[The ninth edition of TNM staging for lung cancer: precise staging for precise diagnosis and treatment].

The ninth edition of TNM staging for lung cancer has been announced at the 2023 World Lung Cancer Congress and implemented from January 1, 2024. The focus of the ninth TNM staging change is dividing N2 into N2a and N2b, as well as M1c into M1c1 and M1c2. Although the T staging has not changed, it has played an important role in verifying the eighth edition of the T staging. The subdivision of stage N2 has led some patients with ⅢA of the eighth edition to experience ascending or descending stages, which will more accurately help to assess the condition and prognosis of patients with mediastinal lymph node metastasis, as well as the design of related clinical studies. Modifying the M1c staging will help define oligometastasis and explore new treatment models in the future. The ninth edition of the TNM staging system provides a more detailed division of different tumor loads, but there is no clear explanation for the staging of lung cancer after neoadjuvant therapy. Further data analysis is needed, and it is expected to be answered in the tenth edition of TNM staging.

[Gene mutation profiles and clinicopathological features of patients with non-small cell lung cancer harboring KRAS G12C mutation: a single-center retrospective study].

Objective: To accurately screen non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation and to evaluate their clinicopathological features, prognostic factors and current treatment status. Methods: A total of 19 410 NSCLC cases diagnosed at the Department of Pathology of Shanghai Chest Hospital, Shanghai, China from January 2018 to September 2021 were retrospectively reviewed, and the cases with KRAS gene mutation detected by next-generation sequencing were included. The clinicopathological and genetic mutation data of these cases were collected and analyzed. Results: A total of 1 633 (8.4%) NSCLC patients carried a KRAS gene mutation, among whom G12C was the most frequent (468 cases, 28.7%) mutant subtype. The mutation was more commonly found in males (414/468, 88.5%), patients with a history of smoking (308/468, 65.8%), and patients with a pathological type of invasive adenocarcinoma (231/468, 49.4%). The most common co-mutated genes in KRAS G12C mutant NSCLC were TP53 (52.4%, 245/468), STK11 (18.6%, 87/468) and ATM (13.2%, 62/468). The proportion of PD-L1 expression (≥1%) in KRAS G12C mutant NSCLC was significantly higher than that in patients without G12C mutation [64.3% (90/140) vs. 56.1% (193/344), P=0.014]. Immune checkpoint inhibitors (ICIs) treatment significantly prolonged progression-free survival (PFS) in NSCLC patients (10.0 months vs. 5.0 months, P=0.011). However, combination of chemotherapy and ICIs with anti-angiogenesis inhibitors or multi-target inhibitors did not significantly improve PFS in patients with KRAS G12C mutant NSCLC (P>0.05). Patients with KRAS G12C mutation NSCLC treated with ICIs and KRAS G12C patients with TP53 mutation had significantly longer median PFS than those with STK11 mutation (9.0 months vs. 4.3 months, P=0.012). Conclusions: Patients with KRAS G12C mutant NSCLC have relatively higher levels of PD-L1 expression and can benefit from ICIs treatment. The feasibility of chemotherapy, ICIs therapy and their combination needs further investigation.

[Diagnosis and treatment strategies of 56 cases of middle ear myoclonus].

