Clinicopathological features, treatment modalities, and prognosis of esophageal neuroendocrine carcinoma: A single-center retrospective study.

OBJECTIVES: Esophageal neuroendocrine carcinoma (ENEC) is a rare cancer that is highly malignant and related to a poor prognosis. In this retrospective study we aimed to elucidate the clinical characteristics, diagnosis and management of patients with ENEC and to evaluate the potential prognostic factors. METHODS: Altogether 82 patients diagnosed with ENEC between January 2009 and December 2020 at the Fudan University Shanghai Cancer Center were retrospectively enrolled. Patients' survival was analyzed using the Kaplan-Meier and log-rank methods. Univariate and multivariate analyses and a Cox regression model were used to identify the prognostic factors. RESULTS: The median overall survival (mOS) was 13 months in all patients. Multivariate analysis revealed that advanced tumor stage (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.07-6.66, P = 0.0353), liver (HR 3.36, 95% CI 1.53-7.41, P = 0.0026) and lung metastasis (HR 3.37, 95% CI 1.20-9.51, P = 0.0214) were associated with a poor prognosis. While positive chromogranin A (CgA) expression was related to a favorable outcome (HR 0.21, 95% CI 0.09-0.49, P < 0.001). Also, patients had adjustment of chemotherapy (dose reduction or less than three cycles) were prone to a worse prognosis compared with those did not (HR 4.36, 95% CI 2.10-9.08, P < 0.001). CONCLUSION: In patients with ENEC, advanced cancer stage, adjustment of chemotherapy, liver and lung metastasis were associated with a poor survival, while CgA expression was related to a favorable prognosis.

Prognostic and predictive value of serum carcinoembryonic antigen levels in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutations and receiving tyrosine kinase inhibitors.

BACKGROUND: Despite the widespread use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced or recurrent non-small cell lung cancer (NSCLC), no biomarkers for predicting the efficacy of EGFR-TKIs in patients with EGFR-sensitive mutations have yet been identified. The purpose of our study was to explore the effect of baseline serum tumor markers in stage IIIB/IV NSCLC patients treated with EGFR-TKIs. METHODS: One hundred and seventy-seven patients with stage IIIB/IV NSCLC who harbored EGFR-sensitive mutations and were treated with EGFR-TKIs were retrospectively reviewed. Their levels of CEA, CYFRA 21-1, NSE and CA199 were measured before treatment with EGFR-TKIs. RESULTS: The response rate for all patients was 54.8%, with a median progression-free survival of 6.6 months and overall survival of 14.8 months. In univariate analyses, patients with CEA levels below the cutoff point (10 ng/ml) had higher RR, better PFS, and better OS than those with CEA levels above 10 ng/mL (RR: 69.2% vs. 43.4%, p= 0.001; mPFS: 7.8 months vs. 5.3 months, p=0.029; mOS: 18.8 months vs. 11.8 months, p=0.000). The baseline serum CEA level was an independent factor for RR (odds ratio [OR] =0.322, p=0.001), PFS (hazard ratio [HR] =1.45, p=0.025), and OS (HR=2.133, p=0.000). CONCLUSION: Our study suggests that baseline serum CEA levels may play a role in predicting the efficacy of EGFR-TKIs in stage IIIB/IV NSCLC patients with EGFR-sensitive mutations who are treated with EGFR-TKIs.

Significance of glucocorticoid receptor expression in patients with non-small cell lung cancer treated with pemetrexed-based chemotherapy.

BACKGROUND: Pemetrexed is the preferred chemotherapy agent in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), but lacks biomarkers predicting its efficacy. Dexamethasone, one of the premedications of pemetrexed, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cells (PBMC) and its role in predicting pemetrexed efficacy. METHODS: In all, 122 patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC was measured before treatment with pemetrexed using real-time PCR was used to detect the levels of GRα and GRß. RESULTS: The response rate for all patients was 38.5%, with a median progression-free survival (PFS) of 5.9 months and overall survival (OS) of 14.3 months. In univariate analyses, patients with a low GRα/GRß ratio in PBMC had higher RR, better PFS, and better OS than those with a high GRα/GRß ratio (RR: 48.2 vs. 30.3%, p = 0.043; mPFS: 6.9 vs. 4.0 months, p < 0.001; mOS: 18.7 vs. 12.2 months, p = 0.005). The baseline GRα/GRß ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95% CI 0.208-0.978; p = 0.044), PFS (HR = 1.584, 95% CI 1.094-2.295; p = 0.015), and OS (HR = 1.761, 95% CI 1.195-2.595; p = 0.004). CONCLUSIONS: Baseline GRα/GRß ratio in PBMC may play a role in predicting the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sq NSCLC patients.

