Comparison of the tumor immune microenvironment and checkpoint blockade biomarkers between stage III and IV non-small cell lung cancer.

BACKGROUND: Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored. METHODS: Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status. RESULTS: PD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P < 2.2e-16, ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081). CONCLUSION: Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.

Functional nodules in primary aldosteronism: identification of CXCR4 expression with 68Ga-pentixafor PET/CT.

OBJECTIVES: We analyzed the diagnostic efficiency of 68Ga-pentixafor PET/CT for functional nodules in primary aldosteronism (PA). Furthermore, we compared the correlation of CXCR4 expression with aldosterone synthase (CYP11B2) expression and PET/CT uptake in these patients. METHODS: We prospectively assessed 50 patients diagnosed with PA and 10 patients with non-functional adrenal adenoma (NFA). All patients underwent 68Ga-pentixafor PET/CT before adrenalectomy. Immunohistochemistry (IHC) was performed to detect the protein expression of CYP11B2 and the G-protein-coupled receptor CXCR4. RESULTS: CYP11B2 IHC revealed the presence of 43 functional nodules. Subsequently, 40/43 functional nodules could be detected on 68Ga-pentixafor PET/CT, while negative imaging findings were noted for 11/13 non-functional nodules (sensitivity, 93.0%; specificity, 84.6%). The optimum SUVmax cut-off for the identification of functional nodules was 8.95 (AUC 0.914 [0.828-1.000], p < 0.001). Regarding the size of functional nodules, diagnostic efficiency appeared to be much higher for nodules greater than 1 cm in size (sensitivity, up to 97.3%). Moreover, we examined the relationship between CXCR4 and CYP11B2 expression in 56 lesions. All 43 CYP11B2-positive nodules were CXCR4-positive, but one of the 13 CYP11B2-negative nodules (7.7%) showed false-positive staining for CXCR4. Moreover, the consistency between PET/CT uptake and CXCR4 staining results was 92.9% (52/56). CONCLUSIONS: At least 90% of functional nodules show positive uptake on 68Ga-pentixafor PET/CT, and the detection ability is much better for nodules with a diameter ≥ 1 cm. With its high sensitivity and specificity, 68Ga-pentixafor PET/CT can be considered a promising surgical decision-making tool for patients with PA. KEY POINTS: • 68Ga-pentixafor PET/CT could be a useful tool for the identification of functional adrenal nodules in APAs and even IHAs. • The diagnostic efficiency appears to be much higher for nodules ≥ 1 cm in size. • There is high consistency between the results of 68Ga-pentixafor PET/CT imaging and CXCR4 immunohistochemistry.

Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation.

BACKGROUND: Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. METHODS: This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. RESULTS: Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. CONCLUSIONS: EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.

IP10 and Anti-HBc can Predict Virological Relapse and HBsAg Loss in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Discontinuation.

INTRODUCTION: To assess predictive ability of serum interferon-inducible protein 10 (IP10) and hepatitis B core antibody (anti-HBc) levels for virological relapse (VR) and hepatitis B surface antigen (HBsAg) loss after nucleos(t)ide analog (NA) discontinuation. METHODS: In this multicenter prospective study, overall 139 patients were followed up for 24 months after NA discontinuation. RESULTS: End of treatment (EOT) IP10 and anti-HBc were 29.2 (5.1-66.4) pg/mL and 193.6 (136.9-221.4) IU/mL. EOT IP10 and anti-HBc were independent predictors for VR and HBsAg loss in Cox regression analysis. Cumulative rates of VR in patients with EOT IP10 > 26.99 pg/mL was 31.9% (vs. 70.1%, hazard ratio [HR] 2.998, p < 0.001). Cumulative incidences of VR in patients with EOT anti-HBc ≤141.35 IU/mL was 49.1% (vs. 60.6%, HR 2.99, p < 0.001). Cumulative probabilities of VR was 16.7% in patients with EOT IP10 > 26.99 pg/mL plus anti-HBc ≤141.35 IU/mL (vs. 73.6%, HR 6.464, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT IP10 > 93.5 pg/mL was 46.2% (vs. 4.7%, HR 10.94, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT anti-HBc ≤78.42 IU/mL were 47.1% (vs. 5%, HR 12.27, p < 0.001). Patients with EOT IP10 > 93.5 pg/mL plus anti-HBc ≤78.42 IU/mL had the highest 24-month cumulative HBsAg loss rate (53.8% vs. 4%, HR 16.83, p < 0.001). CONCLUSION: High EOT IP10 and low EOT anti-HBc levels were related to both lower risk of VR and higher probability of HBsAg loss.

