopic practice. The study aimed to compare outcomes following emergency endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) in cirrhotic patients with acute EVB. Methods: Cirrhotic patients with acute EVB who underwent emergency endoscopy were retrospectively enrolled from 2013 to 2020 across 34 university hospitals from 30 cities. The primary outcome was the incidence of 5-day rebleeding after emergency endoscopy. Subgroup analysis was stratified by Child-Pugh class and bleeding history. A 1:1 propensity score matching (PSM) analysis was performed. Results: A total of 1,017 and 382 patients were included in EIS group and EVL group, respectively. The 5-day rebleeding incidence was similar between EIS group and EVL group (4% vs. 5%, P = 0.45). The result remained the same after PSM (P = 1.00). Among Child-Pugh class A, B and C patients, there were no differences in the 5-day rebleeding incidence between the two groups after PSM (P = 0.25, 0.82, and 0.21, respectively). As for the patients with or without bleeding history, the differences between EIS group and EVL group were not significant after PSM (P = 1.00 and 0.26, respectively). Conclusion: The nationwide cohort study indicates that EIS and EVL are both efficient emergency endoscopic treatment strategies for acute EVB. EIS should not be dismissed as an economical and effective emergency endoscopic treatment strategy of acute EVB. ClincialTrials.gov number NCT04307264.

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

BACKGROUND & AIMS: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD. METHODS: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination. RESULTS: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8-28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained. CONCLUSIONS: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD. LAY SUMMARY: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.

Abdominal skin inflammation as an initial symptom of a perforating gastric foreign body: A case report.

RATIONALE: Foreign bodies are frequently ingested, but only approximately 1% of them cause perforation. Perforations in the lesser curvature of the stomach are exceedingly rare. Here, we report a case of gastric perforation in the lesser curvature caused by a foreign body. The patient presented to the clinic complaining of abdominal skin swelling and reddening with upper abdominal discomfort as the initial symptoms. PATIENT CONCERNS: An 83-year-old female presented with a mass in the middle of the epigastrium for 10 days. Physical examination found an apparent local tenderness and inflammatory mass in the upper abdominal wall. Her body temperature was normal (37.5°C) and the white blood cell count was elevated (8.12 × 10/L [reference value 3.5-9.5 × 10/L]). DIAGNOSES: The ultrasound examination of the abdomen revealed a 4 cm strip-like hyperechoic object entangled in the muscles of the abdominal wall. The computed tomography scan revealed a thin strip of bone-like hyperdense shadow. Intraoperative findings showed a sharp fishbone protruding from the lesser curvature of the stomach into the abdominal cavity, part of which remained in the gastric cavity. The postoperative pathological report revealed chronic suppurative inflammation with abscess and sinus canal formation. INTERVENTIONS & OUTCOMES: The patient underwent a gastric foreign body removal with partial gastrectomy. Anti-inflammatory treatment post-surgery rapidly relieved the patient's symptoms of discomfort in the upper abdomen. At the 1-month follow-up, the patient showed no discomfort in the upper abdomen and the inflammatory mass was no longer present. LESSONS: A foreign body had penetrated through the lesser curvature of the stomach, an area with a flat gastric wall, which occurs infrequently. In such cases, computed tomography is the gold standard for diagnosis of foreign bodies in the digestive tract. Ultrasound can also be used as a supplemental diagnostic technique. It is recommended that people who wear dentures should exercise caution while eating, especially when the food contains bones.

Long-term response to second-line afatinib treatment for advanced squamous cell carcinoma non-small cell lung cancer: a rare case report.

The ErbB family is composed of four cell membrane receptors: ErbB-1 (epidermal growth factor receptor or human epidermal growth factor receptor [HER]1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). All members of the ErbB family play a critical role in regulating cell growth, proliferation and migration of tumours. Afatinib is an irreversible ErbB family inhibitor that is approved for second-line treatment of advanced squamous cell carcinoma (SqCC) that has progressed following platinum-based chemotherapy. Here we describe the case of a 56-year-old male Chinese patient with SqCC who had previously failed chemotherapy and radiotherapy and was subsequently enrolled in the LUX-Lung 8 study. The patient responded well to treatment with afatinib (40 mg/day). His disease stabilised after 8 weeks and a complete response was achieved after 12 weeks of treatment. Follow-up of this patient is ongoing; he is still alive and has not experienced disease progression in the 7 years since initiation of afatinib. The long-term response and prolonged survival in this patient provide additional evidence for second-line treatment with afatinib in patients with SqCC.

[PROCEDURE OF RECONSTRUCTING TRANSVERSE ARCH OF THE FOREFOOT BY TRANSFERING TENDONS FOR CORRECTING HALLUX VALGUS].

OBJECTIVE: To explore the effectiveness of the procedure of reconstructing the transverse arch of the forefoot by anastomosing adductor hallucis and abductor hallucis tendons in correcting hallux valgus. METHODS: A retrospective analysis was made on the clinical data from 28 patients (40 feet) with hallux valgus treated with the procedure of reconstructing the transverse arch of the forefoot by anastomosing adductor hallucis and abductor hallucis tendons between January 2010 and January 2014. There were 3 males (6 feet) and 25 females (34 feet), with an average age of 51.7 years (range, 20-71 years). The unilateral foot was involved in 16 cases and bilateral feet in 12 cases. The mean disease duration was 8.9 years (range, 1-30 years). All the cases had pain of the first metacarpophalangeal joint; 22 feet had collapsed transverse arch of the forefoot combined with plantar callus, and 8 feet had collapsed transverse arch of the forefoot combined with hammer toe deformity. American Orthopaedic Foot and Ankle Society (AOFAS) score was 59.07 +/- 8.49. Preoperative X-ray showed that the hallux valgus angle (HVA) was (33.68 +/- 8.10) degrees, and the intermetatarsal angle (IMA) was (15.60 +/- 4.07) degrees. According to classification of the hallux valgus by Mann, 9 feet were rated as mild, 23 feet as moderate, and 8 feet as severe. RESULTS: Superficial infection of incision occurred in 1 case (1 foot) after surgery, and healing by first intention was obtained in the others. Two cases (3 feet) had numbness in the toes. All of 28 cases were followed up from 6 months to 4 years (1.8 years on average). Based on the AOFAS score, the results were excellent in 24 feet, good in 9 feet, fair in 4 feet, and poor in 3 feet, and the excellent and good rate was 82.5%. At last follow-up, the HVA, IMA, and AOFAS score were (15.10 +/- 5.28), (9.05 +/- 2.42) degrees, and 86.03 +/- 7.45 respectively, showing significant differences compared with preoperative ones (P=0.00). The collapsed transverse arch of the forefoot was recovered to some extent, plantar callus disappeared (14 feet), or decreased (8 feet). Recurrence of hallux valgus deformity was observed in 2 cases (3 feet) at 2 and 3 months after surgery respectively, and no hallux varus was found. CONCLUSION: This procedure not only can effectively reduce the increased hallux valgus angle, and narrow the angle between the 1st and 2nd metatarsal, but also can relocate the sesamoid system, reconstruct the transverse arch of the forefoot, and effectively restore the physiological anatomy structure and biological function of the forefoot.