Objective: To analyze the clinical characteristics and treatment of middle ear myoclonus. Methods: Fifty-six cases of middle ear myoclonus were enrolled in Shandong Provincial ENT Hospital, Shandong University from September 2019 to August 2021, including 23 males and 33 females. The age ranged from 6 to 75 years, with a median age of 35 years; Forty-seven cases were unilateral tinnitus, nine cases were bilateral tinnitus. The time of tinnitus ranged from 20 days to 8 years. The voice characteristics, inducing factors, nature (frequency) of tinnitus, tympanic membrane conditions during tinnitus, audiological related tests, including long-term acoustic tympanogram, stapedius acoustic reflex, pure tone auditory threshold, short increment sensitivity test, alternate binaural loudness balance test, loudness discomfort threshold, vestibular function examination, facial electromyography, and imaging examination were recorded. Oral carbamazepine and/or surgical treatment were used. The patients were followed up for 6-24 months and the tinnitus changes were observed. Results: Tinnitus was diverse, including stepping on snow liking sound, rhythmic drumming, white noise, and so on. The inducing factors included external sound, body position change, touching the skin around the face and ears, speaking, chewing and blinking, etc. Forty-four cases were induced by single factor and 9 cases were induced by two or more factors. There was no definite inducing factor in 1 case. One patient had tinnitus with epilepsy. One case of traumatic facial paralysis after facial nerve decompression could induce tinnitus on the affected side when the auricle moved. Tympanic membrane flutter with the same frequency as tinnitus was found in 12 cases by otoscopy, and the waveform with the same frequency as tinnitus was found by long-term tympanogram examination. There were 7 patients with no tympanic membrane activity by otoscopy, the 7 cases also with the same frequency of tinnitus by long-term tympanogram examination, but the change rate of the waveform was faster than that of the patients with tympanic membrane flutter. All patients with tinnitus had no change in hearing. One case of tinnitus complicated with epilepsy (a 6-year-old child) was treated with antiepileptic drug (topiramate) and tinnitus subsided. One case suffered from tinnitus after facial nerve decompression for traumatic facial paralysis was not given special treatment. Fifty-four cases were treated with oral drug (carbamazepine), of which 10 cases were completely controlled and 23 cases were relieved; 21 cases were invalid. Among the 21 patients with no effect of carbamazepine treatment, 8 patients were treated by surgery, 7 patients had no tinnitus after surgery, 1 patient received three times of operation, and the third operation was followed up for 6 months, no tinnitus occurred again. The other 13 cases refused the surgical treatment due to personal reasons. Conclusions: Middle ear myoclonus tinnitus and the inducing factors manifestate diversity. Oral carbamazepine and other sedative drugs are effective for some patients, and surgical treatment is feasible for those who are ineffective for medication.

[The surgical management of benign tumors of the lateral skull base with intracranial invasion: experience from a single centre over ten years].

Objective: To investigate the clinical features, pathological types, imaging features, and surgical strategies of lateral skull base benign tumors with intracranial invasion. Methods: From January 2011 to March 2021, 36 patients of lateral skull base benign tumors with intracranial invasion were included in this retrospective study. Among the 36 patients, 14 cases were male, 22 cases were female, the aged range from 20-67, with the median age of 48. The clinical manifestations, characteristic imaging findings, pathological types, surgical approach selection, and prognosis were analyzed. Results: 36 cases of lateral skull base tumors with intracranial invasion were all accepted surgeries. 23 cases were neurogenic tumors, facial nerve tumors (n=8), neurogenic tumors in jugular foramen with unknown origin(n=6), hypoglossal schwannoma (n=3), transotic intralabyrinthine schwannoma (n=3), vestibular schwannoma involving the middle ear(n=2), vagal nerve schwannoma(n=1). Other types of tumors included meningioma (n=10) and paraganglioma (Di 1 or 2,n=3). Different pathological types of tumors had different clinical manifestations and imaging manifestations. Sixteen cases were subjected to primary resection, while, other 20 cases underwent staged operation. Among the patients with staged operation, 10 patients had completed the second stage operation, five patients were waiting for the second stage operation, the other five patient's residual intracranial tumor were significantly reduced and the space between tumor and brain tissues widened after the first stage operation, so, the following up with "wait and scan"policy was suggested. The total resection rate of tumors was related to the pathological nature, in which neurogenic tumors were 15/17, and meningiomas were 5/8. The main postoperative complications were cerebrospinal fluid leakage and infection in the operation area. There were two cases of postoperative intracranial infection, and three cases of cerebrospinal fluid leakage occurred in non staged operation cases. Conclusions: Lateral skull base tumors with intracranial invasion are rare. The most common pathological type is schwannoma, followed by meningioma and paraganglioma. For this type of tumor, if there is infection in the operation area and neck invasion is large, it is suggested to choose staged surgery, which can reduce the risk of intracranial infection and the incidence of cerebrospinal fluid leakage. Staged surgery strategy can also reduce the difficulty of second stage surgery, so the operation is much safer than non staged surgery.

Expression of miR-207 in renal tissue of renal fibrosis rats and its correlation analysis with protein expression of TGF-ß1 and Smad3.