High prevalence of hypertension and target organ damage in patients with 11ß-hydroxylase deficiency.

BACKGROUND: Prevalence of hypertension and hypertension-mediated organ damage (HMOD) had not been well studied in patients with 11ß-hydroxylase deficiency (11ß-OHD). OBJECTIVE: The study was to assess the prevalence and risk factors of hypertension and HMOD in patients with 11ß-OHD. DESIGN: Retrospective cohort analysis in a single medical centre. PATIENTS: Twenty-eight patients with 11ß-OHD were recruited between January 2003 and June 2021, and their diagnosis had been confirmed by Sanger sequencing. MEASUREMENTS: Blood pressure and clinical indicators for the assessment of HMOD occurrence were collected from the medical records. Medication adherence of antihypertensive drugs and glucocorticoids were determined by the patients' biochemistry. Logistic regression was used to identify factors associated with HMOD. RESULTS: Prevalence of hypertension and HMOD in the cohort was 100% and 50%, respectively. The kidneys (71.43%) are the organ most commonly damaged by high blood pressure, followed by the heart (64.29%), eyes (57.14%) and brain (21.43%). Risk factors of HMOD were hypokalemia (odds ratio [OR]: 9.16; 95% confidence interval [CI]: 1.634-51.43; p = .012), blood pressure ≥ 180/110 mmHg (OR: 22.0, 95% CI: 3.08-157.34; p = .002) and irregular glucocorticoid use (OR: 3.18, 95% CI: 1.13-8.98; p = .021). Blood pressure ≥ 180/110 mmHg was an independent predictor for HMOD. CONCLUSION: Hypertension and HMOD are prevalent in patients with 11ß-OHD in our study. These findings illustrate the importance of early HMOD evaluation and optimal glucocorticoid medication in 11ß-OHD patients.

Bone mineral density and trabecular bone score in patients with 21-hydroxylase deficiency after glucocorticoid treatment.

OBJECTIVE: Patients with 21-hydroxylase deficiency (21-OHD) are at risk of reduced bone mineral density (BMD) and fracture due to long-term glucocorticoid treatment. Trabecular bone score (TBS) is complementary to conventional BMD as a marker for bone quality in patients with glucocorticoid-induced osteoporosis. The purpose of this study is to evaluate the BMD and TBS in a cohort of patients with 21-OHD and analyse factors related to TBS. DESIGN: An observational study. PATIENTS: A total of 46 21-OHD adult patients treated with glucocorticoid for over 10 years who visited Peking Union Medical College Hospital between 2015 and 2019 were recruited. Eight male patients included in this study were all under 50 years old, and 38 female patients were all premenopausal. MEASUREMENTS: Diagnosis was confirmed by multiplex ligation-dependent probe amplification combined with sequencing. Data were collected on physical characteristics, serum hormones and glucocorticoid treatment. Skeletal quality was evaluated by BMD and TBS, and factors related to TBS were analysed. RESULTS: Among the 46 patients, 2 (4.3%) had low BMD (Z-score ≤ -2), while 11 (23.9%) patients had low TBS (degraded or partially degraded microarchitecture). The proportion of bone abnormality evaluated by TBS was higher than that by BMD (p < .001). Patients with lower TBS had significantly higher daily hydrocortisone dosage (p = .009 for males; p = .019 for females). TBS value was negatively correlated with daily hydrocortisone dosage (r = -.317, p = .026), and positively correlated with BMI in female patients (r = .345, p = .034). And there was a negative correlation between TBS value and the current age in male patients (r = -.741, p = .036). The distribution of genotypes (p = 1.000 for male; p = .567 for female) or phenotypes (p = .486 for male; p = .075 for female) had no statistical difference in patients with normal or abnormal TBS. CONCLUSIONS: Approximately 24% of patients with 21-OHD had abnormal microarchitecture of their bone in our study, and TBS score was negatively correlated with daily glucocorticoid dosage in patients. TBS may be used alongside conventional BMD as a complementary marker for bone evaluation in 21-OHD patients.

