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.

Katanin subunits p60 and p80, potential biomarkers for papillary thyroid carcinoma to distinguish nodular goiter: STROBE.

ABSTRACT: Katanin subunits p60 and p80 are involved in microtubule-mediated cytoskeletal organization during cell division. Their aberrant expression has been found in prostate, breast, and non-small cell lung (NSCLC) cancers. It has recently been reported that compared with adjacent papillary thyroid carcinoma (PTC) tissues, both are highly expressed in tumor tissues. Here, we investigated whether katanin subunits p60 and p80 can be used as potential biomarkers for PTC to distinguish nodular goiter (NG).Immunohistochemistry was performed to investigate the expression of katanin subunits p60 and p80 in the tissues of 97 cases of PTC and NG. This cohort included 87 cases with PTC (74 classical or conventional (CPTC) and 13 follicular (FVPTC) variants) and 10 cases with NG.We found that katanin subunits p60 and p80 were expressed in PTC, but not in NG. The cutoff values of katanin p60 and p80 for PTC were 22.43% and 0.83%, respectively. The katanin subunit p60 was significantly associated with lymph node metastasis. Katanin subunit p80 was more highly expressed in CPTC than in FVPTC. The expression of the katanin subunit p60 was positively correlated with the expression of katanin p80 in PTC. Importantly, we found that overexpression of katanin p60 increased the expression of katanin p80 in a human papillary thyroid carcinoma KTC-1 cell line, which further supports the existence of katanin p60 and p80 feedback loops.Our results indicate that katanin subunits p60 and p80 may be used as potential PTC biomarkers to distinguish NG and may be novel therapeutic targets for PTC.

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.

Phase 1 dose-escalation study of apatinib and irinotecan in esophageal squamous cell carcinoma patients.

BACKGROUND: Apatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), has been used to treat esophagogastric adenocarcinoma. However, the dosage of apatinib varies greatly in clinical practice, and its safety in esophageal squamous cell carcinoma (ESCC) patients is unclear. Therefore, we initiated a phase 1 dose-escalation trial to identify the maximum tolerated dose (MTD) of apatinib when combined with irinotecan in ESCC. METHODS: The trial had a standard 3+3 design. The dosage of irinotecan was fixed at 150 mg/m2 repeated every 2 weeks, while the daily dosage of apatinib was escalated from 250 mg, to 500 mg, to 750 mg. Dose-limiting toxicity (DLT) was defined as grade 4 hematological or grade 3-4 non-hematological adverse events (AEs). RESULTS: Twelve patients were enrolled. Three DLTs occurred, comprising a grade 3 perianal abscess and a grade 3 case of kaliopenia in the level 3 cohort, and a grade 4 leukopenia in the level 2 cohort. Based on these DLTs, the MTD of apatinib was 500 mg daily. The most common AEs were leukopenia (91.7%), fatigue (91.7%), anemia (66.7%), and diarrhea (58.3%). One case of grade 2 hematochezia and one case of grade 2 subclavian vein thrombosis were observed. In the nine evaluable cases, the disease control rate (DCR) was 66.7% (6/9). The median progression-free and overall survival (OS) times were 3.6±1.2 and 6.6±3.4 months, respectively. CONCLUSIONS: This phase 1 dose-escalation trial showed that, when combined with irinotecan, a daily dose of 500 mg apatinib was the optimum dose to treat ESCC.

Increased expression of CX3CL1 and CX3CR1 in papillary thyroid carcinoma.

CX3CL1 and its receptor CX3CR1 axis are involved in the development, progression and metastasis of many types of cancers. It has been reported that CX3CL1 and CX3CR1 expression was upregulated in some solid tumors. However, their roles in thyroid cancer remain unknown. In the present study, we investigated the expression of CX3CL1 and CX3CR1 in human papillary thyroid carcinoma (PTC) and their clinical significance. In this study, using immunohistochemistry, we examined the expression of CX3CL1 and CX3CR1 in the tissues of 26 human PTC (including 17 classical or conventional (CPTC) and 9 follicular (FVPTC) variants of PTC; 15 cases without and 11 cases with lymph node metastasis) and 10 cases of nodular goiter (NG). Compared to NG, a significant increase in the expression of CX3CL1 and CX3CR1 was found in PTC overall, as well as in CPTC and FVPTC separately. Higher CX3CL1 expression was found in CPTC than in FVPTC, but there was no significant difference in CX3CR1 expression between these subtypes of PTC. When analyzing their expressions in PTC without and with lymph node metastasis, an increased expression of CX3CL1 and CX3CR1 was observed when compared to NG respectively. There was however no significant difference in CX3CL1 and CX3CR1 expressions in PTC without lymph node metastasis when compared to PTC with lymph node metastasis. Furthermore, when compared to NG, an increased expression of CX3CL1 was correlated with an increased expression of CX3CR1 in PTC. Our data indicate that CX3CL1 and CX3CR1 can be used as tumor markers for PTC and may be potential novel targets for cancer prevention and treatment.

