Severe congenital neutropenia (SCN) is a rare inherited bone marrow failure syndrome characterized by profound neutropenia from early infancy, most commonly caused by heterozygous pathogenic variants in the ELANE gene. Affected children are predisposed to recurrent, severe bacterial and fungal infections. Palatal perforation has rarely been described in the setting of SCN. We report a seven-month-old infant with recurrent severe infections, profound neutropenia, palatal perforation, and nasal septal necrosis. Although invasive fungal infection was strongly suspected, repeated microbiological and histopathological investigations were negative. Genetic testing confirmed ELANE-associated SCN. This case highlights a rare presentation of SCN and emphasizes the importance of considering inherited neutropenia in infants with recurrent infections and destructive midline lesions for early diagnosis and timely treatment. This case highlights palatal perforation in ELANE-associated SCN. Recognition of such manifestations is important to avoid diagnostic delay and prompt early consideration of inherited neutropenia syndromes in infants with necrotic midline lesions.

Antibody-drug conjugates (ADCs) have shown promising efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases. This study aimed to investigate the efficacy and safety of brain radiotherapy combined with ADCs in patients with HER2-positive breast cancer and brain metastases in routine Chinese clinical practice. We retrospectively analyzed data from 35 patients with HER2-positive breast cancer and brain metastases treated with brain radiotherapy plus trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) at the Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, between January 2023 and January 2025. Most patients had prior pyrotinib treatment. Intracranial progression-free survival (iPFS), progression-free survival (PFS), overall survival (OS), and treatment safety were analyzed. Median follow-up was 15.7 months (interquartile range [IQR], 8.7-20.8). Median iPFS was 8.4 months (95% confidence interval [CI] 6.9-9.8), median PFS was 7.9 months (95% CI 5.9-10.4), and median OS was 11.8 months (95% CI 8.6-13.8). Intracranial objective response rate (ORR) was 74.3%, and intracranial disease control rate (DCR) was 94.3%. Median iPFS was 7.6 months in the T-DM1 group versus 10.9 months in the T-DXd group (P < 0.001); median PFS was 6.5 months versus 9.7 months (P = 0.021); median OS was 10.4 months versus 12.9 months (P = 0.046). The most common grade ≥3 adverse events were decreased appetite (23%), fatigue (11%), leukopenia (11%), and thrombocytopenia (9%). Among adverse events of special interest, radiation necrosis occurred in 9% (3/35), all were grade 1-2 and occurred exclusively in patients receiving concurrent radiotherapy plus T-DM1; interstitial lung disease occurred in 3% (1/35), grade 1, in the T-DXd group. In Chinese clinical practice, brain radiotherapy combined with either T-DXd or T-DM1 showed promising preliminary efficacy and tolerable safety signals in heavily pyrotinib-pretreated HER2-positive breast cancer patients with brain metastases in this retrospective single-center cohort. In this unadjusted retrospective cohort, patients receiving radiotherapy combined with T-DXd exhibited longer univariate survival outcomes compared with those treated with T-DM1. However, these univariate observational results are preliminary and require prospective multicenter validation with multivariate adjustment.

Anthracycline-free regimens have attracted growing interest because of less cardiac toxicity, especially in HER2-positive breast cancer when used in combination with trastuzumab and pertuzumab. This prospective, single-center trial (NEOPATH) aimed to assess the efficacy and safety of nab-paclitaxel combined with carboplatin in the neoadjuvant therapy of non-luminal breast cancer. The study was conducted in Ruijin Hospital between April 2019 and October 2021. Patients who had stage II-III TNBC or HER2-positive breast cancer were enrolled. Participants were treated with neoadjuvant nab-paclitaxel (100 mg/m[2]) and carboplatin (area under the curve 2) on days 1, 8, and 15, for four 4-week cycles. Concurrent trastuzumab at 2 mg/kg (loading dose 4 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) were given in patients with HER2-positive tumors. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included pCR rate in predefined subgroups, objective response rate (ORR), event-free survival (EFS), and safety profile. A total of 106 patients were enrolled in the study and 99 of them proceeded to surgery. The pCR (ypT0/is N0) rate was 41.41% in total, 33.78% in TNBC and 64.00% in HER2-positive breast cancer. Three-year EFS were 87.24% and 91.43% in TNBC and HER2-positive groups. ORR was 72.49% in total, 67.12% in TNBC and 88.00% in HER2-positive breast cancer. The most frequent grade 3 or higher adverse events were neutropenia (57%), vomiting (11%), and thrombocytopenia (8%). In conclusion, this anthracycline-free neoadjuvant regimen of nab-paclitaxel combined with carboplatin in non-luminal breast cancer demonstrated promising efficacy and was well-tolerated. Trial Registration: ClinicalTrials.gov under identifier NCT03907800.