OBJECTIVE: This study was designed to analyze the expression of miR-207 in renal tissue of renal fibrosis rats and its correlation with the protein expression of TGF-ß1 and Smad3. MATERIALS AND METHODS: Rat models with renal fibrosis were established via unilateral ureteral obstruction (UUO). Then, the expression levels of miR-207, TGF-ß1 and Smad3 in renal tissue of rats were intervened by over-expression vector miR-207 mimic, miR-207 inhibitor and TGF-ß/Smad3 signal SIS3 free base, and the effect and mechanism of action of miR-207 on renal fibrosis were analyzed. RESULTS: In UUO models established in this study, the expression levels of fibrosis related factors TGF-ß1, Smad3, Smad2, α-SMA, BMP-7, MMP7 and MMP9 were elevated, and staining results showed that evident fibrosis occurred in renal tissue of rats. Moreover, we also found that the miR-207 expression increased in UUO model rats. After inhibiting miR-207 expression, their degree of renal fibrosis also reduced significantly, and the expression levels of TGF-ß1, Smad3, Smad2, α-SMA, BMP-7, MMP7 and MMP9 were inhibited. Besides, miR-207 had a positive correlation with TGF-ß1/Smad3 expression. We designed a group of rats, and found that while miR-207 expression was up-regulated, TGF-ß1/Smad3 signals were inhibited, and compared with those with up-regulation of miR-207 expression, the severity of renal fibrosis reduced significantly, and the expression of other fibrosis indicators Smad2, α-SMA, BMP-7, MMP7 and MMP9 also reduced dramatically. CONCLUSIONS: The miR-207 expression in renal tissue of rats with renal fibrosis increased, which was positively correlated with TGF-ß1/Smad3, and miR-207 could promote the progression of renal fibrosis through TGF-ß1/Smad3 signals.

Effect of atorvastatin on expression of TLR4 and NF-κB in stroke rats and its protective effect on brain.

OBJECTIVE: This study aimed at investigating the effect of atorvastatin on the expression of TLR4 and NF-κB in brain tissue of stroke rats and its protective effect on brain. MATERIALS AND METHODS: Sixty SD rats were selected. The control group (n=20) was raised without treatment. MCAO was used in the experimental group (n=20) and model group (n=20) for stroke modeling. The experimental group was treated with atorvastatin intragastric administration, while the model group received no treatment. The blood lipid level was detected by a full-automatic biochemical analyzer. The expression levels of TLR4 and NF-κB proteins were detected by Western-Blot (WB), and the mRNA expression of NF-κB and TLR4 in brain tissues was detected by real-time quantitative fluorescence (qtPCR). The neurological deficit score was performed. RESULTS: TC, TG, LDL-C in blood lipid indexes of the experimental group and the model group were remarkably higher than those of control group, while HDL-C was remarkably lower than that of control group (p<0.05). After treatment, TC, TG, LDL-C in the experimental group gradually decreased, while HDL-C concentration gradually increased (p<0.05). The expression of TLR4 and NF-κB protein in the experimental group was significantly lower than that in the model group (p<0.01) but significantly higher than that in the control group (p< 0.01). The expression of TLR4 and NF-κB mRAN in the experimental group was also considerably lower than that in the model group (p<0.01) but higher than that in the control group (p<0.01). After atorvastatin treatment, the neurological deficit score of the experimental group was remarkably lower than that of the model group (p<0.001). CONCLUSIONS: Atorvastatin can effectively reduce the expression of TLR4 and NF-κB in brain tissue of stroke rats, and has a certain protective effect on cerebral nerve function, which is expected to be the first choice for stroke treatment in the future.

The single nucleotide polymorphism rs11643718 in SLC12A3 is associated with the development of diabetic kidney disease in Chinese people with type 2 diabetes.

AIMS: To examine the association between 24 literature-based single nucleotide polymorphisms and diabetic kidney disease in Chinese people with type 2 diabetes. METHODS AND RESULTS: Twenty-four candidate diabetic kidney disease-susceptible single nucleotide polymorphisms were genotyped in 208 participants with type 2 diabetes and diabetic kidney disease and 200 participants with type 2 diabetes without diabetic kidney disease (case and control groups, respectively), together with 206 healthy participants using MassARRAY. Rs11643718 in the SLC12A3 gene was associated with diabetic kidney disease in the recessive model after adjusting for confounding factors, such as age and gender (adjusted odds ratio 2.056, 95% CI 1.120-3.776; P = 0.020). Meta-analyses further confirmed the association (P = 0.002). In addition, participants with the GG genotype had worse renal function and more albuminuria than those with the AA+AG genotype (P < 0.05). Renal section immunohistochemistry was conducted in participants with type 2 diabetes, diabetic kidney disease and AA+AG or GG genotypes and in participants with glomerular minor lesions. Together with data from the Nephroseq database, it was shown that the abundance of SLC12A3 was reduced in patients with the GG genotype, while elevated expression of SLC12A3 was associated with better renal function. In addition, rs10951509 and rs1345365 in ELMO1, which were determined to be in high linkage disequilibrium by SHEsis software, were also associated with diabetic kidney disease (adjusted P = 0.010 and 0.015, respectively). CONCLUSIONS: The G allele and GG genotype of SLC12A3 rs11643718 are associated with the development of diabetic kidney disease in a Chinese population with type 2 diabetes.

