Comparative efficacy and safety of anti-PD-1 therapies used in metastatic colorectal cancer: a systematic review and network meta-analysis

Objective: Systemic studies on anti-PD-1 therapy in patients with metastatic colorectal cancer (mCRC) with microsatellite instability or mismatch repair defects are lacking. We aimed to summarize the evidence regarding the efficacy and safety of pembrolizumab, nivolumab, ipilimumab, and tislelizumab in mCRC. Methods: Network meta-analyses (NMAs) can provide comparative efficacy and safety data for clinical decision-making. In this NMA, eligible publications from PubMed, EMBASE, Web of Science, and Cochrane Library from 2016 to April 2023 were identified through a systematic literature review. Literature screening and data extraction were performed according to established criteria. The quality of the literature was evaluated using the Cochrane risk of bias tool, and statistical analysis was performed using Revman5.4 and R language. The main outcome indicators, DCR, ORR, PFS, and OS, were used to evaluate the effectiveness of the drugs, and the main outcome indicators AE and SAE were used to evaluate the safety of each program. Results: Fifteen studies with a sample size of 798 patients were included. In terms of effectiveness, the disease control rate DCR of PD-1 inhibitors was 0.727[95% CI:0.654-0.794]; objective response rate ORR was 0.448[95% CI:0.382-0.514]; and the 1-year progression-free survival rate was 0.551[95% CI:0.458-0.642]. The 1-year overall survival rate was 0.790[95% CI:0.705-0.865]. The adverse events associated with anti-PD-1 were 0.567[95% CI:0.344-0.778] in terms of safety. The total incidence of grade 3 or higher adverse events was 0.241[95% CI:0.174-0.313]. In the subgroup analysis results, the incidence of DCR in the nivolumab + ipilimumab group was 0.826[95% CI:0.780-0.869], the ORR was 0.512[95% CI:0.377-0.647], and the PFS was 0.668[95% CI:0.516-0.804]. The incidence of AE was 0.319 [95% CI:0.039-0.700] and SAE was 0.294 [95% CI:0.171-0.433]... (AU)

Sun-Cross Running Suture Combined with Transverse to Longitudinal Skin Closure to Correct Severe Inverted Nipple.

BACKGROUND: Inverted nipple deformity presents an unsatisfactory appearance that may induce an unpleasant sex life, but can also be associated with psychological discomfort and increased the functional problems, such as local irritation and inflammation. METHODS: Multiple techniques have been used to correct inverted nipples, but they mostly lead to different problems such as deficiency of the nerve or duct, recurrence of the inverted nipple, and hypopigmented scars in the areola. To minimize complications and maintain the stability of the reconstructed nipple, we presented a minimal incision technique that designed four 3-mm-sized horizontal microincisions, which ran a sun-cross through the periphery and the core of the nipple to push the nipple together, then a vertical suture ran longitudinal to close the transverse incision to stabilize the projection. RESULTS: This technique was performed in 71 patients classified as grade II or III of the inverted nipples, comprising 53 congenital cases and 18 patients with acquired deformity. Thirty-four patients had bilateral inverted nipples, and 37 patients had unilateral inverted nipple. During a mean follow-up period of 15 months, 70 corrected nipples remained raised without recurrence, and one nipple was found retracted at the outpatient clinic after 3 months. There were no serious complications associated with surgery regarding nipple necrosis, seven patients got temporary swelling, two patients got infected after touching water, three patients got extravasated blood, eight patients indicated that they touched scar under the nipple, and two patients reflected nipple dysesthesia. In the 15 months follow-up, the patients with Grade II nipple inversion maintained a nipple average height of 9.54 ± 0.95, and the patients with Grade III nipple inversion maintained a nipple average height of 9.19 ± 1.09, and 86.63% of patients were satisfied with their results. CONCLUSION: This is a simple, safe, effective and reliable technique that should be considered, providing sustained results over the long-term follow-up period with a high rate of stable eversion and low incidence of ischemia, necrosis, scarring and dysesthesia. The vertical scar of the transverse incision closure leads to an esthetic appearance without apparent scarring and minimizes the risk of an altered nipple sensation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Effect of medication therapy management on discharged patient with Ulcerative Colitis with initial stage biotherapy: a randomized study