Acute myeloid leukemia (AML) is accompanied by perturbations of the intestinal microbiome, but causal relationships remain incompletely defined because most patient data are cross-sectional and confounded by age, diet, antibiotic exposure, hospitalization, neutropenia, and chemotherapy. This review evaluates current evidence for AML-microbiome crosstalk, considering patient microbiome/metabolome associations; AML mouse and cell models; treatment-induced dysbiosis during induction chemotherapy and antimicrobial exposure; and microbiome-targeted interventions. The strongest AML-specific mechanistic evidence implicates intestinal barrier injury, microbial translocation/lipopolysaccharide (LPS) signaling, depletion of short-chain fatty acid (SCFA)-producing bacteria, altered propionate and butyrate availability, and bile-acid remodeling, including preclinical AML-inhibitory activity of chenodeoxycholic acid. Evidence for indoles, hydrogen sulfide, serotonin, precision probiotics, dietary interventions, time-restricted feeding, methionine restriction, and curcumin is more preliminary or extrapolated from non-AML cancer models. Fecal microbiota transplantation restores microbial diversity after induction therapy in early clinical trials, but infection-prevention and survival benefits remain unproven, and safety is a central concern in neutropenic and hematopoietic stem cell transplantation (HSCT) patients. We describe mechanistic gaps and propose a translational scheme that recommends longitudinal sampling, compartment-specific metabolite measurements, antimicrobial surveillance, and trial designs that distinguish microbiome restoration from clinical efficacy.

Glucose-6-phosphatase catalytic subunit 3 deficiency, also known as Dursun syndrome, is a rare autosomal recessive disorder characterized by severe congenital neutropenia and variable multisystem malformations, particularly affecting the cardiovascular system. Most reported cases have been identified postnatally, following infectious or hematologic complications. Prenatal identification remains exceptionally rare. We describe the case of a fetus from consanguineous parents with a history of multiple neonatal deaths. Serial prenatal imaging demonstrated progressive fetal growth restriction, cardiomegaly with biventricular hypertrophy, significant tricuspid regurgitation, right-sided cardiac dominance, right atrial enlargement, ventriculomegaly, and evolving craniofacial dysmorphism. Whole-exome sequencing revealed a homozygous nonsense variant in G6PC3 (NM_138387.3:c.481C > T; p.(Arg161Ter)), confirming that both parents were heterozygous carriers. Postnatally, the neonate developed severe neutropenia, complex right-sided cardiac outflow obstruction physiology, and refractory cardiorespiratory failure, leading to death on day 4 of life. This report expands the prenatal phenotypic spectrum of glucose-6-phosphatase catalytic subunit 3 deficiency and emphasizes the importance of considering this diagnosis in fetuses presenting with cardiomyopathy, dysmorphic features, fetal growth restriction, and parental consanguinity. Early molecular diagnosis enables accurate counseling, informed reproductive planning, and consideration of preconception or early prenatal genomic testing in high-risk families.

The prognosis of Richter Transformation (RT) with standard chemo-immunotherapy (CIT) remains poor. Several previous experiences with Venetoclax (V) in combination with CIT demonstrated the feasibility and safety of V-CIT based regimens in RT. This is a retrospective, observational multicenter study aimed to assess the efficacy and safety of the real-life use of V-CIT in the treatment of RT. Response assessments were evaluated according to the Lugano 2014 criteria. 20 consecutive patients treated with V-CIT based regimens from October 2018 to July 2024, were included. Median age was 63.5 years (33-73), with 75% of males. 11/17 were IGHV unmutated and 8/18 carried a mutation for Tp53 and/or a del17p. The median time from CLL diagnosis to RT was 6.5 years (0-17). A clonal relationship was demonstrated in 16/16 evaluable patients. The median number of prior treatments for CLL was 2 (0-4): CIT in 10, BTKi in 10, V based treatment in 4, no previous therapy in 5. V was associated with R-DA-EPOCH, R-CHOP, and BFM in 10, 9 and 1 patients for a median number of 4 cycles (1-6). ORR was 55% with 10 CR (50%) and 1 PR (5%). 3 patients had progressive disease (PD) and 1 died for multiorgan failure. 7 patients received allogeneic-HSCT consolidation. At a median follow up of 11.5 months (1-78), 10 patients, including 5 who received HSCT, are alive in CR; median PFS and OS were not reached. All patients experienced grade 3-4 hematological toxicities: neutropenia (100%), anemia (50%) and thrombocytopenia (25%). Non-hematological toxicities included: febrile neutropenia (15%), covid19 (25%), other infections (30%), nausea (10%), thrombotic/hemorrhagic events (10%). Data from this real-life experience confirm the feasibility and the activity of V-CIT based combination in younger fit RT patients, where the high rate of initial response may allow a significant proportion to receive allogeneic-HSCT consolidation. New studies with V combinations are ongoing and the comparison with this real-life data may be worthwhile to better understand their therapeutic impact.

