The association between plasma trans-fatty acids level and migraine: A cross-sectional study from NHANES 1999-2000.

OBJECTIVES: Trans-fatty acid (TFA) has been linked to an increased risk of a variety of diseases, such as cardiovascular disease (CVD), diabetes, and cancer. However, the relationship between plasma TFAs and migraine is little known. The current study aimed to determine the association between plasma TFAs and migraine in a large cross-sectional study among U.S. adults. METHODS: The participants from the US National Health and Nutrition Examination Survey (NHANES) were included during the period 1999-2000. The plasma concentrations of four major TFAs, including palmitelaidic acid (C16:1n-7t), elaidic acid (C18:1n-9t), vaccenic acid (C18:1n-7t), and linolelaidic acid (C18:2n-6t, 9t) were measured by gas chromatography/mass spectrometry (GC/MS). The presence of migraine headache was determined by self-report questionnaire. Weighted multivariable logistic regressions and restricted cubic spline (RCS) regressions were explored to assess the relationship between plasma TFAs and migraine. Furthermore, stratified analysis and testing of interaction terms were used to evaluate the effect modification by sex, age, race/ethnicity, family income, and BMI. RESULTS: A total of 1534 participants were included. The overall weighted prevalence of severe headache or migraine was 21.2 %. After adjusting for all potential covariates, plasma levels of elaidic acid and linolelaidic acid were positively associated with migraine. The adjusted OR values were 1.18 (95 %CI: 1.08-1.29, p=0.014, per 10 units increase) and 1.24 (95 %CI: 1.07-1.44, p=0.024). Then the included participants were divided into 2-quantiles by plasma TFA levels. Compared with participants with lower plasma levels of elaidic acid and linolelaidic acid (Q1 groups), those in the Q2 group had a higher prevalence of migraine when adjusted for all covariates in Model 2. The adjusted OR values were 2.43 (95 %CI: 1.14-5.18, p=0.037) for elaidic acid, and 2.18 (95 %CI: 1.14-4.20, p=0.036) for linolelaidic acid. Results were robust when analyses were stratified by sex, age, race/ethnicity, family income, and BMI, and no effect modification on the association was found. CONCLUSIONS: Our results demonstrated a positive association between migraine prevalence and plasma levels of elaidic acid and linolelaidic acid in US adults. These results highlight the connection between circulating TFAs and migraine.

Trajectories of squamous cell carcinoma antigen and outcomes of patients with advanced penile cancer after chemotherapy based on paclitaxel, ifosfamid, and cisplatin regimen.

INTRODUCTION: Penile cancer (PC) is a lethal malignancy with no effective prognostic biomarker. We aim to investigate associations between trajectories of squamous cell carcinoma antigen (SCC-A) and patient outcomes after chemotherapy based on paclitaxel, ifosfamid, and cisplatin (TIP) regimen. METHODS: Consecutive AJCC staging III/IV PC patients who received TIP chemotherapy and repeated SCC-A measurements in 2014-2022 were analyzed. Latent class growth mixed (LCGM) models were employed to characterize patients' serum SCC-A trajectories. Patient survival, and clinical and pathological tumor responses were compared. Inverse probability treatment weighting was used to adjust confounding factors. RESULTS: Eighty patients were included. LCGM models identified two distinct trajectories of SCC-A: low-stable (40%; n = 32) and high-decline (60%; n = 48). Overall survival (HR [95% CI]: 3.60 [1.23-10.53], p = 0.019), progression-free survival (HR [95% CI]: 11.33 [3.19-40.3], p < 0.001), objective response rate (37.5% vs. 62.5% p = 0.028), disease control rate (60.4% vs. 96.9% p < 0.00), and pathological complete response rate (21.2% vs. 51.9%, p = 0.014) were significantly worse in the high-decline arm. CONCLUSION: PC patients' SCC-A change rate was associated with tumor response and patient survival after TIP chemotherapy. SCC-A might assist tumor monitoring after systemic therapies.

Structural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB.