Purpose: The aim of this study was to explore the effects of medication therapy management in improving perception, medication adherence, and disease control in UC patients with first-stage of biotherapy. Subjects and Methods: A total of 120 patients with UC who received first-stage biotherapy participated in this study. The patients were divided into MTM group and CFU group. Both groups received three times follow-up, which were carried out at first, third, and sixth discharged month, Group A was followed with the MTM method, and Group B received conventional follow-up. MDRKT was used to assess patient perception, adherence to treatment was assessed by MMSA-8, and we also explored disease control and patient satisfaction. Results: A total of 116 patients completed the survey, the MTM group showed a significant improvement in perception, 84.2% of patients can correctly handle ADEs and 82.5% of patients knew what to do when they leak medication, 87.8% of patients in the MTM group had better adherence than 71.2% in the CPU group (P<0.05). The evaluation of disease control showed that 56.1% of patients in the Group A were in remission which was significantly higher than 32.2% in the Group B (P<0.05). Furthermore, the result of the questionnaire survey showed that perception, ADE, self-management, anxiety, and satisfaction were better in the MTM group than in the CPU group (P<0.05). Conclusion: The MTM group was effective in improving medication adherence, perception, and satisfaction in the patient with ulcerative colitis treated with first-stage biotherapy, and the disease control significantly improved (AU)

Giant breast phyllodes tumor with silent thromboembolism: A case report.

BACKGROUND: Phyllodes tumor (PT) is a solid fibroepithelial breast lesion with proliferation of stromal and epithelial elements, usually presents with a rapidly expanding feature. Venous thromboembolism (VTE) have been reported to increase the burden in terms of mortality and morbidity of malignant tumor, and associate with worsened survival. However, benign PTs with silent thromboembolism that have not yet been reported, we report an unusual case of massive benign PT that grew on the left side of the breast in a cauliflower-shaped form and presented severe chronic blood loss and deep VTE. CASE: A 37-year-old woman with uncontrolled pain presented a rapidly enlarging left breast mass, measuring approximately 30 × 20 × 15 cm3 that first started 25 years ago. color Doppler ultrasound showed a large mass lesion on the left breast and deep VTE, several enlarged lymph nodes in the left axilla and mediastinum, which presented a malignant character. However, the biopsies of the mass did not show evidence of malignancy and the pathology result was considered to be benign PT. The patient was treated with an inferior vena cava and anticoagulation, the operation was arranged according to the surgical procedure, the patient recovered very well after mastectomy. CONCLUSION: This case is unique in that the giant breast mass presented with malignant character, was eventually pathologically confirmed to be benign PT, and it's rare that the benign tumor accompanied with silent thromboembolism. This finding describes the atypia features of giant benign PT and reminds the surgeon to consider the factor of VTE and risk when encountering ulcerative benign breast tumor and avoid excessive treatment.

Step-by-Step Method Combined with Simulation-Enhanced Learner Outcomes in Minimally Invasive Breast Surgery Education.

Purpose: Traditional standardized training in ultrasound-guided minimally invasive breast surgery (UMIBS) focused on lecture-based learning (LBL) resulted in students' insufficient analysis, limited spatial visual conversion ability, and poor practical application. This study examined the effects of the step-by-step (SBS) method combined with a simulation model in UMIBS education. Subjects and Methods: A total of 84 residents participated in this study. The residents were divided into the SBS group (experience group, n=42) and the LBL group (control group, n=42), and the same teacher taught the two groups to ensure a comparable result. Based on the pork simulation model, two experts evaluated student performance scores, and the total time taken by each student was also counted. The participants were surveyed with 7 questions after the training, and each answer was assigned a score of 1, 2 or 3 to compare the participants' satisfaction. Results: The average value of the surgical skills for SBS group were significantly higher than LBS group, which was 82.8±4.4 and 72.7±4.0 (t=4.27, P<0.001), the time spend of neoplasm localization by the experience group was significantly less than the control group, which was 17.9±1.6 and 20.9±1.2 secs, (t=1.58, P<0.001), and there were significant differences in puncture accuracy and excision integrity between the two groups (P<0.05). In addition, the results of the questionnaire survey showed that learning interest, surgical ability and satisfaction were better in the SBS group than in the LBS group (P<0.05), and there were no significant differences in clinical thinking and learning pressure between the two groups. Conclusion: The SBS teaching method may help to improve the surgical skills and learning interest, as well as reduce adverse reactions and cultivate clinical thinking of the students in UMIBS training. Future studies could consider multicenter clinical research to further confirm the practicality of this teaching method and reduce the risk of deviation.