PA-MSHA in combination with EGFR tyrosine kinase inhibitor: A new strategy to overcome the drug resistance of non-small cell lung cancer cells.

The inhibition of epidermal growth factor receptor (EGFR) signaling by Gefitinib provides a promising treatment strategy for non-small cell lung cancer (NSCLC); however, drug resistance to Gefitinib and other tyrosine kinase inhibitors presents a major issue. Using NSCLC cell lines with differential EGFR status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth. PC-9, A549, and NCI-H1975 cells were treated with PA-MSHA, Gefetinib, or PA-MSHA plus Gefetinib at different concentrations and times. The effects of the drugs on proliferation, cell cycle distribution and apoptosis were evaluated. The activation of EGFR and apoptotic signaling-related molecules was evaluated by Western blotting in the presence or absence of EGFR siRNA. Tumor growth and pathway signaling activation was assessed by xenografts in nude mice. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in all NSCLC cells tested. The combination of PA-MSHA plus Gefitinib enhanced the growth inhibition, sub-G1 content and apoptosis over that observed with either agent alone. Furthermore, the combination of PA-MSHA plus Gefitinib resulted in caspase-3/caspase-9 cleavage and increased inhibition of EGFR-dependent activation of AKT and ERK phosphorylation. Combination treatment was more effective in reducing tumor size and EGFR activation than either agent alone. These data suggest that PA-MSHA and Gefitinib function additively to suppress the proliferative effects of NSCLC cells of differential EGFR status. The combination of PA-MSHA and Gefitinib provides a potential new strategy to conquer drug resistance for anti-EGFR-targeted therapy of NSCLC.

Rta-IgG as a biomarker for diagnosis and post treatment prognostic of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer. OBJECTIVE: This study aimed to detect the expression of Epstein-Barr viral Rta protein in patients with untreated NPC, and compare the serum Rta-IgG with the VCA-IgA in patients with NPC. METHODS: In the current work, the nasopharyngeal tissues of untreated NPC patients (n= 13) and non-NPC controls (n= 10) were collected for the immunohistochemical (IHC) staining to analyze the levels of Rta protein expression, meanwhile serum samples from the participants were prepared to assess the roles of Rta-IgG level with Enzyme-linked immunosorbence assay (ELISA) in diagnosis of NPC including the patients with NPC, the patients with other cancers, and normal volunteers. RESULTS: The levels of serum Rta-IgG in 26 NPC patients were monitored at pre- and post-treatments, as well as one to two year after. We found that there was a significant difference of the expression levels of Rta protein between NPC and non-NPC groups (P< 0.05). Correspondingly, the levels of serum Rta-IgG in NPC patients (3.05, 1.19-4.95) were significantly higher than those of non-NPC participants (0.15, 0.08-0.30, P< 0.05) including the patients with lung cancer (0.14, 0.08-0.19), the patients with breast carcinoma (0.17, 0.10-0.25), the patients with gastric carcinoma (0.08, 0.05-0.16), the patients with malignant lymphoma (0.13, 0.08-0.20), the patients with benign nasopharyngeal disease (1.65, 0.74-1.93) and healthy volunteers (0.22, 0.13-0.32), respectively. With a receiver operation characteristic (ROC) analysis, the cut-off value to discriminate NPC patients from the controls was established at 0.92 (S/CO) for Rta-IgG (sensitivity 83.6%; specificity 82.4%), the diagnosis efficacy of Rta-IgG was higher than VCA-IgA. The positive rates of Rta-IgG were related to clinical stage, but not metastatic sites. Serum concentrations of Rta-IgG were decreased in NPC patients with effective radiation, and slightly raised or with no change with ineffective radiation. CONCLUSIONS: Rta expression levels are elevated in the patients with NPC, and serum Rta-IgG is a promising biomarker in both differential diagnosis and therapy-monitoring of the patients with NPC.

