A novel anti-CD47 protein antibody and toll-like receptor agonist complex detects tumor surface CD-47 changes in early stage lung cancer by in vivo imaging.

CD47, a cell surface protein known for inhibiting phagocytosis, plays a critical role in the tumor microenvironment (TME) and is a potential biomarker for cancer. However, directly applying αCD47, a hydrophilic macromolecular antibody that targets CD47, in vivo for cancer detection can have adverse effects on normal cells, cause systemic toxicities, and lead to resistance against anti-cancer therapies. In this study, we developed a novel complex incorporating aluminum-based metal-organic frameworks (Al-MOF) loaded with indocyanine green (ICG), αCD47, and resiquimod (R848), a hydrophobic small molecule Toll-like receptor 7/8 (TLR7/8) agonist. Upon activation with an infrared 808 nm laser, the nanocomposites exhibited photothermal effects that triggered the release of the loaded reagents, induced ROS production, and induced changes in the TME. This led to the polarization of immune-suppressive M2 macrophages towards an immune-stimulatory M1 phenotype, promoted dendritic cell (DC) maturation, and enabled mature DCs to facilitate antigen presentation, T-cell activation, and critical roles in tumor immunity. Furthermore, in vivo imaging successfully detected the specific binding of αCD47 with CD47 on tumor cells. Overall, the complex composed of αCD47 antibody and toll-like receptor agonist showed promising efficacy in both tumor diagnosis and therapy, providing a potential strategy for detecting early lung cancer and modulating the tumor microenvironment for improved treatment outcomes.

Real-world outcomes of immunotherapy-based neoadjuvant therapy in resectable non-small cell lung cancer.

Objectives: Recent clinical studies have demonstrated that immunotherapy-based neoadjuvant therapy have promising effectiveness for patients with resectable non-small cell lung cancer (NSCLC) in terms of pathologic response. Therefore, we performed this study to investigate whether immunotherapy-based neoadjuvant therapy is effective and safe for patients with resectable NSCLC. Materials and methods: This open-label observational two-arm clinical study was performed at Shanghai Chest Hospital in China with patients who had resectable NSCLC and received two to three cycles of immunotherapy-based neoadjuvant therapy or neoadjuvant chemotherapy alone, followed by surgical resection. The primary endpoint was a major pathologic response (MPR). The secondary endpoints include a complete pathological response (pCR), a radiologic response to neoadjuvant therapy (TRR), event-free survival (EFS), and overall survival (OS). Results: A total of 51 patients was included in this clinical study, of which 31 patients received immunotherapy-based neoadjuvant therapy and 20 patients received neoadjuvant chemotherapy alone. The percentage of patients achieving a major pathologic response was 41.9% with immunotherapy-based neoadjuvant therapy and 15.0% (95% CI, 0.008 to 0.468; P = 0.043) with neoadjuvant chemotherapy alone. The percentage of patients with pathologic complete response was 19.4% in the immunotherapy-based group and 5% (95% CI, -0.069 to 0.318; P = 0.223) in the chemotherapy group. The radiographic response rate was 71% after immunotherapy-based neoadjuvant therapy and 60% (95% CI, -0.143 to 0.359; P = 0.417) after neoadjuvant chemotherapy. At a median follow-up of 28 months, the median EFS and OS endpoints were not reached. Conclusions: Neoadjuvant immunotherapy offers a considerable advantage over chemotherapy alone for resectable NSCLC in terms of the major pathologic response. Moreover, it did not enhance the risk of adverse events or hinder surgical resection.

An open, observational clinical study of neoadjuvant therapy in resectable stage III non-small cell lung cancer.