[Consistency of ALK Ventana-D5F3 immunohistochemistry interpretation in lung adenocarcinoma among Chinese histopathologists].

Objective: To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy. Methods: This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer's protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS. Results: There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109). Conclusion: There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

Comparison of primary arthrodesis versus open reduction with internal fixation for Lisfranc injuries: Systematic review and meta-analysis.

Objective: Multiple studies have compared primary arthrodesis versus open reduction with internal fixation (ORIF) for surgical treatment of fractures of the Lisfranc joint, but their results have been inconsistent. Therefore, the present systematic review and meta-analysis was performed to compare the clinical efficacy of arthrodesis versus ORIF for the treatment of Lisfranc injuries. Methods: Through searching the Embase, PubMed, PMC, CINAHL, PQDT, and Cochrane Library databases (from July 1998 to July 2018), we identified five case-controlled trials and two randomized controlled trials that compared the clinical efficacy of primary arthrodesis and ORIF for treating Lisfranc injuries. The extracted data were analyzed using Review manager 5.3 software. Results: Through comparisons of data for primary arthrodesis and ORIF groups, we found no significant differences in the anatomic reduction rate, revision surgery rate, and total rate of complications between the different treatment approaches. However, arthrodesis was associated with a significantly better American Orthopedic Foot and Ankle Society (AOFAS) score, return to duty rate, and visual analog scale score with a lower incidence of hardware removal compared with ORIF. Conclusions: For the treatment for Lisfranc injuries, primary arthrodesis was superior to ORIF based on a higher AOFAS score, better return to duty rate, lower postoperative pain, and lower requirement for internal fixation removal. Further evidence from future randomized controlled trials with higher quality and larger sample sizes is needed to confirm these findings.

[A cross-sectional study on the association between frailty and muscular performances in hospitalized elder patients with coronary artery disease].

Objective: To explore the association between frailty and muscle performances of hospitalized elder adults with coronary artery disease. Methods: A total of 122 hospitalized patients aged 65-85 years old with coronary artery disease from Department of Geriatrics and Cardiology, Peking Union Medical College Hospital between December 2017 and March 2018 were enrolled in the study. A comprehensive geriatric assessment was performed to evaluate existing comorbidity and geriatric syndromes of the patients. Frailty was assessed using the Clinical Fraity Scale. The patients were classified as frail and non-frail, according to the scale. Muscle performances were assessed using grip strength, gait speed, etc. Whole body and appendicular skeletal muscle mass was detected with bioelectrical impedance analysis in patients with reduced grip strength or slowed gait speed. Appendicular skeletal muscle index (ASMI) was calculated. Results: Among all subjects, 28 were with frailty (23.0%) and 94 were without (77.0%). The frail patients were older [(76.7±5.4) years vs. (72.2±5.6)years], had higher Charlson comorbidity index [2.0(1.0,2.75)vs. 1.0(0,2.0)], and higher proportion of malnutrition (14.29% vs. 1.06%), urinary incontinence (39.29% vs. 15.96%), using walking-aid (28.57% vs. 6.38%), and more kinds of taken drugs (8.1±3.0 vs. 6.6±2.7), than the non-frail patients. Prealbumin levels [(207.8±60.0)mg/L vs.(234.3±45.4)mg/L] were lower, and highly sensitive C-reactive protein levels [(5.89±9.57)mg/L vs.(1.89±2.49)mg/L] were higher in the frail patients than in the non-frail patients (all P<0.05). Compared with non-frail patients, the frail patients had poorer grip strength [(19.67±7)kg vs.(29.23±8.29)kg] and slower gait speed [(0.54±0.2)m/s vs.(0.91±0.22)m/s] (all P<0.001). Spearman rank correlation analyses showed that grip strength was positively correlated with the appendicular skeletal muscle mass(r=0.811), whole body skeletal muscle mass(r=0.74) and the ASMI (r=0.783), respectively. Conclusions: The incidence of frailty among hospitalized older adults with coronary artery disease is high. Poor muscle performances were common in these patients. Assessment of frailty and muscle performances can help to evaluate the overall function of older adults with cardiovascular disease in a comprehensive way.

