Large cell neuroendocrine carcinoma transformation: A novel acquired drug resistance mechanism in colorectal adenocarcinoma.

Acquired resistance is a major problem limiting the clinical efficacy of treatments for metastatic colorectal cancer (mCRC). Histological transformation is an important mechanism underlying the acquired resistance of non-small cell lung cancer and prostate cancer to targeted therapy. However, no report has examined the role of histological transformation in mCRC. Here, we report the first case of histologically transformed large cell neuroendocrine carcinoma from primary colon adenocarcinoma during antiangiogenesis and anti-PD-1 combination therapy. The histologic conversion was confirmed by the observation that the transformed large cell neuroendocrine carcinoma lesion retained the original mutational signature found in the primary tumor. Sequential tumor biopsy and dynamic changes in tumor markers demonstrated the transformed process. The histological transformation not only resulted in discordant responses to the same treatment but also significantly shortened overall survival. This case calls for more attention to histological transformation in mCRC. Tumor rebiopsy upon disease progression and monitoring dynamic changes in tumor markers would help to identify such cases.

Association between polymorphisms of ABCB1 and prognosis in esophageal squamous cell carcinoma patients treated with taxane.

BACKGROUND: In China, most esophageal cancer patients are squamous cell carcinomas and are treated with taxane-containing regimens; however, few studies have examined taxane pharmacokinetics genes and esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: In total, 227 pathologically confirmed ESCC patients receiving chemotherapy with taxane were included in the analysis. We genotyped seven SNPs (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; and ABCC1 rs246221 and ABCC2 rs3740066) and analyzed their relationship with overall survival. RESULTS: With a retrospective cohort study design, by Cox regression and semi-Bayesian shrinkage, in the genetic recessive model, the variant homozygote of ABCB1 rs1045642 was inversely associated with survival (semi-Bayesian shrinkage crude hazard ratio = 1.82, 95% confidence interval = 1.00, 3.31; p = 0.0482). CONCLUSIONS: Because of inherent defects of the research itself, the finding that the ABCB1 rs1045642 variant was related to poor prognosis in ESCC patients treated with taxane-containing regimens needs to be tested in a larger population and by using more genetic and molecular mechanism experiments.

Polymorphism of FGD4 and myelosuppression in patients with esophageal squamous cell carcinoma.

Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3-4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04-3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3-4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.

Lay abstract Taxane/cisplatin is the main chemotherapy regimen in patients with esophageal squamous cell carcinoma in China. Many patients suffer from neurotoxicity or bone marrow suppression, such as decreased white blood cells. Higher-grade adverse events, in particular, usually result in chemotherapy dose reduction or treatment termination. Researchers explored the associations between genetics and chemotherapy toxicity and found that the genetic variant (SNP rs1239829) of the gene FGD4 was related to serious white blood cell decline in patients with esophageal squamous cell carcinoma who were treated with the taxane/cisplatin regimen.

Integrated bioinformatics analysis to identify key genes related to the prognosis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a serious threat to human health and life. The National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) database provides valuable information on genes related to the pathogenesis and prognosis of ESCC, which helps us to make in-depth understanding about the disease and improve its prognosis. METHODS: Four microarray profiles [GSE77861 (African Americans), GSE26886 (Germans), GSE17351 (Americans), and GSE45670 (Chinese)] from the NCBI-GEO including 49 ESCC tissues and 41 corresponding normal tissues were collected. Integrated bioinformatics methods, including protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and Kaplan-Meier plotter were applied to determine the differentially expressed genes (DEGs) in ESCC together with their core functions and relationship with survival. RESULTS: A total of 220 upregulated and 112 downregulated genes were identified as DEGs in ESCC, of which, 40 upregulated genes were core function genes. The DEGs were mostly involved in DNA replication and cell cycle pathways. Survival analysis and Bonferroni adjustment showed kinesin family member 18A (KIF18A) and TTK protein kinase (TTK) to be related to prognosis in ESCC. CONCLUSIONS: The findings of the present study verified the previously proposed association between TTK and patient survival in ESCC, and identified KIF18A as ESCC prognosis-related gene markers for the first time. The underlying mechanism needs to be further investigated using larger sample size studies and biological experiments in future.

Development and Validation of an Individualized Nomogram for Predicting Survival in Patients with Esophageal Carcinoma after Resection.

An accurate estimation of prognosis of the esophageal carcinoma patients after surgery is urgently needed. Clinical nomogram has been developed to quantify risk by incorporating prognostic factors for individual patient. Based on the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013, a total of 4566 patients were selected. Of those, 3198 patients were assigned to training set to construct the nomogram, which incorporated age, gender, histology, grade, T stage, N stage, nodes examined, radiation and chemotherapy. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram was 0.71(95%CI 0.70-0.72), which was statistically higher than the TNM staging system. The results were then validated using bootstrap resampling and a validation set of 1368 patients in the SEER database. Besides, in the esophageal squamous cell carcinoma and esophageal adenocarcinoma subgroups, the nomogram discrimination was superior to the TNM staging system. It is likely that these results would play a supplementary role in the current staging system and help to identify the high risk population after surgery.