Background: This open, observational clinical study aimed to investigate the efficacy, safety and survival outcomes of neoadjuvant chemotherapy, neoadjuvant immunotherapy with(out) chemotherapy and neoadjuvant targeted therapy among resectable stage III non-small cell lung cancer (NSCLC) patients (NCT04197076) in real world. 48 of the 57 evaluable patients were included in this interim analysis. Methods: This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years or older and had resectable clinical stage III disease. Surgical resection was conducted after neoadjuvant chemotherapy (13 patients), immunotherapy with(out) chemotherapy (26 patients), and targeted therapy (9 patients). Disease-free survival (DFS) was evaluated as the primary endpoint. The secondary endpoint was pathological complete response (pCR) rate. Clinical response rate (cRR), related adverse events (AEs), surgical feasibility and pathological features were also discussed in this study. Results: Significant differences in DFS were noted between chemotherapy and immunotherapy [7.7 months (range, 3.1 to 23.2 months) vs. 9.6 months (range, 4.0 to 47.9 months); P=0.032], and between chemotherapy and targeted therapy [7.7 months (range, 3.1 to 23.2 months) vs. 13.2 months (range, 7.5 to 32.2 months); P=0.015], but not between immunotherapy and targeted therapy (P=0.500). Subgroup analysis also favored neoadjuvant immunotherapy and targeted therapy. 5 patients achieved pathological complete response (pCR), all of whom were in the neoadjuvant immunotherapy arm, leading to a pCR rate of 19.2% in this arm. Treatment-emergent adverse events (TEAEs) of over grade 3 occurred in 11 patients (19.3%), with 5 (29.4%) in the chemotherapy arm, 5 (16.7%) in the immunotherapy arm and 1 (10.0%) in the targeted therapy arm. One grade 4 and one grade 2 surgery-related serious adverse event occurred in the neoadjuvant chemotherapy and immunotherapy arm, respectively. Conclusion: In patients diagnosed with resectable stage III NSCLC, neoadjuvant immunotherapy and neoadjuvant targeted therapy were associated with significantly longer disease-free survival compared with neoadjuvant chemotherapy. Clinical and pathological response rates were also higher in the immunotherapy and targeted therapy arm. Adverse events were found to be manageable and similar across all three groups, and surgical feasibility favored immunotherapy or targeted therapy rather than chemotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04197076.

A durable response to savolitinib in a patient with lung adenocarcinoma harboring two novel MET exon 14 skipping sites.

MET exon 14 ( METex14 ) skipping variants are oncogenic drivers in non-small-cell lung cancer. Several METex14 skipping alterations have been identified, but different mesenchymal-epithelial transition (MET) exon splicing variants tend to present different clinical outcomes. Here, we reported that a patient with lung adenocarcinoma harbored two novel METex14 skipping mutations (c.2888-35_2888-16del and c.2888-4T>G) identified by the tissue-based next-generation sequencing (NGS) and received savolitinib treatment after chemotherapy failed with brain metastasis. The patient responded well to savolitinib until disease progression in brain lesions and achieved a progress-free survival (PFS) of over 19.7 months. Considering the durable response for extracranial lesions and the same METex14 skipping sites identified by circulating tumor DNA-based NGS, the patient was still given savolitinib combined with stereotactic body radiation therapy for brain lesions. An extracranial PFS of 28 months was achieved. This is the first report of a patient with lung adenocarcinoma harboring two novel METex14 skipping mutations that responded to the MET inhibitor savolitinib. Our case may provide evidence for the treatment of patients with two novel METex14 skipping variants and offer a therapy regimen for those with intracranial progression.

Durable response to low-dose pralsetinib in a renal insufficient patient with NSCLC harboring concurrent CCDC6-RET, LINCO1264-RET, and SEMA5A-RET fusions: A case report.

INTRODUCTION: RET-rearranged fusions have been considered as oncogenic drivers in 1% to 2% of non-small cell lung cancers (NSCLC). ARROW study has demonstrated a new selective RET tyrosine kinase inhibitors (TKIs) shows remarkable and durable responses in RET-rearranged NCSLC. In this study mainly recruited patients with common fusion partners KIF5B and CCDC6. There is still a lack of definitive conclusions about effective of rare RET fusion variants to anti-RET therapies. CASE REPORT: A Chinese 58-year-old female renal insufficient patient with no history of smoking was diagnosed as stage IIIA (T2N2M0) lung adenocarcinoma. Next-generation sequencing targeting 520 cancer-related genes was performed on the pleural effusion samples and revealed 2 novel RET fusions LINCO1264-RET and SEMA5A-RET, concomitant with a common CCDC6-RET. MANAGEMENT AND OUTCOME: The patient was first treated with multiple lines of chemotherapy and switched to lenvatinib but failed to respond. Due to renal insufficiency, she subsequently received pralsetinib with gradually reduced dosages (400 mg-300 mg-200 mg-100 mg qd) and achieved a partial response (PR) lasting for more than 10 months, accompanied by the declined allele frequencies of all 3 RET fusions. DISCUSSION/CONCLUSIONS: We reported the first case of the pralsetinib efficacy in NSCLC with 3 concurrent RET fusions. Our case also indicates the sensitivity of the newly identified RET fusions to this RET selective inhibitor pralsetinib, and highlights the low-dose treatment option for patients with renal insufficient background.

