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Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases.

Background The treatments for refractory leptomeningeal metastasis (RLM) of non-small cell lung cancer (NSCLC) are limited, and response assessment is complex and challenging. This clinical trial aimed to evaluate the efficacy of intrathecal pemetrexed (IP) and response assessment using cerebrospinal fluid (CSF) tumor marker in RLM. Methods This was a single-center, single-arm, phase II adaptive clinical trial. Patients with RLM of NSCLC were eligible for inclusion. Patients were assigned to receive 30 mg of IP every 3 weeks for a total of 6 cycles. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS) evaluated according to EANO-ESMO response assessment, disease control rate, the concordance of CSF tumor marker response with EANO-ESMO response assessment, and safety. Results A total of 29 patients were enrolled in the trial. The median PFS was 10.03 months (95% CI, 6.42–13.64), and the median OS was 20.37 months (95% CI, 14.86–25.88), respectively. A ± 35% threshold for CSF tumor marker level change (TML) yielded the optimal predictive performance, with AUCs of 0.890 (95% CI, 0.833–0.947), 0.911 (95% CI, 0.870–0.951), and 0.784 (95% CI, 0.717–0.850) for EANO-ESMO response, progression, and stable, respectively. Most patients (93.1%) experienced grade 1–2 treatment-related adverse events. Conclusions Our therapeutic regimen of IP provided a practical, survival-extending, and tolerant option for RLM patients. CSF tumor marker response was correlated with EANO-ESMO response assessment, offering an effective tool for response monitoring of RLM. Trial registration Chinese Clinical Trial Register (ChiCTR) ChiCTR2200057235. Registered on March 1, 2022. Date of the first patient enrollment: April 29, 2022.

Angioimmunoblastic T-cell lymphoma (AITL) represents the second most prevalent subtype of peripheral T-cell lymphoma, characterized by a dismal prognosis. However, a systematic exploration of tumor microenvironment (TME) features and their prognostic significance in AITL remains notably deficient. To address this knowledge gap, we conducted spatial transcriptome sequencing (ST-SEQ) and whole-exome sequencing in four AITLs and two noncancerous lymph nodes for discovery purposes, complemented by immunohistochemistry analyses on 37 AITL cases for validation. We identified 14 ST clusters, including five neoplastic clusters, wherein a global shift in B-cell phenotypes and enrichment of myeloid cells were observed. These findings underscore a hallmark of exacerbated inflammation and immune dysregulation within the neoplastic TME. Among the 4 ST-sequenced AITLs, 3 expressed high CD40 - CD40LG activity, accompanied by the upregulation of immune-suppressive-associated genes, such as CCL17 and PDCD1 . Conversely, the remaining patient displayed an uncommon absence of CD40 - CD40LG activity but harbored a phagocytosis-associated tumor-associated macrophage (TAM)-enriched TME, which correlated with significantly reduced relapse rates and longer event-free survival (EFS), highlighting the critical value of precise TME stratification in tailoring AITL therapeutic strategies. Finally, trajectory analysis unveiled a distinct trajectory of molecular evolution within this TME landscape. Collectively, our findings illuminate the heterogeneity and prognostic implications of the TME in AITL, providing a robust foundation for the rational design of targeted immunotherapeutic approaches. These insights may substantially advance the development of personalized treatment strategies for AITL patients.

BackgroundCellular senescence is a key element in the occurrence and progression of a variety of tumors. As a result, cellular senescence-related markers can be categorized based on the prognosis status of patients. Due to the heterogeneity and the complexity of the tumor microenvironment (TME), the long-term effectiveness of low-grade glioma (LGG) treatment remains a clinical challenge. Consequently, developing and refining effective treatment approaches to aid with LGG management is critical.MethodsBased on the expressions of cell senescence-related genes (CSRGs) acquired from the cellAge database, consensus clustering was utilized to identify stable molecular subtypes. Clinical features, immune infiltration, route modifications, and genetic changes of various subtypes were also assessed. Following that, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis were used for developing the cell senescence-related risk score (CSRS) model. Finally, a correlation study of the CSRS model with molecular, immunological, and immunotherapy parameters was performed.ResultsC1, C2, and C3, are the three senescence-related subtypes that were identified. Patients belonging to the C1 subtype had poor prognoses and a substantial proportion of them was in the grade G3. The differentially expressed genes (DEGs) among the three subtypes were used to develop the CSRS model. In both the training and independent validation cohort, the model had a high area under the receiver operating characteristic (ROC) curve in predicting the overall survival (OS) of patients. As a result, this model can predict clinical features and responses to immunotherapy in a variety of patients and it is a potential independent prognostic factor for LGG.ConclusionThis research discovered three LGG subtypes related to cell senescence and created a CSRS model for six genes. Cell senescence was highly associated with unfavorable prognosis in LGG. The CSRS model can be used to predict the prognosis of patients and identify patients who would benefit from immunotherapy.

