The patient, a 28-year-old male, had experienced splenomegaly for four years with lymphadenopathy for more than two months and presented to the First Affiliated Hospital of the Naval Medical University on October 16th, 2024. On July 31, 2024, he noticed right upper quadrant pain, and an enhanced abdominal CT performed in an external facility revealed splenomegaly with a rounded nodular lesion at the splenic hilum, suggestive of an accessory spleen; in addition to retroperitoneal lymphadenopathy, while tumor marker levels were unremarkable. A complete blood count on August 22nd, 2024, demonstrated leukopenia (2.22×10 9/L), hemoglobin level of 144 g/L, and thrombocytopenia (60×10 9/L). To further elucidate the diagnosis, the patient visit our hematology clinic on August 26th, 2024. His physical examination was normal in general condition, except for a firm palpable spleen 10 cm below the left costal margin, and ultrasonography revealed right thyroid nodule and hepatosplenomegaly. Because of hepatosplenomegaly and retroperitoneal lymphadenopathy, a PET-CT scan was performed. The scan confirmed marked hepatosplenomegaly, multiple enlarged lymph nodes in the retroperitoneal and mesenteric regions with increased metabolic activity, and evidence of elevated bone metabolic activity in the proximal limbs and axial skeleton. Given the possibility of a hematologic lymphoproliferative disorder, a bone marrow biopsy was recommended. On September 12th, 2024, the patient underwent a bone marrow biopsy for evaluations of cell morphology, initial lymphoma immunophenotyping, cytogenetic analysis, and lymphoma-related FISH testing. Flow cytometry, cytogenetic analysis, and FISH results on September 14th, 2024, were unremarkable, manual microscopy of bone marrow morphological evaluation revealed a small population of poorly differentiated lymphocytes; additionally, AI-assisted automated cell scan identified a subset of abnormal cells suspected to be ′Gaucher cells′. Bone marrow pathology indicated a histiocytic neoplasm accompanied by stage 2 myelofibrosis (MF), with tumor cells comprising approximately 70% of the nucleated cells in the marrow, suggesting immunohistochemistry for confirmation. On October 16th, immunohistochemical analysis confirmed the presence of a histiocytic proliferative disorder suspecting Gaucher disease. After admission, the patient initiated enzyme replacement therapy, receiving an initial intravenous dose of 60 U/kg in a weekly basis. On October 31st, 2024, based on enzyme activity assays, genetic testing, and other results, adult Gaucher disease was finally diagnosed. The patient was scheduled for follow-up with stable vital signs, and reduced size of the spleen compared with previous assessments.

The patient, a 28-year-old male, had experienced splenomegaly for four years with lymphadenopathy for more than two months and presented to the First Affiliated Hospital of the Naval Medical University on October 16th, 2024. On July 31, 2024, he noticed right upper quadrant pain, and an enhanced abdominal CT performed in an external facility revealed splenomegaly with a rounded nodular lesion at the splenic hilum, suggestive of an accessory spleen; in addition to retroperitoneal lymphadenopathy, while tumor marker levels were unremarkable. A complete blood count on August 22nd, 2024, demonstrated leukopenia (2.22×10 9/L), hemoglobin level of 144 g/L, and thrombocytopenia (60×10 9/L). To further elucidate the diagnosis, the patient visit our hematology clinic on August 26th, 2024. His physical examination was normal in general condition, except for a firm palpable spleen 10 cm below the left costal margin, and ultrasonography revealed right thyroid nodule and hepatosplenomegaly. Because of hepatosplenomegaly and retroperitoneal lymphadenopathy, a PET-CT scan was performed. The scan confirmed marked hepatosplenomegaly, multiple enlarged lymph nodes in the retroperitoneal and mesenteric regions with increased metabolic activity, and evidence of elevated bone metabolic activity in the proximal limbs and axial skeleton. Given the possibility of a hematologic lymphoproliferative disorder, a bone marrow biopsy was recommended. On September 12th, 2024, the patient underwent a bone marrow biopsy for evaluations of cell morphology, initial lymphoma immunophenotyping, cytogenetic analysis, and lymphoma-related FISH testing. Flow cytometry, cytogenetic analysis, and FISH results on September 14th, 2024, were unremarkable, manual microscopy of bone marrow morphological evaluation revealed a small population of poorly differentiated lymphocytes; additionally, AI-assisted automated cell scan identified a subset of abnormal cells suspected to be ′Gaucher cells′. Bone marrow pathology indicated a histiocytic neoplasm accompanied by stage 2 myelofibrosis (MF), with tumor cells comprising approximately 70% of the nucleated cells in the marrow, suggesting immunohistochemistry for confirmation. On October 16th, immunohistochemical analysis confirmed the presence of a histiocytic proliferative disorder suspecting Gaucher disease. After admission, the patient initiated enzyme replacement therapy, receiving an initial intravenous dose of 60 U/kg in a weekly basis. On October 31st, 2024, based on enzyme activity assays, genetic testing, and other results, adult Gaucher disease was finally diagnosed. The patient was scheduled for follow-up with stable vital signs, and reduced size of the spleen compared with previous assessments.