Integrative genomic analysis of drug resistance in MET exon 14 skipping lung cancer using patient-derived xenograft models.

Background: Non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. While MET targeted therapy has led to strong clinical results in METex14 patients, acquired drug resistance seemed to be unavoidable during treatment. Limited information is available regarding acquired resistance during MET targeted therapy, nor has there been any report on such patient-derived xenografts (PDXs) model facilitating the research. Methods: We describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) to evaluate their drug response in vivo. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts. Results: PDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly acquired MET D1228H mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off-target resistance through the EGFR bypass signaling pathway. As expected, EGFR-MET bispecific antibodies overcome drug resistant in the PDX model. Conclusions: We detected a novel MET splice site deletion mutation that could lead to METex14. We also established and characterized a pair of METex14 NSCLC PDXs, including the first crizotinib resistant METex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance METex14 lung cancer.

SMO mutation predicts the effect of immune checkpoint inhibitor: From NSCLC to multiple cancers.

Background: The emergence of immune checkpoint inhibitors (ICIs) is one of the most promising breakthroughs for the treatment of multiple cancer types, but responses vary. Growing evidence points to a link between developmental signaling pathway-related genes and antitumor immunity, but the association between the genomic alterations in these genes and the response to ICIs still needs to be elucidated. Methods: Clinical data and sequencing data from published studies and our cohort were collected to analyze the association of the mutation status of SMO with the efficacy of ICI therapy in the non-small cell lung cancer (NSCLC) cohort and the pan-cancer cohort. Furthermore, the correlation between SMO mutation and immunotherapeutic biomarkers such as immune cell infiltration, immune-related genes, and underlying signaling pathways was analyzed. Three SMO mutant plasmids were transfected into cells to explore the SMO mutation status in the context of its expression and cell growth. Result: In the NSCLC discovery cohort, the median progression-free survival in the SMO mutant (SMO_MUT) was longer than that in the wild type (SMO_WT) (23.0 vs. 3.8 months, adjusted p = 0.041). This finding was further confirmed in the NSCLC validation cohort (8.7 vs. 5.1 months, adjusted p = 0.013). In the pan-cancer cohort (n = 1,347), a significant overall survival advantage was observed in patients with SMO mutations [not reached (NR) vs. 18 months, adjusted p = 0.024]. In the subgroup analysis, the survival advantage of SMO_MUT against SMO_WT was prominent and consistent across genders, ages, treatment types, cancer types, and the tumor mutation burden (TMB) status (all p interaction > 0.05). In an in vitro experiment, we found that both the mutant and wild-type plasmids can promote the expression of SMO, but the mutant plasmid had lower SMO mRNA and protein levels than the wild type. In CCK-8 experiments, we found that SMO_MUT plasmids can improve the growth of Calu-1 and PC-9 cells, but this capability varied between different mutations and cells. Upon further exploration, the SMO mutation status was found to be related to a higher TMB, more neoantigen load, more DNA damage repair (DDR) mutations, higher microsatellite instability (MSI) score, and higher CD8+ T-cell infiltration. Conclusions: The SMO mutation status is an independent prognostic factor that can be used to predict better clinical outcomes of ICI treatment across multiple cancer types.

An open, observational, three-arm clinical study of 2-3 cycles of treatment as neoadjuvant therapy in operable locally advanced non-small cell lung cancer: An interim analysis.