Protective effects of 8-MOP on blood-brain barrier via the Nrf-2/HO-1 pathway in mice model of cerebral infarction.

OBJECTIVE: To explore the effect of 8-MOP on the blood-brain barrier in mice model of cerebral infarction and the underlying mechanism. MATERIALS AND METHODS: Middle cerebral artery occlusion (MCAO) model was established to induce permanent cerebral infarction. The neurological function was observed and scored by the modified longa score method after model establishment. Besides, the water content of brain tissue was measured by the standard dry weight method. Evans blue exudation rate was used to evaluate the effect of 8-MOP on the permeability of the blood-brain barrier. Western-blot and quantitative polymerase chain reaction (qPCR) were used to detect the expression of MMP-9, claudin-5, vascular endothelial growth factor (VEGF), as well as the NFE2-related factor 2 (Nrf-2)/hemeoxygenase 1 (HO-1) pathway. RESULTS: 8-MOP could reduce the neurological deficit scores in a dose-dependent manner, thereby reducing cerebral edema. After 8-MOP treatment, the expression of MMP-9 decreased in ischemic brain tissue, whereas the expression of claudin-5, VEGF, and GFAP increased, suggesting that the blood-brain barrier ultrastructure was improved. In addition, the expression of Nrf-2 and HO-1 decreased after the model establishment of cerebral infarction. However, the expression of Nrf-2 and HO-1 increased in ischemic brain tissue after 8-MOP treatment. CONCLUSIONS: 8-MOP may protect the blood-brain barrier via the Nrf-2/HO-1 pathway.

Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

[Simultaneous triple semicircular canal plugging and cochlear implantation in advanced Meniere's disease].

Objective: To evaluate the feasibility of combining simultaneous triple semicircular canal plugging (TSCP) and cochlear implantation (CI) to treat vertigo and hearing loss in advanced Meniere's disease(MD) patients, so as to provide an alternative surgical procedure for treating this disorder. Methods: Data from seven patients, who were referred to our hospital and diagnosed with unilateral MD strictly meeting the criteria issued by Chinese Academy of Otolaryngology-Head and Neck Surgery Committee (2006), from Jan. 2015 to Jan. 2016, were retrospectively analyzed in this work. Seven patients, in whom the standardized conservative treatment had been given for at least one year and frequent vertigo still occurred, underwent simultaneous TSCP and CI under general anesthesia via mastoid approach. Postoperative follow-up time was more than six months. Vertigo control and auditory function were measured. Pure tone audiometry, speech perception scores, caloric test, head impulse test (HIT), and vestibular evoked myogenic potential (VEMP) were performed for evaluation of audiological and vestibular functions. Results: All patients had bilateral severe sensorineural hearing loss preoperatively. One side hearing loss was due to MD and another side was due to reasons including sudden sensorineural hearing loss, mumps and other unknown reason. The total control rate of vertigo in seven MD patients was 100.0% in the six-month follow-up, with complete control rate of 85.7% (6/7) and substantial control rate of 14.3% (1/7). Improved hearing threshold and speech perception scores were observed in all study participants. Postoperative average aided hearing threshold was 32.5 dBHL, the average monosyllabic word score was 42.6% and speech perception scores of sentences tested in quiet was 52.3%. Tinnitus improved in five cases, and no significant change in two patients. Post-operatively, all patients suffered from temporary vertigo and balance disorders. Vertigo was disappeared in all patients within 3-5 days, while, an average recovery time of balance disorders was 19.7 days. Six months after treatment, loss of semicircular canal function by caloric test was found in the operation side of all patients and no change in cVEMP or oVEMP test was noted. All patients had no facial paralysis, cerebrospinal fluid leakage, and other complications. Conclusions: A combined approach of TSCP and CI which could control vertigo effectively and improve hearing loss and tinnitus represents an effective and safe therapy for some advanced MD patients.

[Primary biliary cholangitis and bile acid metabolism].

Primary biliary cholangitis (PBC) is an immune-mediated cholestatic liver disease of unknown pathogenesis. The research on immunologic injury in the past helps us to understand more about this disease, but there are still many problems and challenges in the research on PBC. With a focus on the cholestatic features of PBC, this article reviews the research advances in bile acid metabolism in the field of PBC, in order to provide new thoughts for future research.