Background: Situs inversus totalis (SIT) is a rare genetic congenital disease, characterized with complete right-to-left inversion of all the internal organs. We herein describe a meaningful case which was diagnosed as gallbladder adenosquamous carcinoma, a rare histology type of gallbladder cancer, with SIT. Case Presentation: A 59-year-old Chinese woman was admitted for persistent epigastric distention and intermittent abdominal pain. The abdominal CT scan revealed a huge mass at the gallbladder bottom, involving the adjacent transverse colon and liver. En- bloc radical resection of the gallbladder cancer, including partial colectomy and hepatectomy with regional node dissection, followed by colocolostomy and Roux-en-Y choledochojejunostomy, was successfully performed. Pathology analysis indicated an adenosquamous carcinoma with positive adenocarcinoma markers (CK7, CK19) and squamous carcinoma markers (CK5/6, P63). Conclusion: The SIT anomaly might increase the risk of malignancies by sharing genome mutations, suggesting the importance of surveillance in the SIT settings. Keywords: situs inversus totalis, gallbladder adenosquamous carcinoma

Immunohistochemistry (IHC) is a vital tool to distinguish tumor metastases from primary lesions in addition to morphologic analysis. In this study, a 64-year- old female with a past surgical history of lung adenocarcinoma 11 years ago was presented with recurrence of liver nodular lesions after multiple surgical procedures, including the Whipple procedure for pancreatic head adenocarcinoma and cytoreductive surgery for liver metastasis. Liver biopsy and review of the previous specimens, based on IHC analyses, suggested heterochronous metastases of lung adenocarcinoma to the digestive systems in a long-time span, instead of primary pancreatic adenocarcinoma. This case demonstrates the potential for misdiagnoses from morphologic analysis alone and suggests the necessity of IHC analyses to avoid misjudgment on tumor phenotypes, when a previous oncologic history is presented. Keywords: heterochronous metastases, lung adenocarcinoma, immunohistochemistry

Background Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM. Methods Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well. Results Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia ( p  = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) ( p  = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed. Conclusion Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

Renal angiomyolipoma (AML) is the most common type of benign mesenchymal tumor of the kidney. AMLs typically present as benign lesions without local invasion. However, the tumor may exhibit aggressive behavior. Intravascular extension into the inferior vena cava (IVC) and hemorrhagic aneurysm formation associated with AML has rarely been reported in the past. In the current study, the novel case of a 77-year-old female is described who presented with a tumor thrombus extending to the IVC. The patient subsequently underwent a radical nephrectomy and an IVC tumor thrombectomy. In addition, the available literature regarding this unusual complication of a common renal neoplasm has been reviewed. It is essential for radiologists and clinicians to be aware that AMLs may exhibit these types of aggressive behaviors.

We aimed to explore the association of blood Zn, Fe, and Cu concentrations and changes in the pediatric risk of mortality (PRISM) score in critically ill children, to predict prognosis. We included 31 children (22 boys and 9 girls, 1 month to 5 years old), who had been admitted to the intensive care unit of our hospital and who were critically ill according to PRISM score of III. Another 20 children (12 boys, 8 girls, 3 months to 5 years old) who were brought to the hospital for a health checkup were included as controls. We recorded clinical data, time in the intensive care unit, prognosis, and PRISM III score for critically ill children. Blood Cu, Zn, and Fe values were measured by inductively coupled plasma atomic emission spectrophotometry. Zn and Fe levels were significantly lower in patients than in controls (all p  < 0.05). Cu levels differed between patients and controls, but not significantly ( p  > 0.05). In ill children, blood Zn and Fe concentrations were inversely correlated with PRISM III score (Zn: r  = −0.36; Fe: r  = −0.50, both p  < 0.05), with no significant correlation of blood Cu level and PRISM III score ( r  = −0.13, p  > 0.05). Serious illness in children may lead to decreased Zn and Fe blood concentrations. Zn and Fe supplements may be beneficial for critically ill children.

Developing digital inclusive finance is one of the most effective ways to alleviate financial exclusion in the agriculture sector. For empirical investigation, data from 30 provinces of Rural China is collected from the period 2011 to 2020. The study constructs five dimensions and 22 indicators in total to critically conduct the impact of digital inclusive finance on high-quality agricultural development. The level of agricultural development is measured by entropy weight TOPSIS, and the impact of digital inclusive finance on its high-quality development is empirically tested. The results show that digital inclusive finance has significantly improved the agricultural sector and, particularly, the Eastern region of China has the greatest impact. Three dimensions of digital inclusion finance have regional heterogeneity in terms of impact on agricultural development in Rural China. Data does not show the simple linear relationship between digital inclusion finance and agricultural development quality. The impact of the former on the latter is characterized by the double thresholds. The digital inclusive finance index is the weakest when it is lower than the first threshold that is 4.7704, and the impact of the second threshold that is 5.3186 on high-quality agricultural development is gradually enhanced. After crossing the second threshold, the impact of digital inclusive finance on high-quality agricultural development in Rural China is significantly enhanced. The development of digital inclusive finance should be strengthened in the Central and Western regions to compensate for regional financial imbalances and promote synergy in the high-quality development of agriculture across the country.