Background: An open, observational, three-arm clinical study aimed at investigating the efficacy of different neoadjuvant therapies (neoadjuvant immunotherapy with(out) chemotherapy, neoadjuvant chemotherapy, and neoadjuvant targeted therapy) in operable locally advanced non-small cell lung cancer (NSCLC) was conducted (NCT04197076). We report an interim analysis of 49 of 53 evaluable patients. Methods: This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years old and had clinical stage IIB-IIIB disease. All 49 patients had surgical resection within 4-6 weeks after 2-3 cycles of neoadjuvant treatment consisting of immunotherapy (24 patients), chemotherapy (16 patients), and a targeted therapy (9 patients) regimen starting on the first day of each 21-day cycle. Pathologic complete response (pCR) was evaluated as the primary endpoint. Major pathological response (MPR) and tumor regression rate (TRR) were also evaluated. Results: An improved pathologic complete response was achieved in the neoadjuvant immunotherapy arm compared with the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [20.8% (5/24) vs. 6.3% (1/16) vs. 0.0% (0/9); P = 0.089, 95% CI 0.138-0.151]. More importantly, we found that the curative effect of the neoadjuvant immunotherapy arm in pCR+MPR was better than that of the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [45.8% (11/24) vs. 18.8% (3/16) vs. 0.0% (0/9); P = 0.006, 95% confidence interval, 0.008-0.012]. Different neoadjuvant therapies had a statistically significant effect on postoperative pathological tumor downstaging (P = 0.017). Conclusions: Neoadjuvant immunotherapy was associated with a trend toward better pCR than the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy. Curative effect (pCR + MPR) was significantly better with neoadjuvant immunotherapy (P = 0.006, 95% confidence interval, 0.008-0.012). Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04197076?recrs=a&cond=NCT04197076&draw=2&rank=1.

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.

BACKGROUND: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. METHODS: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. RESULTS: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. CONCLUSIONS: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

Identification of a 15 DNA Damage Repair-Related Gene Signature as a Prognostic Predictor for Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a common malignancy with a poor prognosis due to the lack of predictive markers. DNA damage repair (DDR)-related genes are closely related to cancer progression and treatment. INTRODUCTION: To identify a reliable DDR-related gene signature as an independent predictor of LUAD. METHODS: DDR-related genes were obtained using combined analysis of TCGA-LUAD data and literature information, followed by the identification of DDR-related prognostic genes. The DDRrelated molecular subtypes were then screened, followed by Kaplan-Meier analysis, feature gene identification, and pathway enrichment analysis of each subtype. Moreover, Cox and LASSO regression analyses were performed for the feature genes of each subtype to construct a prognostic model. The clinical utility of the prognostic model was confirmed using the validation dataset GSE72094 and nomogram analysis. RESULTS: Eight DDR-related prognostic genes were identified from 31 DDR-related genes. Using consensus cluster analysis, three molecular subtypes were screened. Cluster2 had the best prognosis, while cluster3 had the worst. Compared to cluster2, clusters 1 and 3 consisted of more stage3 - 4, T2-T4, male, and older samples. The feature genes of clusters1, 2, and 3 were mainly enriched in the cell cycle, arachidonic acid metabolism, and ribosomes. Furthermore, a 15-feature gene signature was identified for improving the prognosis of LUAD patients. CONCLUSION: The 15 DDR-related feature gene signature is an independent and powerful prognostic biomarker for LUAD that may improve risk classification and provide supplementary information for a more accurate evaluation and personalized treatment.

Landscape and Predictive Significance of the Structural Classification of EGFR Mutations in Chinese NSCLCs: A Real-World Study.

Background: Non-classical EGFR mutations demonstrate heterogeneous and attenuated responsiveness to EGFR TKIs. Non-small cell lung cancer (NSCLC) patients with atypical EGFR mutations have limited therapeutic options. A recent study established a novel structural-based classification of EGFR mutations and showed its value in predicting the response to TKI. We sought to interrogate the distribution of different structural types and to validate the predictive value in Chinese NSCLCs. Methods: A total of 837 tumor samples were retrospectively recruited from 522 patients with unresectable EGFR-mutant NSCLC. EGFR mutations were classified into four groups: classical-like, T790M-like, Ex20ins-L, and PACC. Treatment information and clinical outcomes were obtained from 436 patients. The time to treatment failure (TTF) was determined on a per-sample basis. Results: Of the 837 EGFR-mutant samples, 67.9%, 18.5%, 9.0%, and 3.1% harbored classical-like, T790M-like, PACC, and Ex20ins-L mutations, respectively. Thirteen (1.6%) samples carried mutations beyond the four types. Among the 204 samples with atypical mutations, 33.8%, 36.7%, 12.7%, and 10.3% were classical-like, PACC, Ex20ins-L, and T790M-like, respectively. In patients with PACC mutations, second-generation TKIs demonstrated a significantly longer TTF than first-generation TKIs (first-line: 15.3 vs. 6.2 months, p = 0.009; all-line: 14.7 vs. 7.1 months, p = 0.003), and a trend of longer TTF than third-generation TKIs (all-line: 14.7 vs. 5.1 months, p = 0.135). Conclusions: Our study depicted the landscape of structural types of EGFR mutations in Chinese NSCLC patients. Our results also suggest that the structural classification can serve as a predictive marker for the efficacy of various EGFR TKIs, which would guide therapeutic decision making.