The K+ uptake system KtrAB is essential for bacterial survival in low K+ environments. The activity of KtrAB is regulated by nucleotides and Na+. Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na+ activates KtrAB and the Na+ binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na+, as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na+ binding stabilizes the ATP-bound BsKtrAB complex and enhances its K+ flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na+ in activating BsKtrAB is likely applicable to Na+-activated K+ channels in central nervous system.

Identifying Hmga2 preserving visual function by promoting a shift of Müller glia cell fate in mice with acute retinal injury.

BACKGROUND: Unlike in lower vertebrates, Müller glia (MG) in adult mammalian retinas lack the ability to reprogram into neurons after retinal injury or degeneration and exhibit reactive gliosis instead. Whether a transition in MG cell fate from gliosis to reprogramming would help preserve photoreceptors is still under exploration. METHODS: A mouse model of retinitis pigmentosa (RP) was established using MG cell lineage tracing mice by intraperitoneal injection of sodium iodate (SI). The critical time point for the fate determination of MG gliosis was determined through immunohistochemical staining methods. Then, bulk-RNA and single-cell RNA seq techniques were used to elucidate the changes in RNA transcription of the retina and MG at that time point, and new genes that may determine the fate transition of MG were screened. Finally, the selected gene was specifically overexpressed in MG cells through adeno-associated viruses (AAV) in the mouse RP model. Bulk-RNA seq technique, immunohistochemical staining methods, and visual function testing were used to elucidate and validate the mechanism of new genes function on MG cell fate transition and retinal function. RESULTS: Here, we found the critical time point for MG gliosis fate determination was 3 days post SI injection. Hmga2 was screened out as a candidate regulator for the cell fate transition of MG. After retinal injury caused by SI, the Hmga2 protein is temporarily and lowly expressed in MG cells. Overexpression of Hmga2 in MG down-regulated glial cell related genes and up-regulated photoreceptor related genes. Besides, overexpressing Hmga2 exclusively to MG reduced MG gliosis, made MG obtain cone's marker, and retained visual function in mice with acute retinal injury. CONCLUSION: Our results suggested the unique reprogramming properties of Hmga2 in regulating the fate transition of MG and neuroprotective effects on the retina with acute injury. This work uncovers the reprogramming ability of epigenetic factors in MG.

Regional lymph node mapping in patients with penile cancer undergoing radical inguinal lymph node dissection - a retrospective cohort study.

BACKGROUND: Radical inguinal lymph node dissection (rILND) is the most available treatment to cure penile cancer (PC) with limited inguinal-confined disease. However, guidelines regarding acceptable boundaries of rILND are controversial, and consensus is lacking. The authors aimed to standardize the surgical boundaries of rILND with definite pathological evidence and explore the distribution pattern of inguinal lymph nodes (ILNs) in PC. METHODS: A total of 414 PC patients from two centers who underwent rILND were enrolled. The ILN distribution was divided into seven zones anatomically for pathological examination. Student's t test and Kaplan-Meier survival analysis were used. RESULTS: ILNs displayed a funnel-shaped distribution with high density in superior regions. ILNs and metastatic nodes are present anywhere within the radical boundaries. Positive ILNs were mainly concentrated in zone I (51.7%) and zone II (41.3%), but there were 8.7% and 12.3% in inferior zones V and VI, respectively, and 7.1% in the deep ILNs. More importantly, a single positive ILN and first-station positive zone was detected in all seven regions. Single positive ILNs were located in zones I through VI in 40.4%, 23.6%, 6.7%, 18.0%, 4.5%, and 1.1%, respectively, and 5.6% presented deep ILN metastasis directly. CONCLUSIONS: The authors established a detailed ILN distribution map and displayed lymphatic drainage patterns with definite pathological evidence using a large cohort of PC patients. Single positive ILNs and first-station metastatic zones were observed in any region, even directly with deep ILN metastasis. Only rILND can ensure tumor-free resection without the omission of positive nodes.

Identification of an inflammation-related risk signature for prognosis and immunotherapeutic response prediction in bladder cancer.