Relationship between maternal heavy metal exposure and congenital heart defects: a systematic review and meta-analysis.

Congenital heart defects (CHDs) are one of the major causes of death in infants and young children, and heavy metal exposure during pregnancy is one of the possible risk factors. However, the effect of heavy metal exposure on CHDs is still controversial. We searched English (PubMed, Web of Science) and Chinese (CNKI and WanFang database) databases for relevant articles. The summarized effect sizes and 95% confidence intervals (CIs) were calculated by pooling estimates using the random-effects model. Egger's test was used to estimate publication bias. Heterogeneity among studies was indicated by p-values and I2. Finally, we conducted subgroup analyses to elucidate the causes of heterogeneity. Thirteen studies were included in this meta-analysis. A positive association between maternal exposure to heavy metals and CHDs was found. Pooling odds ratios (ORs) for arsenic, cadmium, mercury, and lead were 2.12, 1.30, 1.22, and 2.30, respectively for total CHDs. Regarding CHD subtypes, arsenic was associated with an increased risk of septal defects (OR: 1.82), barium with left ventricular outflow tract obstruction (LVOTO) (OR: 1.15) and septal defects (OR: 1.21), and lead with conotruncal defects (OR: 2.34) and LVOTO (OR: 1.93). A heterogeneous relationship was found between studies using different methods of measurement, which were mainly due to differences in actual exposure levels to heavy metals. This meta-analysis suggests significant associations between arsenic, cadmium, mercury, and lead exposure during pregnancy and an increased risk of specific CHDs in offspring. These findings underscore the importance of heavy metal exposure during pregnancy in the risk of CHDs in offspring.

Maternal serum Lamin A is a potential biomarker that can predict adverse pregnancy outcomes.

BACKGROUND: Maternal serum Lamin A (LMNA) was reported to have potential diagnostic value in the prenatal diagnosis of congenital heart disease (CHD). In this study, we aimed to further assess the prognostic value of maternal serum LMNA in predicting adverse pregnancy outcomes. METHODS: A prospective screening study was performed on singleton pregnancies at 15-18 weeks of gestation. After a routine test for alpha fetoprotein (AFP), chorionic gonadotropin (hCG), and unconjugated estriol (uE3), serum LMNA levels were measured. Serum LMNA levels were then converted into multiples of the median (MoM). The median MoM values for adverse pregnancy outcomes were compared with those in normal pregnancies. For diseases with differential LMNA expression in the prospective study, another case-control cohort was recruited. The diagnostic value of LMNA in these diseases was further evaluated. FINDINGS: Between January 1, 2017 and June 30, 2018, a total of 2906 singleton pregnancies were recruited. Of the 2,906 cases, 2711 had data available for analysis. Congenital structural abnormalities, chromosomal abnormalities, and obstetric complications were observed in 152 (5·6%), 15 (0·6%), and 278 (10·3%) patients, respectively. LMNA was downregulated in pregnancies with fetal CHD, fetal neural tube defects (NTD), and preeclampsia (PE). The case-control study cohort included 256 CHD, 60 NTD, 67 PE, and 400 normal pregnancies. The areas under the curve for the prenatal diagnoses of CHD, NTD, and PE were 0·875, 0·871, and 0·816, respectively. INTERPRETATION: Maternal serum LMNA was found to be a potential biomarker for the prenatal diagnosis of fetal CHD, NTD, and PE. FUNDING: National Key Research and Development Program, National Natural Science Foundation of China, LiaoNing Revitalization Talents Program, National Natural Science Foundation of Liaoning, and 345 Talent Project of Shengjing Hospital.

Comprehensive analysis of the prognostic value of the chemokine-like factor-like MARVEL transmembrane domain-containing family in gastric cancer.