Gonadotropin Therapy Once a Week for Spermatogenesis in Hypogonadotropic Hypogonadism.

OBJECTIVE: Hypogonadotropic hypogonadism (HH) can be caused by congenital HH (CHH), pituitary stalk interruption syndrome (PSIS), and pituitary injury (acquired HH). Gonadotropin therapy, typically administered every other day or twice a week, is commonly used to promote spermatogenesis. The aim of this retrospective study was to evaluate the efficacy of weekly gonadotropin therapy on spermatogenesis in patients with HH (n = 160). METHODS: The patients' diagnoses include Kallmann syndrome (KS) (n = 61), normosmic CHH (nCHH) (n = 34), PSIS (n = 48), and acquired HH (n = 17). The rate of successful spermatogenesis and median time to achieve spermatogenesis among these 4 subgroups were compared as well as between a weekly group (n = 95) and a twice-a-week group (n = 223) of CHH patients. RESULTS: Once-a-week gonadotropin therapy resulted in 74% (119/160) of HH patients achieving spermatogenesis with significantly increased testicular volume and total testosterone levels (P < .001). The median period of spermatogenesis was 13 (interquartile range[IQR] 11.4-14.6) months. Larger basal testicular volume (P = .0142) was an independent predictor for earlier sperm appearance. Six spontaneous pregnancies occurred. Compared with the twice-a-week regimen for spermatogenesis, the weekly injection group had a similar median time of sperm appearance (14 [IQR, 11.6-16.4] vs 15 [IQR, 13.5-16.5] months), success rate (78% [74/95] vs 64% [143/223]), sperm concentration (20.9 [IQR, 5.0-46.3] vs 11.7 [IQR, 2.1-24.4] million/mL), and progressive sperm motility (40.8 ± 27.3% vs 36.9% ± 20.2%). CONCLUSION: Weekly gonadotropin therapy is effective in inducing spermatogenesis, similar to that of twice-a-week therapy. A larger basal testicular size was a favorable indicator for earlier spermatogenesis.

Aromatase Inhibitor Increases the Height of Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

OBJECTIVE: Patients with 21-hydroxylase deficiency (21OHD) typically suffer from short stature due to early exposure to adrenal-derived androgen. The aim of this study was to investigate whether adding aromatase inhibitor (AI) to gonadotropin-releasing hormone (GnRH) analogue (GnRHa) and recombinant human growth hormone (rhGH) therapy would increase the height of patients with 21OHD. METHODS: This retrospective study included 15 patients with 21OHD. The AI/GnRHa/rhGH group consisted of 9 patients, who were treated with AI for at least 12 months in addition to GnRHa/rhGH therapy. The other 6 patients, who received GnRHa/rhGH therapy only, were defined as the GnRHa/rhGH group. RESULTS: Patients were 6.3±1.7 years old, and 7/15 of patients were male. Among them, 12 patients exhibited simple virilization type, and 3 patients were salt-wasting type. In the AI/GnRHa/rhGH group, patients were 6.6±2.0 years old when AI therapy was initiated. Their bone age was 5.9±2.2 years ahead of their chronological age. They received the AI letrizole for an average of 25.1 months (range, 12 to 37 months). In the GnRHa/rhGH group, the patients were 5.9±0.9 years old when they started GnRHa/rhGH therapy, and their bone age was 6.2±1.7 years ahead of their chronological age. Patients received GnRHa/rhGH therapy for an average of 24.5 months (range, 12 to 41 months). The predicted final height increased from 145.9±7.9 to 158.0±8.4 cm in the AI/GnRHa/rhGH group (P = .001, compared with the baseline) and from 141.7±2.7 to 150.7±4.7 cm in the GnRHa/rhGH group (P = .001, compared with the baseline). Bone age progression was 0.15±0.05 per year versus 0.44±0.13 per year in the two groups, respectively (P = .032). CONCLUSION: Addition of letrizole to GnRHa/rhGH therapy significantly delays bone maturation and may increase the final height.