Tumor inflammation is one of the hallmarks of tumors and is closely related to tumor occurrence and development, providing individualized prognostic prediction. However, few studies have evaluated the relationship between inflammation and the prognosis of bladder urothelial carcinoma (BLCA) patients. Therefore, we constructed a novel inflammation-related prognostic model that included six inflammation-related genes (IRGs) that can precisely predict the survival outcomes of BLCA patients. RNA-seq expression and corresponding clinical data from BLCA patients were downloaded from The Cancer Genome Atlas database. Enrichment analysis was subsequently performed to determine the enrichment of GO terms and KEGG pathways. K‒M analysis was used to compare overall survival (OS). Cox regression and LASSO regression were used to identify prognostic factors and construct the model. Finally, this prognostic model was used to evaluate cell infiltration in the BLCA tumor microenvironment and analyze the effect of immunotherapy in high- and low-risk patients. We established an IRG signature-based prognostic model with 6 IRGs (TNFRSF12A, NR1H3, ITIH4, IL1R1, ELN and CYP26B1), among which TNFRSF12A, IL1R1, ELN and CYP26B1 were unfavorable prognostic factors and NR1H3 and ITIH4 were protective indicators. High-risk score patients in the prognostic model had significantly poorer OS. Additionally, high-risk score patients were associated with an inhibitory immune tumor microenvironment and poor immunotherapy response. We also found a correlation between IRS-related genes and bladder cancer chemotherapy drugs in the drug sensitivity data. The IRG signature-based prognostic model we constructed can predict the prognosis of BLCA patients, providing additional information for individualized prognostic judgment and treatment selection.

Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

A SILAC-based accurate quantification of shrimp allergen tropomyosin in complex food matrices using UPLC-MS/MS.

The carryover of trace allergens in complex food matrices poses challenges for detection techniques. Here, we demonstrate an accurate UPLC-MS/MS quantification assay for the shrimp allergen tropomyosin with a full-length isotope-labelled recombinant tropomyosin (TM-I) internal standard in complex food matrices. The TM-I, expressed based on the SILAC technique, exhibited a high isotope labelling ratio (>99%), purity, and alignment with the natural sequence. This method determined the tropomyosin ranging from 0.2 to 100 ng/mL. Mean recoveries ranged from 89 to 116%, with intra- and inter-day RSDs below 12%, for three signature peptides across three types of commercially processed food matrices. The limits of quantitation were 1 µg/g in pop food and sauce, and 10 µg/g in surimi product, respectively. This study supports the use of recombinant full-length isotope-labelled proteins rather than stable-isotope labelling peptides as internal standards to achieve more accurate quantitation of food allergens as the digestion error is corrected.

Serotype distribution and antimicrobial resistance of pediatric Streptococcus pneumoniae isolated from inpatients and outpatients at Beijing Children's Hospital

Abstract Background Understanding the epidemiology of Streptococcus pneumoniae (S. pneumoniae) isolates is important for pneumonia treatment and prevention. This research aimed to explore the epidemiological characteristics of S. pneumoniae isolated from pediatric inpatients and outpatients during the same period. Methods S. pneumoniae were isolated from unsterile samples of inpatients and outpatients younger than five years old between March 2013 and February 2014. The serotypes were determined using diagnostic pneumococcal antisera. The resistance of each strain to 13 antibiotics was tested using either the E-test or the disc diffusion method. The Sequence Types (STs) were analyzed via Multilocus Sequence Typing (MLST). Results The dominant serotypes obtained from inpatients were 19F (32.9 %), 19A (20.7 %), 23F (10.7 %), 6A (10.0 %), and 14 (8.6 %), while those from outpatients were 19F (13.6 %), 23F (12.9 %), 6A (10.0 %), 6B (10.0 %), and 19A (7.9 %). The coverage rates of 13-valent Pneumococcal Conjugate Vaccine (PCV) formulations were high in both groups. The nonsusceptibility to penicillin, cefuroxime, imipenem, erythromycin, and trimethoprim-sulfamethoxazole among the inpatient isolates was 7.1 %, 92.8 %, 65.7 %, 100 %, and 85.0 %, respectively, while that among the outpatient isolates was 0.7 %, 50.0 %, 38.6 %, 96.4 %, and 65.7 %, respectively. There were 45 and 81 STs detected from the pneumococci isolated from inpatients and outpatients, respectively. CC271 was common among both inpatients and outpatients (43.6 % and 14.3 %). Conclusions Pneumococcal vaccine-related serotypes are prevalent among both inpatients and outpatients, especially among inpatients, who exhibit more severe antibiotic resistance. Therefore, universal immunization with PCV13 would decrease the hospitalization rate due to S. pneumoniae and the antibiotic resistance rate of S. pneumoniae.