The aim of this study was to evaluate the efficacy and safety of afatinib combined with oral metronomic vinorelbine as a second-line treatment for patients with advanced lung squamous cell carcinoma (LSCC). A retrospective analysis was conducted on 38 patients with advanced LSCC who had failed first-line platinum-based doublet chemotherapy combined with immunotherapy between January 2022 and June 2024. All patients received afatinib (30 mg or 40 mg orally once daily) combined with oral metronomic vinorelbine (20 mg or 30 mg orally three times weekly on Monday, Wednesday, and Friday) until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR), and treatment-related adverse events (TRAEs). Based on the data, the ORR was 26.3%, and the DCR was 68.4%. The median PFS was 5.0 months (95% CI: 4.7-5.4), and the median OS was 9.0 months (95% CI: 8.6-10.0). Grade ≥3 TRAEs occurred in 23.7% (9/38) of patients, including diarrhea (5.3%), rash (5.3%), neutropenia (5.3%), stomatitis (2.6%), and fatigue (2.6%). No grade 4-5 TRAEs or treatment-related deaths occurred. To conclude, the combination of afatinib and oral metronomic vinorelbine demonstrates promising antitumor activity and a manageable safety profile as a second-line treatment for advanced LSCC. This combo could represent an option as second-line after failure of chemo+IO.

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted treatment options. Platinum agents, particularly carboplatin's DNA damaging properties suggest efficacy, its impact on survival outcomes and toxicity remains uncertain.MethodsPubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov were searched from inception to February 2026. Phase II/III RCTs comparing carboplatin plus standard chemotherapy with standard therapy alone in TNBC were included. Primary outcomes were disease-free survival (DFS), overall survival (OS), and pathological complete response (pCR). Pooled hazard ratios (HRs) and risk ratios (RRs) were calculated using random-effects models.ResultsTwenty-three trials (n = 8797) were included. Carboplatin significantly improved DFS (HR 0.68, 95% CI 0.60-0.76), OS (HR 0.65, 95% CI 0.53-0.80), and pCR (RR 1.46, 95% CI 1.30-1.64). Improvements were also observed in distant disease-free survival and recurrence-free survival. However, carboplatin was associated with increased hematological toxicities, including anemia, neutropenia, and thrombocytopenia, and higher rates of dose reduction and treatment discontinuation, though treatment-related mortality was not significant.ConclusionCarboplatin-containing chemotherapy improves survival outcomes and pCR in TNBC. Despite increased toxicity, adverse effects are generally manageable. These findings support the incorporation of carboplatin into TNBC treatment, with careful patient selection to balance efficacy and safety.

Depletion of calcium from ER stores leads to the activation of calcium channels on the plasma membrane known as store-operated calcium entry. The proteins STIM1 and STIM2 function as ER calcium sensors, and upon store depletion, they undergo a conformational change that allows them to bind to and gate Orai calcium channels on the plasma membrane. We have shown that both Orai1 and STIM1 are dynamically S-acylated after store depletion, which is required for SOCE. These results suggest the requirement of a calcium-activated protein S-acyltransferase (PAT) such as DHHC21. Here, we show that DHHC21 is essential for SOCE in vitro and in vivo. Using the depilated mouse model that expresses DHHC21 but cannot be activated by calcium, we show that DHHC21 activation is a major mediator of STIM1 S-acylation and subsequent calcium entry. Plasma membrane-localized DHHC21 is dynamically recruited into Orai1/STIM1 puncta upon store depletion, where it physically binds to STIM1. Finally, we show that depilated mice phenocopy many aspects of autoimmune lymphoproliferative syndrome (ALPS), including defective Fas-mediated calcium release, T cell death, neutropenia, and increased serum vitamin B12 levels. Targeting DHHC21 may be therapeutically beneficial for ALPS and diseases associated with deregulated activation of STIM1, such as tubular aggregate myopathy and Stormorken syndrome.