An inter-correlation among chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2 and CXCL8, and their diversified potential as biomarkers for tumor features and survival profiles in non-small cell lung cancer patients.

BACKGROUND: The aim was to explore the interaction among chemokine (C-X-C motif) ligand (CXCL) 1/2/8 expressions, and their associations with clinicopathologic features and survival profiles in non-small cell lung cancer (NSCLC) patients. METHODS: The tumor tissue specimens from 232 primary NSCLC patients with TNM stage I-IIIA underwent resection were obtained and the expressions of CXCL1, CXCL2 and CXCL8 were measured by immunohistochemical assay. Disease-free survival (DFS) and overall survival (OS) were calculated according to survival data. RESULTS: There were 117(50.4%) CXCL1 low expression patients versus (vs.) 115 (49.6%) CXCL1 high expression patients, 107(46.1%) CXCL2 low expression patients vs. 125 (53.9%) CXCL2 high expression patients, 93 (40.1%) CXCL8 low expression patients vs. 139 (59.9%) CXCL8 high expression patients. Meanwhile, CXCL1 expression was positively correlated with CXCL2 expression and CXCL8 expression; CXCL2 expression was also positively correlated with CXCL8 expression. For tumor features, CXCL1, CXCL2 and CXCL8 were positively correlated with lymph node (LYN) metastasis and TNM stage, but not correlated with differentiation, tumor size or carcinoembryonic antigen (CEA) level. For prognosis, CXCL1 high expression was associated with worse DFS and OS, so did CXCL2 high expression, while there was no correlation of CXCL8 with DFS or OS; Multivariate Cox's regression disclosed that high expression of CXCL1, but not CXCL2 or CXCL8, was an independent factor predicting shorter DFS and OS. CONCLUSIONS: An inter-correlation is observed among CXCL1, CXCL2 and CXCL8 expressions, and they show diversified potential as biomarkers for tumor features and survival profiles in NSCLC patients.

Non-significant efficacy of icotinib plus pleurodesis in epidermal growth factor receptor positive mutant lung cancer patients after malignant pleural effusion drainage compared to icotinib alone.

BACKGROUND: To investigate the efficacy and safety of icotinib plus pleurodesis or icotinib alone in epidermal growth factor receptor (EGFR) positive mutant lung cancer patients after malignant pleural effusion (MPE) drainage. METHODS: In this retrospective study from initially reviewed case reports of 230 lung adenocarcinoma patients with MPE who were EGFR mutation positive and treated in our hospital between Jan 2014 and Dec 2016 consecutively, 51 patients who met the inclusion criteria were divided into treated with oral icotinib plus pleurodesis and without pleurodesis after pleural effusion drainage groups. Case records including patient gender, age, smoking status and local treatments, as well as adverse events were collected and retrospectively analyzed. The clinical outcomes which were measured by progression free survival (PFS), objective response rate (ORR) & adverse reactions were analyzed by a Kaplan-Meier curve and a log-rank test after follow-ups. RESULTS: The median PFS of patients who received icotinib plus pleurodesis was 8.4 months, while the median PFS of icotinib alone patients was 9.0 months (P=0.996, χ2=7.241). Similarly, the ORR for MPEs, with or without pleurodesis were not significantly difference (64.29% vs. 67.57%, P=0.824, χ2=0.049). Adverse reactions of pleurodesis were mainly fever, chest pain, gastrointestinal reactions and myelosuppression. CONCLUSIONS: Our results suggested that pleurodesis after MPE drainage had no difference on outcomes of icotinib therapy patients. However, pleurodesis may increase some adverse reactions, which might be inconvenient for patients in clinical practice.