Extraperitonealization of the ileal conduit decreases the risk of parastomal hernia: A single-center, randomized clinical trial.

Parastomal hernia (PSH) is a common complication in patients receiving ileal conduit urinary diversion after radical cystectomy. In this randomized controlled clinical trial, we validate our previous finding that extraperitonealization of ileal conduit decreases incidence of PSH. In total, 104 consecutive patients undergoing radical cystectomy at Sun Yat-sen University Cancer Center are randomized 1:1 to receive either modified (extraperitonealized) ileal conduit (n = 52) or conventional ileal conduit (n = 52). Primary endpoint is incidence of radiological PSH during follow-up. Incidence of radiological PSH is lower in the modified group than in the conventional group (11.5% vs. 28.8%; p = 0.028) after a median follow-up of 32 months, corresponding to a hazard ratio of 0.374 (95% confidence interval: 0.145-0.965, p = 0.034) in the modified conduit group. The results support our previous finding that extraperitonealization of the ileal conduit is effective for reducing risk of PSH in patients receiving ileal conduit diversion.

SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer.

BACKGROUND: The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC. METHOD: Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer. RESULTS: Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer. CONCLUSION: Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.

Regular gastroscopy and colonoscopy during the evaluation of urachal cancer: do we really need them?

PURPOSE: Urachal cancer is similar to gastrointestinal adenocarcinoma in histology, and gastroscopy/colonoscopy is often administered during perioperative evaluation. However, gastroscopy and colonoscopy have corresponding disadvantages. This study discusses whether gastroscopy/colonoscopy is truly necessary for patients with urachal cancer. PATIENTS AND METHODS: A total of 166 bladder adenocarcinoma cases diagnosed at Sun Yat-sen University Cancer Center were retrospectively reviewed and divided into two groups (urachal cancer and nonurachal cancer), and perioperative evaluations were retrieved. RESULTS: There were 78 patients with urachal cancer, the median age was 48 years, and 59 were male. Perioperative gastroscopy/colonoscopy revealed 5 intestinal polyps and 1 adenoma during these evaluations, and no primary gastrointestinal cancer was found. Meanwhile, preoperative imaging evaluation did not detect significant gastrointestinal lesions. For 88 patients with nonurachal cancer, including primary bladder adenocarcinoma and metastatic tumors from gastrointestinal cancer, the median age was 56 years, and 64 were male. Preoperative imaging evaluation demonstrated 36 cases of gastrointestinal lesions, and 32 were confirmed by gastroscopy/colonoscopy; the other 4 were negative. Another 4 cases of colon cancer were detected by regular colonoscopy for suspected primary bladder adenocarcinoma. In all, 35 cases of colon cancer and 1 case of gastric cancer were identified by endoscopic examination. The diagnostic consistency of imaging and gastrointestinal endoscopy was favorable (P < 0.001), and the negative predictive value and diagnostic efficiency of imaging were 96.9% and 94.6%, respectively. CONCLUSIONS: The vast majority of gastrointestinal cancer cases can be identified by assessment of the patient's clinical symptoms, meticulous physical examination, and imaging evaluation. We recommend that gastroscopy/colonoscopy only be applied to patients with urachal cancer when the above examinations are positive.

Optimal interval timing between transurethral resection of bladder tumors and Bacillus Calmette-Guerin perfusion.