Survival comparison of right and left side non-small cell lung cancer in stage I-IIIA patients: A Surveillance Epidemiology and End Results (SEER) analysis.

BACKGROUND: Primary tumors located in the right and left side have distinctive prognoses, but the details have not been fully identified in non-small cell lung cancer (NSCLC). This study investigated the impact of primary tumor side on long-term survival in NSCLC patients. METHODS: Data of 90 407 patients from the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed. To avoid bias between groups, we used innovative propensity score matching (PSM) analysis. RESULTS: There was no significant distinction in overall survival (OS) between right (n = 53 496) and left (n = 36 911) side tumors (hazard ratio [HR] 0.993, 95% confidence interval [CI] 0.9756-1.011; P = 0.432). Left side was associated with superior five-year cancer-specific survival (CSS) compared to right side NSCLC (HR 0.977, 95% CI 0.9574-0.9969; P = 0.024). No significant difference was observed in OS (P = 0.689) or CSS (P = 0.288) after PSM analysis. In the 51 319 patients who underwent surgery, left side (n = 21 245) was associated with poor OS compared to right side (n = 30 074) NSCLC (HR 1.039, 95% CI 1.011-1.067; P = 0.006), while CSS was similar (HR 1.031, 95% CI 0.997-1.065; P = 0.069). In patients who underwent surgery, there was also no significant difference in OS (P = 0.986) or CSS (P = 0.979) after PSM analysis. CONCLUSION: The prognosis between right and left side NSCLC in stage I-IIIA was similar regardless of whether patients underwent surgery. Primary tumor side cannot be considered a prognostic factor when choosing appropriate treatment.

Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity.

AIM: Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma. METHODS: We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens: CBV (cyclophosphamide, carmustine and etoposide; n = 16), BEAM (carmustine, etoposide, cytarabine and melphalan; n = 36) and BEAC (carmustine, etoposide, cytarabine and cyclophosphamide; n = 77). RESULTS: At a median follow-up of 42.5 months, the estimated 5-year overall survival for the CBV, BEAM and BEAC groups was 68.8%, 77.8% and 81.8%, respectively (P = 0.584). The estimated 5-year progression-free survival in the CBV group (43.8%) was relatively inferior to the BEAM (66.7%) and BEAC (67.5%) groups, but the differences were not significant (P = 0.403). Grade 2 or higher mucositis, diarrhea and fever were relatively more common in the BEAM group (P < 0.05). No differences were observed in the time to hematopoietic recovery and the duration of hospitalization. The amount of transfused platelet was significantly less in the CBV. CONCLUSION: CBV, BEAM and BEAC regimens are all optional high-dose chemotherapy before AHSCT for NHL patients.

A prognostic model for platinum-doublet as second-line chemotherapy in advanced non-small-cell lung cancer patients.

Poor prognosis of advanced non-small-cell lung cancer (NSCLC) patients and the promising therapeutic effect of platinum urge the oncologists to evaluate the role of platinum doublet as second-line chemotherapy and establish the definition of platinum sensitivity in NSCLC. We retrospectively analyzed 364 advanced NSCLC patients who received platinum-doublet regimens as second-line chemotherapy after platinum-based first-line treatment. Patients were divided into four groups by their time-to-progression (TTP) after first-line chemotherapy: 0-3, 4-6, 7-12, and >12-month group, respectively. Treatment efficacy of patients' overall survival (OS), progression-free survival (PFS), and response rate (RR), as well as treatment-related toxicity, were compared among the four groups. A prognosis score system and a nomogram were established by Cox proportional hazard model, and validated by concordance index (c-index). Median OS was 14.0, 16.0, 20.0, 25.0 months for patients in the 0-3, 4-6, 7-12, >12-month group, respectively. Age ≤60 years (P = 0.002), female (P = 0.019), and TTP>12 months (P = 0.003) were independent prognostic factors. Prognostic score was calculated by adding 1 point each for any of the above three indicators, with a c-index of 0.590 (95% confidential interval [CI], 0.552-0.627). Median OS were equal to 25.0, 16.0, and 11.0 months for best (2-3 points), intermediate (1 point) and worst (0 point) category, respectively (P < 0.0001). A nomogram that integrated patient's age, gender, and TTP for OS has a c-index of 0.623 (95% CI, 0.603-0.643). Female, younger than 60 years, and TTP greater than 12 months may indicate prolonged survival after platinum-doublet second-line chemotherapy in advanced NSCLCpatients.

Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis.

OBJECTIVE: The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation (AHSCT) in the treatment of lymphoblastic lymphoma (LL). METHODS: We retrospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation (HSCT) from December 1989 to December 2009 in a single institution. RESULTS: HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months (range, 24.6-173.1 months). The 5-year overall survival (OS) and event-free survival (EFS) rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow (BM) involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. CONCLUSIONS: These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission (CR1).