Flexibility Analysis of Bacillus thuringiensis Cry1Aa.

OBJECTIVE: To investigate the flexibility and mobility of the Bacillus thuringiensis toxin Cry1Aa. METHODS: The graph theory-based program Constraint Network Analysis and normal mode-based program NMsim were used to analyze the global and local flexibility indices as well as the fluctuation of individual residues in detail. RESULTS: The decrease in Cry1Aa network rigidity with the increase of temperature was evident. Two phase transition points in which the Cry1Aa structure lost rigidity during the thermal simulation were identified. Two rigid clusters were found in domains I and II. Weak spots were found in C-terminal domain III. Several flexible regions were found in all three domains; the largest residue fluctuation was present in the apical loop2 of domain II. CONCLUSION: Although several flexible regions could be found in all the three domains, the most flexible regions were in the apical loops of domain II.

Resection of the main trunk of the superior mesenteric vein without reconstruction during surgery for giant pancreatic mucinous cystadenoma: A case report.

Pancreatic tumors, with peri-pancreatic main vascular invasion, especially the superior mesenteric vein (SMV) or the portal vein, are very common. In some cases, vascular resection and reconstruction are required for complete resection of pancreatic tumors. However, the optimum surgical method for venous management is controversial. Resection of the SMV without reconstruction during surgery for pancreatic tumors is rarely reported. Here we present the case of a 58-year-old woman with a giant pancreatic mucinous cystadenoma adhering to the SMV, who underwent an en bloc tumor resection, including the main trunk of the SMV and the spleen. No venous reconstruction was performed during surgery. No ischemic changes occurred in the bowel. The presence of several well-developed collateral vessels was shown by 3-dimensional computed tomography examination. The patient had an uneventful postoperative period and was discharged. This case indicated that the main trunk of the SMV can be resected without venous reconstruction if adequate collateralization has formed.

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

PURPOSE: The difference between combinational and pre-planned sequential therapies using regimens that include non-anthracycline and taxane in the first-line setting remains unclear. The purpose of this study is to explore the interaction between vinorelbine (N) and capecitabine (X) in breast cancer cells and to compare the simultaneous or sequential administration of the two drugs in patients with metastatic breast cancer (MBC) as first-line treatment. METHODS: First, we explored the effects of vinorelbine on thymidine phosphorylase (TP) and thymidylate synthase (TS) expression in breast cancer cells. Next, we designed a prospective randomized phase II trial of MBC patients comparing the combinational and pre-planned sequential administration of vinorelbine and capecitabine in the first-line metastatic setting. The primary end point was progression-free survival (PFS). The correlation between clinical characteristics and class III ß-tubulin expression and patient survival was also explored. RESULTS: Vinorelbine upregulates TP and downregulates TS in breast cancer cells, thereby further sensitizing tumor cells to capecitabine, which indicated the proper order for sequential therapy should be N → X. Sixty patients were eligible for the phase II trial. No significant difference was observed between the combinational arm and the sequential arm in terms of progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Only in the subgroup of patients with liver metastases were median PFS and OS significantly prolonged in the combinational arm (8.5 vs. 6.4 months, P = 0.041 and 23.8 vs. 13.9 months, P = 0.028, respectively). No association between class III ß-tubulin expression and patient outcome was identified. Grade 3/4 adverse events were more common in the combinational arm. CONCLUSIONS: Both the NX regimen and pre-planned sequential N → X regimen are acceptable as first-line treatments with comparable efficacies for MBC patients previously treated with anthracyclines and/or taxanes. Sequential monotherapies are recommended as the preferred approach to first-line chemotherapy for most MBC patients in the absence of an imminent visceral crisis and the need for rapid symptom and/or disease control.

Homology modeling of mosquitocidal Cry30Ca2 of Bacillus thuringiensis and its molecular docking with N-acetylgalactosamine.