Global identification of circular RNAs in chronic myeloid leukemia reveals hsa_circ_0080145 regulates cell proliferation by sponging miR-29b.

Circular RNAs (circRNAs) are a class of non-coding RNAs that participate in various biological processes and disease pathogenesis. However, the role of circRNAs in chronic myeloid leukemia (CML) remains largely unknown. In this study, high-throughput sequencing was performed to explore the expression profile of circRNAs in CML patients for the first time, and a large number of differentially expressed circRNAs were identified. In addition, we constructed potential circRNA-miRNA interaction networks in CML, including a detailed hsa_circ_0080145-mediated competing endogenous RNA (ceRNA) regulatory network. Furthermore, functional experiments demonstrated that hsa_circ_0080145 knockdown significantly suppressed CML cell proliferation and hsa_circ_0080145 regulated CML cell proliferation by acting as an miR-29b sponge.

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia.

AIMS: To investigate the safety and efficacy of the triple therapy of decitabine, idarubicin, and cytarabine in the treatment of refractory or recurrent acute myeloid leukemia (R/R AML). METHODS: We conducted a single-center retrospective study in which decitabine treatment was administered prior to full-dose idarubicin and cytarabine (D-IA) for 21 R/R AML patients. RESULTS: After 1 cycle of D-IA, 10/21 (47.6%) patients experienced a complete remission (CR) and 2/21 (9.5%) showed a partial response. There was a 1-month response rate (RR) in 12/21 patients (57.14%); these patients achieved CR after 2 cycles of D-IA. Five of these 12 (40%) patients then received sequential allogeneic stem cell transplantation. At the last follow-up date, 9/21 (42.8%) patients had survived, and 7/21 (33.3%) were in continuous CR. Hematological toxicity and infections were the most prominent toxicities of this regimen. Other toxicities included nausea, vomiting, bleeding, and liver enzyme abnormalities. No mortalities were recorded due to treatment-related toxicity during remission. CONCLUSIONS: The combination was well tolerated, and the RR was encouraging. Our study suggests that D-IA may offer a novel and potentially effective treatment regimen for R/R AML patients.

[IL-32 mRNA Expression of Bone Marrow Stromal Cells and Its Correlation with Cell Apoptosis in Patients with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the IL-32 mRNA expression of bone marrow stromal cells and its correlation with apoptosis of bone marrow mononuclear cells in patients with myelodysplastic syndrome (MDS). METHODS: Bone marrow samples from 26 MDS patients and 10 iron deficiency anemia (IDA, as control) patients were collected, RT-PCR was used to detect the IL-32 mRNA expression of bone marrow stromal cells, and the apoptosis of bone marrow mononuclear cells was detected by flow cytometry with Annexin V-FITC/PI dowble staining. The born marrow lymphocytes and NK cells were detected by means of direct immunofluorescence labeling whole blood hemolysis and flow cytometry. RESULTS: IL-32 mRNA expression of bone marrow stromal cells in the MDS patients was significantly higher than that of control group, the IL-32 mRNA expression of bone marrow stromal cells in patients with RA, RAS and RCMD was significantly higher than that in patients with RAEB. There was no obvious difference between RAEB and the control groups. The apoptosis of bone marrow mononuclear cells in MDS group was significantly higher than that in the control group, the apoptosis of bone marrow mononuclear cells in patients with RA, RAS and RCMD was significantly higher than that in RAEB. There was no significant difference between RAEB group and control group. The IL-32 mRNA expression in bone marrow stromal cells significantly correlated with the apoptosis of bone marrow mononuclear cells in MDS patients. The NK cell number in born marrow of MDS patients and the control group had no significant difference. CONCLUSION: The expression of IL-32 mRNA in bone marrow stromal cells significantly relates with the apoptosis of MDS cells, and the secretion of IL-32 by bone marrow stromal cells may be one of the reasons for the apoptosis of MDS bone marrow cells. It is speculated that the abnormal MDS bone marrow microenvironment is involved in the apoptosis of bone marrow cells.

Clinical analysis of 95 cases of pulmonary sarcomatoid carcinoma.