BACKGROUND: The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family refers to a family of transcriptional repressor genes. CMTMs are closely associated with the epigenetic regulatory mechanisms and development of multiple malignancies, including gastric cancer. However, their specific biological functions and prognostic values in gastric cancer have yet to be elucidated. METHODS: Tumor sample datasets were retrieved and analyzed using databases including Oncomine, STRING, GEPIA2, cBioportal, and Kaplan-Meier plotter. To investigate the prognostic role of CMTMs in gastric cancer, we applied unsupervised hierarchical clustering analysis of CMTM gene expression patterns. RESULTS: While the mRNA levels of CMTM1/3/6/7/8 were upregulated in gastric cancer, CMTM2/4/5 showed no statistically significant difference at the mRNA level in patients with gastric cancer. Moreover, the mRNA expressions of different CMTMs exhibited strong correlations with various clinical parameters of patients with gastric cancer, including tumor stage, metastatic lymph node status, H. pylori status, and tumor grade. Also, the results suggested that elevated levels of CMTM3/5 mRNA had a significant association (P<0.05) with poor overall survival, progression-free survival, and post-progression survival. Conversely, elevated expression of CMTM2/4/6 mRNA had a significant association with better overall survival, progression-free survival, and post-progression survival. Unsupervised hierarchical clustering analysis successfully identified 2 major clusters of patients as follows: signature #1: CMTM4/6/8 and signature #2: CMTM1/2/3/5/7. Signature #2 was closely correlated with poorer overall survival, which indicated that the expression pattern of the CMTM family could be a novel prognostic factor for patients with gastric cancer. CONCLUSIONS: These results suggest that the expression levels of CMTM genes possibly have prognostic value as a biomarker of gastric cancer.

Identification of candidate biomarkers and therapeutic drugs of colorectal cancer by integrated bioinformatics analysis.

Most colorectal cancer (CRC) patients are diagnosed with advanced stages and low prognosis. We aimed to identify potential diagnostic and prognostic biomarkers, as well as active small molecules of CRC. Microarray data (GSE9348, GSE35279, and GSE106582) were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by the GEO2R platform. Common DEGs were selected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Cytoscape software was used to construct protein-protein interaction networks and identify hub genes. Hub genes were evaluated by Kaplan-Meier survival analysis in the GEPIA database and validated in two independent microarray data (GSE74602 and GSE83889). Common DEGs were used to select active small molecules by the connectivity map database. A total of 166 DEGs were identified as common DEGs. GO analysis demonstrated that common DEGs were significantly enriched in the apoptotic process, cell proliferation, and cell adhesion. KEGG analysis indicated that the most enriched pathways were the PI3K-Akt signaling pathway and extracellular matrix-receptor interaction. COL1A2, THBS2, TIMP1, and CXCL8 significantly upregulated in colorectal tumor. High expressions of COL1A2, THBS2, and TIMP1 were associated with poor survival, while high expressions of CXCL8 were associated with better survival. We selected 11 small molecules for CRC therapy. In conclusion, we found key dysregulated genes associated with CRC and potential small molecules to reverse them. COL1A2, THBS2, TIMP1, and CXCL8 may act as diagnostic and prognostic biomarkers of CRC.

Structural insight into a novel neutral metalloproteinase from Paenibacillus spp. BD3526: Implications for mechanisms of rapid inactivation and calcium-dependent stability.

The proteinase with milk-clotting activity (MCA) from Paenibacillus spp. BD3526 is characterized as a neutral metalloproteinase of 35kDa. However, the rapid reduction of its MCA during separation and purification leads to low enzyme recovery. The effects of metal ions, inactivation kinetics, and concentration of calcium on the enzymatic activities and thermal stability of the BD3526 metalloproteinase were investigated. In the absence of calcium, the residual activities of the BD3526 metalloproteinase sharply declined during the first three hours, and continued to slowly decrease thereafter. The activities were well fitted by a double-exponential decay model. The inactivation rates were significantly inhibited by calcium and the residual enzyme activities were maintained at more than 80% for 30d at room temperature with 50-100mM calcium. An intermolecular autoproteolytic mechanism was responsible for BD3526 metalloproteinase inactivation. The target protein band with MCA remained largely undegraded in the enzyme solution that was supplemented with 100mM of calcium, but gradually diminished over time in the absence of calcium. N-terminal amino acid sequencing showed that cleavage at the His252-Ala253 peptide bond facilitated the conversion of the zymogen into the active enzyme. Sequence alignment revealed the presence of two highly conserved motifs, HEXXH and GXXNEXXSD, indicating that the enzyme belonged to the metalloproteinase family M4, also known as thermolysin-like proteinases (TLPs). Further structural analysis showed that the observed calcium-dependent stability of the BD3526 TLP may be attributable to a partly degenerated calcium-binding site, Ca1-2, and a mutant calcium-binding site, Ca3.