OBJECTIVE: To investigate the theoretical model of the three-dimensional structure of mosquitocidal Cry30Ca2 and its molecular docking with N-acetylgalactosamine. METHODS: The theoretical model of Cry30Ca2 was predicted by homology modeling on the structure of the Cry4Ba. Docking studies were performed to investigate the interaction of Cry30Ca2 with N-acetylgalactosamine on the putative receptor. RESULTS: Cry30Ca2 toxin is a rather compact molecule composed of three distinct domains and has approximate overall dimensions of 95 by 75 by 60Å. Domain II is a helix bundle, Domain II consists of three antiparallel ß-sheets, Domain III is composed of two ß-sheets that adopt a ß-sandwich fold. Residue 321Ile in loop1, residues 342Gln 343Thr and 345Gln in loop2, residue 393Tyr in loop3 of Cry30Ca2 are responsible for the interactions with GalNAc via 7 hydrogen bonds, 6 of them were related to the oxygen atoms of hydroxyls of the ligand, and one to the nitrogen of the ligand. CONCLUSION: The 3D structure of Cry30Ca2 resembles the previously reported Cry toxin structures but shows still some distinctions. Several residues in the loops of the apex of domain II are responsible for the interactions with N-acetylgalactosamine.

The p21 Ser31Arg polymorphism and breast cancer risk: a meta-analysis involving 51,236 subjects.

Published data on the association between p21 Ser31Arg polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between the p21 Ser31Arg polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (Ser/Arg vs. Ser/Ser, Arg/Arg vs. Ser/Ser), dominant model (Arg/Arg + Ser/Arg vs. Ser/Ser), and recessive model (Arg/Arg vs. Ser/Arg + Ser/Ser). A total of 21 studies including 22,109 cases and 29,127 controls were involved in this meta-analysis. Overall, no significant associations were found between p21 Ser31Arg polymorphism and breast cancer risk when all studies pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly increased risk was found for Caucasians (Arg/Arg vs. Ser/Ser: OR 1.496, 95% CI 1.164-1.924; and recessive model: OR 1.492, 95% CI 1.161-1.919). When stratified by study design, statistically significantly elevated risk was found for population-based studies (Ser/Arg vs. Ser/Ser: OR 1.085, 95% CI 1.019-1.156). In conclusion, this meta-analysis suggests that the p21 Ser31Arg polymorphism may be associated with breast cancer development in Caucasian. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding.

XPD Lys751Gln polymorphism and breast cancer susceptibility: a meta-analysis involving 28,709 subjects.

Published data on the association between Xeroderma Pigmentosum complementation group D (XPD) Lys751Gln polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 30 studies including 14,283 cases and 14,426 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with XPD 751Gln allele when all studies were pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR = 1.13, 95% CI = 1.02-1.25; Gln/Gln vs. Lys/Lys: OR = 1.21, 95% CI = 1.06-1.38; dominant model: OR = 1.16, 95% CI = 1.05-1.29; and recessive model: OR = 1.14, 95% CI = 1.02-1.27). In the subgroup analysis by ethnicity, borderline significantly increased risks were found for Caucasians (Lys/Gln vs. Lys/Lys: OR = 1.09, 95% CI = 0.98-1.22; dominant model: OR = 1.10, 95% CI = 0.99-1.22) and significantly increased risks were found for Africans in dominant model (OR = 1.10, 95% CI = 1.04-1.15). When stratified by study design, statistically significantly elevated risk was found in population-based studies (Lys/Gln vs. Lys/Lys: OR = 1.10, 95% CI = 1.01-1.20; Gln/Gln vs. Lys/Lys: OR = 1.15, 95% CI = 1.01-1.31; dominant model: OR = 1.12, 95% CI = 1.03-1.23). In conclusion, this meta-analysis suggests that the XPD 751Gln allele is a low-penetrant risk factor for developing breast cancer.

[Prognosis of primary non-Hodgkin's lymphoma of the breast].

OBJECTIVE: To analyze the clinical characteristics and prognosis of primary non-Hodgkin's lymphoma of the breast (PNHLB). METHODS: The characteristics, treatment methods and outcomes of 45 patients with PNHLB were retrospectively analyzed. Chemotherapy including CHOP and CHOP-like regimens was administered in 43 patients, and monoclonal antibody therapy in 6 patients. Furthermore, 19 patients underwent radiotherapy after chemotherapy. RESULTS: Of these 45 patients, 37 patients had diffuse large B cell lymphoma (DLBCL), patients with T cell or mucosa-associated lymphoid tissue (MALT) lymphoma were 4, respectively. Overall response rate of first-line chemotherapy was 90.7%. Median overall survival (OS) and progression-free survival (PFS) of all patients was 6.82 and 4.25 years, respectively. The results of Cox regression model analysis showed that international prognostic index score (IPI) (RR = 5.682, P = 0.002) and Ann Arbor stage (RR = 1.836, P = 0.040) were negative independent prognostic factors for OS. Central nervous system involvement (RR = 1.107, P = 0.005) was a negative independent prognostic factor for PFS. CONCLUSION: The patients with PNHLB have early occurrence in lifespan. Most pathologic type was DLBCL. IPI and Ann Arbor stage are two independent prognostic factors for survival.