Clinical Characteristics and Risk Factors in Coronavirus Disease 2019 Patients with Liver Injury.

BACKGROUND Emerging studies noted that liver injury in coronavirus disease 2019 (COVID-19) patients may be induced by virus-mediated inflammation, which was confirmed by liver pathology. The aim of this study was to observe clinical characteristics and explore risk factors in COVID-19 patients with liver injury. MATERIAL AND METHODS In this retrospective study, 40 confirmed COVID-19 patients with normal alanine transaminase (ALT) on admission were divided into a group of normal ALT patients whose ALT was always less than 40 U/l during hospitalization and a group of elevated ALT patients whose ALT was at least once more than 40 U/l after admission. Clinical data, especially virus-induced inflammatory parameters, were analyzed for risk factors and predictive value. The Mann-Whitney U test and t test for comparing means and logistic regression were performed for analysis of risk factors. Area under the ROC curve was used for predictive values. RESULTS Sixteen of 40 (40.0%) patients developed elevated ALT, many of them with more severe COVID-19. The highest ALT level was 101 U/l. The risk factors for liver injury were C-reactive protein (CRP), interleukin 6 (IL6), erythrocyte sedimentation rate (ESR), CD8+T cell count, and severity of disease, and CRP (OR 1.13, 95% CI 1.045-1.222, p=0.002) was the independent risk factor. CONCLUSIONS Liver injury in COVID-19 patients was mild and associated with inflammatory markers, especially CRP, which suggests that liver injury may be induced by virus-mediated inflammation in COVID-19 patients.

Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development.

OBJECTIVE: To analyze nuclear receptor subfamily 5 group A member 1 (NR5A1) gene mutations in a cohort of Chinese patients with 46, XY Disorders of Sex Development (DSD). METHODS: Sixty 46, XY DSD patients were recruited at Peking Union Medical College Hospital. Targeted next-generation and Sanger sequencing were performed to investigate pathogenic gene variants and validate NR5A1 gene variants, respectively. In silico tools and in vitro function studies were used to analyze the pathogenicity of rare variants. The clinical and endocrinological characteristics of patients with NR5A1 variants were retrospectively analyzed. RESULTS: A total of four novel and three recurrent NR5A1 variants were identified in seven 46, XY DSD patients. These variants widely spread almost all the functional domains. Functional studies showed that novel mutations including p.S32N, p.N44del and p.G91D reduced transactivation of CYP11A1, while the other missense variant p.A168E did not impact protein function. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects. Results of the genitalia examination showed female external genitalia (three patients), ambiguous external genitalia (two patients), female external genitalia with clitoromegaly (one patient), and hypospadias (one patient). All seven patients had bilateral testis and five of seven patients lacked Müllerian structures. CONCLUSIONS: Four novel mutations in the NR5A1 gene were identified in our cohort with 46, XY DSD, expanding the spectrum of NR5A1 gene mutations. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects.

Assisted reproductive techniques with congenital hypogonadotropic hypogonadism patients: a systematic review and meta-analysis.

BACKGROUND: After hormonal replacement therapy (HRT) including androgen replacement or sequential therapy of estrogen and progesterone, The combination of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) and pulsatile GnRH, is not sufficient to produce sufficient gametes in some patients with Congenital hypogonadotropic hypogonadism (CHH). A Systematic review and meta-analysis was performed to determine that assisted reproductive techniques (ART) can effectively treat different causes of infertility. METHODS: To determine the effect of ART on fertility of CHH patients and investigate whether outcomes are similar to infertility due to other causes, we conducted a systematic review and meta-analysis of retrospective trials. Clinical trials were systematically searched in Medline, Embase, and the Cochrane central register of controlled trials databases. The keywords and major terms covered "hypogonadotropic hypogonadism", "kallmann syndrome", "assisted reproductive techniques", "intrauterine insemination", "intracytoplasmic sperm injection", "testicular sperm extraction", "in vitro fertilization", "embryo transplantation" and "intra-Fallopian transfer". RESULTS: A total of 388 pregnancies occurred among 709 CHH patients who received ART (effectiveness 46, 95% confidence interval 0.39 to 0.53) in the 20 studies we included. The I2 in trials assessing overall pregnancy rate (PR) per embryo transfer (ET) cycle was 73.06%. Similar results were observed in subgroup analysis by different gender. Regression indicates pregnancy rate decreases with increasing age. Fertilization, implantation and live birth rates (72, 36 and 40%) showed no significant differences as compared to infertility due to other causes. CONCLUSIONS: Despite CHH patients usually being difficult to generate gametes, their actual chances of fertility are similar to subjects with other non-obstructive infertility. ART is a suitable option for CHH patients who do not conceive after long-term gonadotropin treatment.