OBJECTIVE: There is no consensus regarding the best interval time between transurethral resection of a bladder tumor and Bacillus Calmette-Guerin (BCG) perfusion. This study was to explore whether the interval time has an impact on the prognosis and adverse effects. METHODS: We retrospectively reviewed the clinical data of patients who received BCG intravesical perfusion at Sun Yat-sen University Cancer Center (SYSUCC) from September 2015 to October 2021. Recurrence-free survival (RFS) and progression-free survival were the primary endpoints. Cox regression was used to explore independent predictors. The association between interval time and adverse effect grade was detected by logistic regression. Propensity score matching (PSM) was performed. RESULTS: A total of 403 patients were enrolled, the median interval time was 24 days (6-163 days), and the follow-up was 28 months (7-82 months). Eighty-eight (20.9%) patients relapsed, and 40 patients (10.0%) suffered progression. The multivariate Cox regression analysis confirmed that interval time was an independent predictor of RFS (p = 0.017). Notably, when the interval time was less than or equal to 26 days, there was a trend toward better RFS, PSM resulted in 65 matched pairs in each group, and Kaplan-Meier analysis showed that there was a significant difference in RFS between groups (p = 0.009). The logistic regression analysis showed that there was no correlation between interval time and adverse effects and their grades (p > 0.05). CONCLUSIONS: We considered that the first BCG perfusion could be performed within 2-4 weeks after surgery.

Gemcitabine/nab-paclitaxel vs gemcitabine/carboplatin for advanced urothelial carcinoma.

OBJECTIVE: To compare in a phase III trial the efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine (GA) with that of carboplatin plus gemcitabine (GCb) as a first-line treatment for patients with cisplatin-ineligible metastatic urothelial cancer (mUC). PATIENTS AND METHODS: Treatment-naive, cisplatin-ineligible patients with mUC were assigned randomly to either the GA (both nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days) or GCb group (carboplatin area under the free carboplatin plasma concentration versus time curve of 4.5 on Day 1, gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and patient-reported outcomes (PROs). RESULTS: The trial was terminated early because of slow accrual after 54 patients were enrolled: 26 in in the GA group and 28 in the GCb groups. The median PFS was 6.7 vs 5.9 months for the GA and GCb groups, respectively (P = 0.248). The median OS time was 12.1 vs 10.7 months for the GA and GCb groups, respectively (P = 0.837). The ORR and DCR were 40% vs 46.4% (P = 0.637) and 72% vs 68% (P = 0.188) in the GA and GCb groups, respectively. Patients treated with GA showed significantly lower incidence of Grade 3-4 thrombocytopenia and does reduction and delay. Although peripheral sensory neuropathy was higher in the GA arm, no Grade 3 neuropathy occurred. There was no difference in the PROs between the two groups. CONCLUSION: While not powered for comparison, first-line GA showed similar efficacy and better tolerability and might be considered a rational alternative to GCb.

Effect of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma: a real-world retrospective study.

BACKGROUND: Genitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC). METHODS: We performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed. RESULTS: Forty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84-21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08-0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism. CONCLUSIONS: Among patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

The role of Her-2 in penile squamous cell carcinoma progression and cisplatin chemoresistance and potential for antibody-drug conjugate-based therapy.

BACKGROUND: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. There is no standard second-line therapy for advanced PSCC. Human epidermal growth factor receptor 2 (Her-2)-targeted antibody-drug conjugates (ADCs) are novel low-toxicity agents which have greatly improved clinical outcomes for several advanced cancers. We aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of Her-2-targeted ADCs in PSCC. METHODS: Her-2 immunohistochemistry was performed for the largest single-centre PSCC cohort to date (367 patients). PSCC cell lines, cisplatin-resistant cell lines, subcutaneous xenograft, and footpad metastatic models were used to investigate the biological roles of Her-2 in PSCC progression. Cytotoxicity, apoptosis assays, and western blotting investigated the mechanism of Her-2 induced cisplatin-chemoresistance. The efficacy of Disitamab Vedotin (RC48), a Her-2-targeted ADC, was evaluated in PSCC. RESULTS: Her-2 was identified as an adverse prognostic indicator associated with advanced Tumor-Node-Metastasis (TNM) stages and poor survival with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 promotes cell proliferation, migration, invasion, tumour progression, and cisplatin resistance in PSCC. Mechanistically, Her-2 inhibits cisplatin-induced cell apoptosis by the activation of Akt phosphorylation at Ser473 and disrupts the balance between proapoptotic and antiapoptotic proteins. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, RC48 displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumours. CONCLUSION: Our study suggests that Her-2 is an available therapeutic biomarker for PSCC. Her-2-targeted ADC might have the potential to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and provide precious second-line clinical choice for appropriate cisplatin-based chemoresistance patients.