Objective: To investigate the clinical features of regional portal hypertension (RPH) in children whose primary presentation was isolated gastric fundal varices. Methods: This case series study reviewed clinical data from 8 children diagnosed with RPH complicated with isolated gastric fundal varices at Beijing Children's Hospital, Capital Medical University from June 2017 to January 2026. Data on demographics, clinical manifestations, laboratory findings, diagnosis, and treatment were extracted and analyzed for etiology, clinical characteristics, and outcomes. Results: Among 8 children there were 6 males and 2 females, with a diagnostic age of 2.2-11.5 years. The underlying etiologies were pancreatic in 6 children (5 with severe pancreatitis complicated by pancreatic pseudocyst, and 1 with pancreatic involvement secondary to acute leukemia), all involving pancreatic body and tail. One child was of splenic origin (disseminated tuberculosis with splenic involvement), and 1 child was retroperitoneal (secondary to retroperitoneal neuroblastoma). Presenting features included abdominal pain (7 children), vomiting (6 children), and gastrointestinal bleeding (2 children, 1 of whom with isolated hematemesis, another 1 with hematemesis and melena). Splenomegaly occurred in 7 children. Ascites observed in 5 children, was attributed to the primary disease rather than to RPH. All 8 children had normal platelets, 3 children presented with leukopenia and anemia, which were attributed to the primary disease and secondary lesions. All 8 children had normal liver function, and coagulation function, but all demonstrated splenic vein abnormalities. All 8 children received treatment targeting at the underlying etiology. Somatostatin was administered to 5 children, and hemostatic agents to the 2 children with gastrointestinal bleeding. No child underwent endoscopic intervention. The follow-up ranged from 2 months to 8 years; 1 child with tuberculosis was lost to follow-up. The remaining 7 children showed symptomatic relief and improvement or complete resolution of gastric fundal varices. Conclusions: Regional portal hypertension often manifests as isolated gastric fundus varices and splenomegaly, and may be accompanied by gastrointestinal bleeding. Pancreatic, splenic, and retroperitoneal etiologies should be vigilanted. Individualized treatment strategies focused on the primary disease are crucial for improving pediatric RPH outcomes.

Objective: To evaluate the efficacy and safety of obinutuzumab (OBZ) in children with refractory nephrotic syndrome (RNS) who have a poor response to rituximab (RTX) therapy. Methods: This retrospective cohort study enrolled children with primary RNS who received OBZ because of poor response to RTX at the Children's Medical Center of Peking University First Hospital from July 2024 to December 2025. For each patient, outcomes during the OBZ treatment phase were compared with those during their preceding RTX treatment phase. Comparative parameters included duration of sustained B-cell depletion, duration of urinary protein remission, tapering of glucocorticoids and immunosuppressants, relapse frequency, and adverse events. Paired t-test, Wilcoxon signed-rank test, Mann-Whitney U test, χ[2] test and Fisher's exact test were adopted for statistical analysis according to the data type and distribution characteristics. Results: Thirteen children (10 males, 3 females) were enrolled. The age at disease onset was (47±13) months, and the age at first OBZ administration was (121±35) months. There were 3 cases of steroid-resistant and 10 cases of steroid-sensitive but frequently relapsing nephrotic syndrome. Compared with the RTX phase, the OBZ phase was associated with significantly longer durations of sustained B-cell depletion, sustained urinary protein remission, and annual glucocorticoid and calcineurin inhibitor (CNI) withdrawal (all P<0.05). The annual relapse frequency was significantly lower during OBZ treatment than during RTX treatment (0 (0, 0.3) vs. 1.9 (1.4, 2.6), Z=3.06, P=0.002). Regarding safety, 2 children developed mild transient infusion reactions (gastrointestinal discomfort and elevated blood pressure), which resolved with reduced infusion rate; 1 child discontinued OBZ due to concurrent pneumonia and otitis media; and 7 developed asymptomatic hypogammaglobulinemia. No severe adverse events, such as severe neutropenia, thrombocytopenia or organ dysfunction, were documented. Conclusions: For children with RNS who experience short B-cell depletion duration and frequent relapse after RTX therapy, OBZ provides more durable B-cell depletion, effectively prolongs urinary protein remission, reduces relapse risk, and facilitates safer glucocorticoid tapering. These findings suggest that OBZ may serve as a viable alternative therapeutic option for this specific pediatric population.

Therapeutic plasma exchange is a second-line therapy for severe hyperthyroidism when anti-thyroid drugs (ATD) are contraindicated or ineffective. We report five patients (three males, two females, age range: 30-70 years old): ATD-induced agranulocytosis (n = 2); ATD-induced cholestatic hepatitis (n = 1); refractory hyperthyroidism with large goiter (n = 1); thyroid storm during pregnancy (n = 1). A total of six TPE sessions were performed (five with fresh frozen plasma, one with 5% albumin). Among sessions with quantifiable baseline fT4, levels decreased by a mean of 39.0% per session; two sessions had baseline fT4 above the assay's upper limit of quantification, precluding exact calculation, though both showed reductions of at least 50%. Four patients underwent successful thyroidectomy; one continued medical management. No intraoperative thyroid storms occurred. TPE could be an effective bridging strategy for patients with severe hyperthyroidism and ATD intolerance.