OBJECTIVE：To evaluate th e effectiveness ，safety and economy of albu min-bound paclitaxel （nab-PTX）in the treatment of breast cancer by using rapid health technology assessment （HTA），and to provide evidence-based reference for drug selection. METHODS ：Retrieved from PubMed ，the Cochrane Library ，CNKI，Wangfang database and other databases ，systematic evaluation/Meta-analysis，HTA and pharmacoeconomic studies about nab-PTX in the treatment of breast cancer were included ；the conclusions were classified and analyzed by using descriptive analysis. RESULTS ：A total of 5 systematic reviews/Meta-analysis ， 8 pharmacoeconomic studies were included in this study. Compared with conventional taxanes ，nab-PTX increased pathological complete response （pCR）rate [OR ＝1.39，95％CI（1.16，1.67），P＜0.001] and event-free survival （EFS）[HR＝0.69，95％CI（0.57， 0.85），P＜0.001] in neoadjuvant chemotherapy （NAC）-treated breast cancer patients. However ，there were no significant differences in overall survival （OS），progression-free survival （PFS），objective response rate （ORR）and disease control rate （DCR）in metastatic breast cancer （MBC）patients between 2 groups. In the terms of safety ，nab-PTX increased the incidence of grade 3-4 sensory neuropathy [OR ＝1.89，95％CI（1.36，2.61），P＜0.001] in MBC patients ，and increased the incidence of neutropenia [OR ＝ 1.52，95％CI（1.23，1.88，P＜0.001]，sensory neuropathy [OR ＝ 2.17，95％CI（1.38，3.40），P＜0.001]，rash [OR ＝1.46，95％CI mei1213@163.com （1.18，1.80），P＜0.001] and fatigue [OR ＝1.28，95％CI（1.04， 1.56）， P＝0.02] in NAC -treated breast cancer patients.Pharmacoeconomic studies showed that nab-PTX could improve the quality adjusted lif e years of MBC patients compared with traditional taxanes ，and it was a economical option. CONCLUSIONS：Nab-PTX enhances pCR in NAC-treated breast cancer patients ，but has no significant advantage in the effectiveness of MBC patients ，and increases the occurrence of ADR. Nab-PTX may have a cost-utility advantage over conventional taxanes for MBC.

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1 cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
Anilides ; pharmacology ; Basal Cell Nevus Syndrome ; Hedgehog Proteins ; genetics ; pharmacology ; Humans ; Molecular Targeted Therapy ; Odontogenic Cysts ; genetics ; physiopathology ; therapy ; Odontogenic Tumors ; genetics ; physiopathology ; therapy ; Pyridines ; pharmacology

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS).OKCs are locally aggressive,cause marked destruction of the jaw bones and have a propensity to recur.PTCH1 mutations (at ～80％) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs,suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis.Thus,small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs.However,studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture.Here,we constructed an isogenic PTCH1R135X/+ cellular model of PTCH1 inactivation by introducing a heterozygous mutation,namely,c.403C＞T (p.R135X),which has been identified in OKC patients,into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Casg) system.This was followed by the induction of epithelial differentiation.Using this in vitro isogenic cellular model,we verified that the PTCH1R135X/+ heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency.This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449.In addition,through inhibition of activated SHH signalling,the enhanced proliferation observed in these induced cells was suppressed,suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.