OBJECTIVES: To collect data on the clinical characteristics, pathologic presentation, and prognosis of patients with pulmonary sarcomatoid carcinoma. METHODS: From September 24, 2008 to June 3, 2014, 95 patients were hospitalized at the Shanghai Chest Hospital for the treatment of pulmonary sarcomatoid carcinoma. We retrospectively collected patient gender, age, smoking history, time of initial diagnosis, diagnostic methods, tumor location, pathohistological subtype, tumor size, TNM stage, immunohistochemical results, subsequent treatments, and patient survival. RESULTS: Of the 95 patients included in this study, 80 were male and 15 were female. Median patient age was 64 years (range: 43-80 years). There were 29 cases of pleomorphic carcinoma, one case of giant cell carcinoma, six cases of spindle cell carcinoma, and six cases of carcinosarcoma. The other 53 cases were not subtyped. The median survival was 11.54 months (range: 0.9-100.9 months). 1-, 2-, 3-, and 5-year survival was 32%, 30%, 25%, and 21%, respectively. Univariate analysis showed that tumor size, stage, T1+T2 vs T3+T4 stage, N stage, and M stage were prognostic factors for survival. Multivariate regression analysis showed that T stage and lymph node metastases were independent prognostic factors. CONCLUSION: Pulmonary sarcomatoid carcinoma is an uncommon, aggressive cancer. T1+T2 vs T3+T4 stage and lymph node metastases were independent prognostic factors. Our results underscore the importance of early detection and early diagnosis. Effective treatments for this disease are lacking.

Detection and correlation analysis of serum cytokines in non-small-cell lung cancer patients with bone and non-bone metastases.

OBJECTIVE: To detect and analyze 13 cytokines that may be related to bone metastasis in the serum of non-small-cell lung cancer (NSCLC) patients with bone metastases and NSCLC patients with non-bone metastases. PATIENTS AND METHODS: The Luminex LiquiChip system was used to detect the concentration of 13 cytokines that may be related to bone metastasis in the serum of 30 NSCLC patients with bone metastases and 30 with non-bone metastases. RESULTS: The concentration of insulin-like growth factor binding protein-3 (IGFBP-3) in the serum of NSCLC patients with bone metastases was obviously higher than in non-bone metastasis patients (P=0.014). The serum concentration of other cytokines showed no significant difference (P>0.05) between the two groups. The concentration of IGFBP-3 in the serum of the bone metastasis group was positively correlated to VEGF concentration (r=0.804, P=0.009) and monocyte chemotactic protein 1 (MCP-1) concentration (r=0.785, P=0.012), but had no correlation to other factors (P>0.05). No correlation was found between serum concentrations of cytokines in bone metastasis. Concentration of IGFBP-3 in the serum of bone metastasis patients was positively correlated to the presence or absence of pain at diagnosis (r=0.701, P=0.036) and performance status (PS) score (r=0.670, P=0.048), and correlated with the number of bone metastases, sex, age, pathological characteristics, T stage, and N stage (P>0.05). CONCLUSION: The findings of this study suggest important clinical implications to detect the concentration of IGFBP-3 in the serum of lung cancer patients so as to evaluate the diagnosis and degree of bone metastasis. Concentration of IGFBP-3 in the serum of bone metastasis patients was positively correlated to concentration of VEGF and MCP-1, which may be highly relevant for the development of new treatments for bone metastasis of lung cancer.

[Mutation detection of mitochondrial DNA D-loop region in bone marrow cells of acute leukemia].

This study was aimed to detect the mutations and microsatellite instability (mtMSI) in mitochondrial DNA (mtDNA) D-loop region in bone marrow cells of acute leukemia (AL) patients, and to analyze their relationship with the pathogenesis of AL. 19 cases of newly diagnosed AL were enrolled in this study. Through extracting mtDNA, the D-loop region was amplified by polymerase chain reaction (PCR), the sequences of PCR products were detected by the pros- and cons-direct sequencing methods. The sequencing results were compared with the revised Cambridge reference sequence (rCRS) and the relevant database (MITOMAP database, GenBank database, mtDB database). The results showed that the mutation rate of mtDNA D-loop region in AL was 79% (15/19). 215 variations (35 mutations, 180 SNP) and a kind of mtMSI in the D-loop region were detected. A new type of mutation nt150 C-CT was found. Also, there was no significant difference in the number of mutations between patients with different ages and different types of AL (AML, B-ALL). It is concluded that there is high frequency of mutations in the mtDNA D-loop, and the mutations may be associated with the pathogenesis of AL.