The theoretical 3D structure of Bacillus thuringiensis Cry5Ba.

Cry5Ba is a delta-endotoxin produced by Bacillus thuringiensis PS86A1 NRRL B-18900. It is active against nematodes and has great potential for nematode control. Here, we predict the first theoretical model of the three-dimensional (3D) structure of a Cry5Ba toxin by homology modeling on the structure of the Cry1Aa toxin, which is specific to Lepidopteran insects. Cry5Ba resembles the previously reported Cry1Aa toxin structure in that they share a common 3D structure with three domains, but there are some distinctions, with the main differences being located in the loops of domain I. Cry5Ba exhibits a changeable extending conformation structure, and this special structure may also be involved in pore-forming and specificity determination. A fuller understanding of the 3D structure will be helpful in the design of mutagenesis experiments aimed at improving toxicity, and lead to a deep understanding of the mechanism of action of nematicidal toxins.

Primary non-Hodgkin's lymphoma of the breast: eight-year follow-up experience.

The objective of this study is to analyze the clinical characteristics and treatment of patients with primary non-Hodgkin's lymphoma of the breast (PNHLB). Forty-five patients with PNHLB treated in our hospital during a 15-year period were retrospectively analyzed. Forty-four were females and one male, with a median age of 47 years. Forty-two patients were at stage I or II and 82.2% had diffuse large B cell lymphoma (DLBCL). Local control rate was 95.2 and 66.7% for patients with and without radiotherapy, respectively (P = 0.020). Median overall survival and progression-free survival (PFS) of all patients was 6.8 and 4.3 years, respectively. For patients with DLBCL or T cell lymphoma, median PFS was 6.5 years with chemoradiation and 3.9 years with chemotherapy or radiation only (P = 0.029). Patients who used rituximab had not reached median PFS, while those treated without rituximab had a median PFS of 5.1 years (P = 0.301). International prognostic index (IPI) score and bilateral breast involvement were two independent prognostic factors for survival. Chinese patients with PNHLB have early occurrence in lifespan. Radiation confers a better local control. Patients with intermediate or high-grade PNHLB might be treated with chemotherapy, radiotherapy, and for CD-20 positive disease, rituximab. Bilateral disease and IPI are two prognostic factors.

[Cytogenetic and interphase FISH studies in the diagnosis of malignant lymphomas].

OBJECTIVE: To evaluate the role of cytogenetic study and interphase FISH analysis in differential diagnosis of patients with clinical and/or cytological diagnosis as lymphoma or "suspicious for lymphoma". METHODS: Routine histology, immunohistochemistry, cytogenetics and interphase FISH studies were used to assess 223 cases with superficial lymph nodes of not less than 1. 5 cm in diameter. The probe used in the interphase FISH assays is the Vysis' LSI IGH Dual Color, Break Apart Rearrangement Probe. RESULTS: Based on these studies, forty-four patients were diagnosed as Hodgkin's lymphomas ( HL) , 162 as Non-Hodgkin's lymphomas ( NHL) , 11 with benign diseases and 4 as other malignancies, while the remaining 2 cases were discarded due to tissue necrosis. Using interphase FISH, abnormalities of immunoglobulin heavy chain gene (IGH) were detected in 6/44 (13.6%) and 83/162 (51.2%) in the HIL and NHL cases, respectively, while none was observed in 11 cases with a benign disease (P <0. 001). Combining cytogenetics and FISH studies, the detection rates for HL and NHL cases then increased to 15.9% and 77. 8%, respectively, otherwise, 3 of whom could not have made definite diagnosis. CONCLUSION: Interphase FISH assay is a rapid and sensitive tool for detecting IGH abnormalities. Both cytogenetics and interphase FISH analyses may play a significant role in diagnosis of lymphomas.