[The clinical analysis of orthotopic liver transplantation for primary biliary cirrhosis].

OBJECTIVE: To analyze the clinical outcome and complications of orthotopic liver transplantation (OLT) for patients with primary biliary cirrhosis(PBC). METHODS: Clinical data of 25 patients with PBC who underwent OLT were analyzed retrospectively. The postoperative cumulative survival rate of the patients was calculated. The postoperative recurrence of PBC, de novo diseases and other complications were analyzed. RESULTS: A total of 25 patients were recruited including 22 females and 3 males. The average age was 49.1 years (range from 40 to 64 years). The score of model for end-stage liver disease (MELD) was 21.80±5.49, and the Mayo score 8.01±1.38. Four patients died after liver transplantation. The 1-year, 2-year and 7-year patient cumulative survival rates were 92.0%, 87.8% and 75.3%, respectively. Eight cases (32.0%) developed recurrent PBC based on histological evidence. The median time to recurrence was 17.5 months. One of the eight patients with recurrent PBC was diagnosed with de novo auto-immune hepatitis (AIH) simultaneously, who eventually died. Acute rejection and de novo hepatitis B virus (HBV) infection developed in thirteen (52.0%) patients and five (20.0%) patients, respectively. Two cases (8.0%) of de novo AIH were diagnosed, one of which was fatal. CONCLUSIONS: OLT is an effective procedure for end-stage PBC. Much attention needs to be paid to the post-transplantation complications, including recurrence of primary disease, combined de novo HBV infection, de novo AIH, etc.

[Clinical analysis of liver transplantation for autoimmune hepatitis].

OBJECTIVE: To describe the outcomes and recurrence of autoimmune hepatitis (AIH) after liver transplantation. METHODS: Clinical data of 16 patients with AIH who underwent liver transplantation were analyzed retrospectively. The postoperative cumulative survival rate of the patients was calculated. The postoperative rejections and AIH recurrence were analyzed. The Kaplan-Meier method was used for statistical analysis of survival. RESULTS: All patients were female, with an average age of 52.6 years (range: 41-66 years), and an average MELD score of 21.4. According serological analysis, 15 patients were AIH type 1 and 1 patient was AIH type 2. Three patients died, including 2 of pulmonary infection and 1 of graft dysfunction.The 1-, 2-and 5-year cumulative survival rates were 93.8%, 87.1% and 79.1%, respectively. Five cases (31.3%) of recurrent AIH were diagnosed based on histological evidence. Acute rejection occurred in 6 (37.5%) patients, and de novo HBV infection occurred in 1 (6.3%) patient. CONCLUSION: Liver transplantation is an effective treatment for end-stage AIH. Recurrence and rejection were commonly associated with AIH, but did not negatively impact patient survival.

Clinical-pathological analysis of hepatitis B virus recurrence after liver transplantation in Chinese patients.