Purification and characterization of a novel milk-clotting metalloproteinase from Paenibacillus spp. BD3526.

In this study, a milk-clotting enzyme (MCE) isolated from Paenibacillus spp. BD3526 was purified and characterized. The MCE was purified 8.9-fold with a 10.11% recovery using ammonium sulfate precipitation and anion-exchange chromatography and the specific milk-clotting activity (MCA) reached 6791.73 SU/mg. The enzyme was characterized as a 35kDa metalloproteinase, and the zymogen of which was encoded by a 1671 bp gene named zinc metalloproteinase precursor (zmp) with a predicted molecular weight of 59.6 kDa. The optimal temperature for MCA and proteolytic activity (PA) was 65°C and 60°C, respectively. The enzyme was stable over a pH range of 5.0-9.0 and at temperatures below 50°C. The MCA was completely inactivated when the enzyme was heated at 60°C for 30 min, and the PA was totally inactivated for 20 and 10 min when the enzyme was heated at 55°C and 60°C, respectively. The BD3526 enzyme was preferentially active towards κ-casein (κ-CN) and ß-casein (ß-CN), as determined by sodium dodecyl sulfate-polyacrylamide gels (SDS-PAGE), whereas the hydrolysis of αs-casein (αs-CN) was slow and comparable to that caused by chymosin and asparatic acid proteinase from Rhizomucor miehei. The cleavage site of the metalloproteinase in κ-CN was located at the Met106-Ala107 bond, as determined by mass spectrometry analysis.

High Milk-Clotting Activity Expressed by the Newly Isolated Paenibacillus spp. Strain BD3526.

Paenibacillus spp. BD3526, a bacterium exhibiting a protein hydrolysis circle surrounded with an obvious precipitation zone on skim milk agar, was isolated from raw yak (Bos grunniens) milk collected in Tibet, China. Phylogenetic analysis based on 16S rRNA and whole genome sequence comparison indicated the isolate belong to the genus Paenibacillus. The strain BD3526 demonstrated strong ability to produce protease with milk clotting activity (MCA) in wheat bran broth. The protease with MCA was predominantly accumulated during the late-exponential phase of growth. The proteolytic activity (PA) of the BD3526 protease was 1.33-fold higher than that of the commercial R. miehei coagulant. A maximum MCA (6470 ± 281 SU mL(-1)) of the strain BD3526 was reached under optimal cultivation conditions. The protease with MCA was precipitated from the cultivated supernatant of wheat bran broth with ammonium sulfate and purified by anion-exchange chromatography. The molecular weight of the protease with MCA was determined as 35 kDa by sodium dodecyl sulfate-polyacrylamide gels electrophoresis (SDS-PAGE) and gelatin zymography. The cleavage site of the BD3526 protease with MCA in κ-casein was located at the Met106-Ala107 bond, as determined by mass spectrometry analysis.

On the critical radius in generalized Ostwald ripening.

The relation between the critical radius and the particle size distribution for generalized Ostwald type ripening processes whereby the mass transfer coefficient is modelled by a power law was derived. The critical radius is determined by the growth rate, the mass transfer coefficient and the mass balance, and is independent of whether the limiting stationary growth regime has been obtained.

Calpain inhibition protects against Taxol-induced sensory neuropathy.

Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide alpha-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. In mice with Taxol neuropathy, AK295 reduced the degree of axonal degeneration in sensory nerve roots, and improved clinical measures of neuropathy, including behavioural and electrophysiological function. These findings were consistent for both 3- and 6-week models of neuropathy. In vitro, Taxol caused activation of both calpains and caspases in PC12 cells. AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.