Prognostic Significance of HER2 Expression in Patients with Bacillus Calmette-Guérin-exposed Non-muscle-invasive Bladder Cancer.

BACKGROUND: Guidelines recommend intravesical instillation of bacillus Calmette-Guérin (BCG) as the first-choice treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). However, there is no therapeutic biomarker for predicting BCG efficacy, especially in high-risk cases with high failure rates. HER2 expression is considered a prognostic factor for bladder cancer. OBJECTIVE: To elucidate the predictive value and significance of HER2 expression in patients with BCG-exposed NMIBC. DESIGN, SETTING, AND PARTICIPANTS: A total of 454 patients with NMIBC were included. All patients started BCG intravesical instillation (1.2 × 108 CFU, strain D2PB302) 2-6 wk after transurethral resection of bladder tumor and received 19 treatments over a period of 1 yr. HER2 immunohistochemistry (IHC) results available for 314 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes investigated were recurrence-free survival (RFS) and progression-free survival (PFS). Outcome relationships were explored using multivariable Cox regression and log-rank analysis. RESULTS AND LIMITATIONS: In the IHC population, 35.7% of patients had HER2 overexpression (IHC score 2/3+). This group had a poor 5-yr RFS rate of 16.5%, in comparison to 68.0% in the group with low HER2 expression (p < 0.001). Patients with high-risk NMIBC and HER2 overexpression had the highest risk of BCG treatment failure, with 5-yr RFS and PFS rates of 19.0% and 58.2%, respectively. Conversely, HER2-negative (IHC score 0) patients with high-risk NMIBC experienced a long-term BCG benefit, with 5-yr RFS and PFS rates of 80.8% and 92.1%, respectively. Limitations include the retrospective study design and the limited details regarding BCG use. CONCLUSIONS: HER2 was an independent predictor of poor BCG efficacy in NMIBC. Patients with high-risk NMIBC and HER2 overexpression had the highest risk of disease recurrence and progression after exposure to BCG. Anti-HER2 targeted therapies could be considered for these patients. PATIENT SUMMARY: Measurement of blood levels of the protein HER2 can be used to predict outcomes after BCG (bacillus Calmette-Guérin) bladder therapy for patients with intermediate- or high-risk non-muscle-invasive bladder cancer. Measurement results for HER2 may help in guiding personalized treatment for these patients.

SAVE Testis-sparing score: a multicenter retrospective study of a novel predictive tool for quantifying testicular tumors.

BACKGROUND: Testis-sparing surgery (TSS) is a safe treatment for patients with benign testicular tumors. Presently, assessments for evaluating the suitability of TSS are poorly standardized, partially because testicular anatomical elements cannot be quantitatively described. MATERIALS AND METHODS: The authors developed a scoring method known as the SAVE testis-sparing score based on four critical and accessible anatomical features of a testicular tumor. The SAVE score ranges from 0 to 8 and is divided into four risk classes ( low , medium , high , and extremely high ) to evaluate the feasibility of TSS, wherein low-risk indicates high feasibility and vice versa. This study included 444 testicular tumor patients from eight centers. Among them, 216 patients (model group: 151 patients, validation group: 65 patients) were included in the modeling analysis, and the other 228 patients from children's centers were included in the proportion analysis. Using retrospective data, patient characteristics associated with surgical methods were identified. Furthermore, a multivariate logistic regression model was built quantify the associations between these characteristics and the surgery method. The receiver operator characteristic curve was used to evaluate the classification efficiency of SAVE. RESULTS: The SAVE testis-sparing score includes size (tumor size as maximal diameter), available testicular tissue volume, volume ratio of the tumor to the testis, and the exophytic / endophytic properties of the tumor. The SAVE scoring system accurately classified the suitability of TSS based on the complexity of benign testicular tumors. CONCLUSION: The SAVE score is a reproducible and robust tool for quantitatively describing the anatomical characteristics of benign testicular tumors and guide the preoperative evaluation of TSS.