BACKGROUND AND AIM: Liver transplantation (LT) for hepatitis B virus (HBV)-related disease can be complicated by HBV recurrence. The aim of this study was to evaluate the risk factors, prophylaxis treatment, and histological characteristics of HBV recurrence after LT when using long-term, low-dose hepatitis B immunoglobulin (HBIG) plus nucleoside analog (lamivudine [LAM] or entecavir [ETV]). METHODS: Retrospective data from 253 adult LT patients using long-term, low-dose HBIG plus nucleoside analog after LT, for a mean treatment duration of 1-72 months, were collected from a single center in Beijing, China. Univariate analyses were conducted to determine the association among gender, age, hepatocellular carcinoma, hepatitis B e antigen-positive status, HBV-DNA level and tyrosine-methionine-aspartate-aspartate (YMDD) mutations on HBV recurrence in these patients. RESULTS: Overall, the HBV recurrence rate was 6.32% (16/253). There was no significant difference in the survival rate between the HBV recurrence and non-recurrence groups. Risk factors for HBV recurrence were: hepatitis B e antigen positivity, HBV-DNA > 10(5) copies/mL, hepatocellular carcinoma, and YMDD mutation. Sixteen patients receiving LAM had HBV recurrence (16/169; mean treatment duration: 61.8 ± 18.3 months). No HBV recurrence occurred in patients receiving ETV after LT (0/84; mean treatment duration: 57.1 ± 15.9 months). Differences in rate of mortality and HBV recurrence were not significant between the two groups. CONCLUSIONS: LT is an effective treatment for HBV-related end-stage liver disease. The combination of ETV and intramuscular HBIG for HBV recurrence prophylaxis after LT was more effective than LAM, especially in Chinese patients with HBV recurrence risk factors.

Clinical Value of 68Ga-Pentixafor PET/CT in Subtype Diagnosis of Primary Aldosteronism Patients with Adrenal Micronodules.

Our objective was to investigate the clinical value of 68Ga-pentixafor PET/CT in subtype diagnosis of primary aldosteronism (PA) patients with adrenal micronodules less than 1 cm in diameter and compare it with the routine clinical methods. Methods: We used prospective enrollment of PA patients with adrenal micronodules identified by adrenal CT scans to undergo 68Ga-pentixafor PET/CT. Patients were divided into surgically eligible and ineligible groups based on surgical pathology and postoperative follow-up or adrenal venous sampling (AVS) results. Patient management was discussed by a multidisciplinary team. The semiquantitative parameters of PET/CT included SUVmax for adrenal lesion and SUV ratios for lesion to liver and lesion to normal adrenal gland. Results: In total, 123 PA patients with adrenal micronodules were examined using 68Ga-pentixafor PET/CT, and 104 patients who underwent surgery or successful AVS were included in the analysis (48 ± 10 y old). The sensitivity, specificity, and accuracy of visual analysis using 68Ga-pentixafor PET/CT to identify surgically eligible patients were 90.2%, 72.7%, and 86.5%, respectively, which were significantly higher than those of adrenal CT (73.1%, 53.8%, and 68.3%, respectively) and yielded consistent results in different CT morphologic or age subgroups. In 36 patients who had both AVS and 68Ga-pentixafor PET/CT, the tests showed a 66.7% concordance rate. However, PET/CT was significantly more concordant with surgical outcomes than was AVS in 17 patients who underwent adrenalectomy (82.4% vs. 68.86%). Among the 183 adrenal micronodules included in the study, the semiquantitative diagnostic thresholds for 92 lesions eligible for surgical treatment were an SUVmax of at least 4.55, an SUV ratio of at least 2.17 for lesion to liver, and an SUV ratio of at least 1.90 for lesion to normal adrenal gland. All patients benefited from surgical removal of 68Ga-pentixafor-avid microlesions. Conclusion: In PA patients with adrenal micronodules, 68Ga-pentixafor PET/CT demonstrated promising diagnostic accuracy in classification and appeared to perform better than adrenal CT. Furthermore, there was also a suggestion of some potential in predicting postoperative efficacy compared with AVS, although these observations require further investigation and verification in larger cohorts.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B.

BACKGROUND AND AIMS: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB). METHODS: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss. RESULTS: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period. CONCLUSION: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse Advanced Cancers Treated With Immunotherapy.

Importance: There are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers. Objective: To clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay. Design, Setting, and Participants: A prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022. Exposure: Treatment with US Food and Drug Administration (FDA)-approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI. Main Outcomes and Measures: The primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP). Results: In the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non-small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02). Conclusions and Relevance: In this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.

Development and internal validation of a novel predictive model for SDHB mutations in pheochromocytomas and retroperitoneal paragangliomas.

Aim: To develop and internally validate a novel predictive model for SDHB mutations in pheochromocytomas and retroperitoneal paragangliomas (PPGLs). Methods: Clinical data of patients with PPGLs who presented to Peking Union Medical College Hospital from 2013 to 2022 and underwent genetic testing were retrospectively collected. Variables were screened by backward stepwise and clinical significance and were used to construct multivariable logistic models in 50 newly generated datasets after the multiple imputation. Bootstrapping was used for internal validation. A corresponding nomogram was generated based on the model. Sensitivity analyses were also performed. Results: A total of 556 patients with PPGLs were included, of which 99 had a germline SDHB mutation. The prediction model revealed that younger age of onset [Odds ratio (OR): 0.93, 95% CI: 0.91-0.95], synchronous metastasis (OR: 6.43, 95% CI: 2.62-15.80), multiple lesion (OR: 0.22, 95% CI: 0.09-0.54), retroperitoneal origin (OR: 5.72, 95% CI: 3.13-10.47), negative 131I-meta-iodobenzylguanidine (MIBG) (OR: 0.34, 95% CI: 0.15-0.73), positive octreotide scintigraphy (OR: 3.24, 95% CI: 1.25-8.43), elevated 24h urinary dopamine (DA) (OR: 1.72, 95% CI: 0.93-3.17), NE secretory type (OR: 2.83, 95% CI: 1.22- 6.59), normal secretory function (OR: 3.04, 95% CI: 1.04-8.85) and larger tumor size (OR: 1.09, 95% CI: 0.99-1.20) were predictors of SDHB mutations in PPGLs, and showed good and stable predictive performance with a mean area under the ROC curve (AUC) of 0.865 and coefficient of variation of 2.2%. Conclusions: This study provided a novel and useful tool for predicting SDHB mutations by integrating easily obtained clinical data. It may help clinicians select suitable genetic testing methods and make appropriate clinical decisions for these high-risk patients.

Functional Cure of Chronic Hepatitis B with Antiviral Treatment in Children having High-level Viremia and Normal or Mildly Elevated Serum Aminotransferase.

Background and Aims: There is a lack of data supporting the notion that antiviral treatments can benefit children with chronic hepatitis B (CHB) having high viremia and normal or mildly elevated serum alanine aminotransferase (ALT) levels. We aimed to analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure. Methods: Forty-eight children with CHB having high viremia and normal or mildly elevated serum ALT levels were screened in this real-world study. Thirty-two children received either interferon-alpha (IFN-α) monotherapy, IFN-α therapy with a nucleoside analog (NA) add-on, or IFN-α and NA combination therapy. The 16 children in the control group did not receive antiviral treatment. All 48 children were available for follow-up assessments for the entire 36-month study period. We identified a functional cure with respect to hepatitis B virus (HBV) DNA loss, loss /seroconversion of circulating hepatitis B e antigen (HBeAg), and loss of hepatitis B surface antigen (HBsAg) with or without seroconversion. Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure. Results: After 36 months, the cumulative functional cure rate was 56.25% (18/32) in the treated group and 0% (0/16) in the control group (p<0.001). In the treated group, the serum HBV DNA levels declined rapidly at the end of a 6-month visit and the cured children achieved a loss rate of 100% (18/18) within 16 months of beginning treatment, compared with 64.29% (9/14) of the uncured children (p<0.001). The rates of HBeAg seroconversion were significantly higher among the cured children than among the uncured children (p<0.001). All 16 children in the control group maintained high levels of serum HBV DNA and were positive for both serum HBeAg and HBsAg during the entire 36 months of the study period. Functional cure was associated with younger ages (1-6 vs. 7-14 years, p=0.013), CD8+ T lymphocyte counts (p=0.013), and B lymphocyte counts (p=0.003). No serious adverse events were observed. Conclusions: Antiviral treatment achieved a functional cure of CHB in a high proportion of children having high-level viremia and normal or mildly elevated ALT levels. Younger age and high peripheral lymphocyte counts were associated with this functional cure.