Association Between Multiple Lines of Active Therapy and Prognosis in Esophageal Squamous Cell Carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a critical threat to health and life. More than half of ESCC patients have recurrent or metastatic disease. Most late-stage patients undergo first-line treatment but experience further progression. Many of these patients have good performance status and are able to receive second-line therapy and even further treatments rather than best supportive care. Our analysis aimed to explore whether multiple lines of active treatment are beneficial in ESCC patients. METHODS: We conducted a retrospective cohort study. Univariate and multivariate survival analyses were used to identify whether the number of active treatment lines was related to prognosis. All analyses and the corresponding survival curves were based on the Cox proportional hazard regression model and the Kaplan-Meier method. Comparisons between groups were conducted using the t-test, chi-square test, and Fisher's exact test, as applicable. RESULTS: Of a total of 138 patients with recurrent or metastatic disease, 66 (61.1%) received one line of active treatment, and 42 (38.9%) patients received two and more lines. Multiple lines of active therapy were statistically significantly associated with better prognosis (crude hazard ratio (HR) (95% confidence interval (CI))=0.21 (0.06-0.73)), even after adjusting for relevant confounders (adjusted HR (95% CI)=0.19 (0.04-0.86)). More grade 3-4 hepatotoxicity patients were observed in the multiple-line treatment group (p=0.033). A small number of patients were cured by palliative management; these patients were more likely to have received both systematic and local treatment than other patients with repeated progression (9/15 versus 40/117, p=0.051). CONCLUSION: Multiple lines of active treatment are related to prolonged survival in recurrent and metastatic ESCC patients, and adverse effects are acceptable. Comprehensive therapy modalities are recommended.

Nimotuzumab Plus Paclitaxel and Cisplatin as a 1st-Line Treatment for Esophageal Cancer: Long Term Follow-up of a Phase II Study.

The effect of anti-epidermal growth factor receptor targeted treatment in esophageal squamous cell carcinoma (ESCC) is still unclear. We conducted a prospective phase II study of paclitaxel, cisplatin, and nimotuzumab (TPN) as a first-line treatment for unresectable or metastatic ESCC and the objective response rate was 51.8%. Here, we report the long-term follow-up results of the initial trial. Fifty-nine patients were enrolled from Mar 2011 to Apr 2013 and were treated with the TPN regimen. Palliative sequential radiotherapy was given if all tumor lesions were confined to 1-2 radiation fields. Fifty-six patients were eligible for evaluation. After a median follow-up of 32.2months, the median progression-free survival (PFS) and the overall survival (OS) time were 18.1±4.2 months (95% CI: 9.8-26.4) and 26.2±10.0 months (95% CI: 6.6-45.8), respectively, in 29 patients with unresectable local-regional disease, while they were 6.6±0.4 months (95% CI: 5.8-7.5) and 11.5±3.7 months (95% CI: 4.2-18.8), respectively, in 27 patients with metastatic disease. Patients who were male, those with multiple station lymph node metastases, those with visceral metastasis, those who did not response to TPN treatment, and those who did not receive radiotherapy, had a worse OS. In 6 patients with multiple station lymph node metastasis and in 3 patients with recurrent disease and oligo-metastasis (local lymph nodes), TPN with sequential radiation resulted in a mean OS of 17.67±9.50 months and a mean OS of over 40 months, respectively. In conclusion, TPN is effective as a first-line treatment for patients with unresectable and metastatic ESCC. In addition, TPN treatment with sequential radiation might improve survival in patients with limited or oligo lymph node metastases.

Increased Expression of GARP in Papillary Thyroid Carcinoma.

Regulatory T cells (Tregs) are immunosuppressive immune cells that play an important role in tumor development. Suppression of Treg function is considered to be an effective strategy for cancer therapy. Glycoprotein A repetitions predominant (GARP) has been found on the surface of activated Tregs. GARP has been recently observed in only a few solid tumors including breast, colon, lung cancers, and melanoma. However, its function in cancers remains unknown. Here, we investigated the expression of GARP in human papillary thyroid carcinoma (PTC) and its prognostic significance. In this study, immunohistochemistry was performed to examine the expression of GARP and Foxp3 in 19 human PTC tissues (including 10 cases with and 9 cases without lymph node metastasis) and 20 benign thyroid diseases (including 10 cases with nodular goiter and 10 cases with adenoma). Compared with benign thyroid diseases, we found a significant increase in the expression of GARP in PTC. Increased GARP expression in PTC was positively correlated with increased expression of Foxp3, which is very important for development of Tregs. But, there is no significant association of elevated expression of GARP with lymph node metastasis in PTC. Our results indicate that GARP is implicated in the development of PTC and might be a potential novel target for anticancer therapy. In addition, our findings further support the existence of a positive-feedback loop between GARP and Foxp3.

Clinical significance of serum tumor markers for advanced gastric cancer with the first-line chemotherapy.

BACKGROUND: Tumor markers play an important role in the diagnosis, monitoring and prognostic prediction of cancers. But the predictive value of serum tumor markers in gastric cancer is still unclear. METHODS: In this study, we detected serum levels of tumor markers to evaluate their relation to treatment response and prognosis in patients with unresectable advanced or metastatic gastric cancer. RESULTS: We collected the clinical data of 109 patients with unresectable advanced or metastatic gastric cancer who had received the first-line chemotherapy in Peking University Cancer Hospital from July 2013 to May 2015, and collected the value of serum carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 72.4 (CA72.4) and carbohydrate antigen 125 (CA125) before and after chemotherapy. At diagnosis, the positive rates of CEA, CA199, CA72.4 and CA125 were 46.8%, 40.2%, 53.5% and 35.0%, respectively. And the positive rate of combined detection of the four markers was 87.2%. Although patients with prechemotherapy CA199 ≥80 U/mL (92.3% vs. 68.5%, P=0.016) or CA72.4 ≥20 U/mL (91.4% vs. 62.5%, P=0.003) had higher clinical benefit rate after chemotherapy, they showed poorer prognosis (P=0.023 and P=0.006, respectively). CA72.4 ≥20 U/mL was an independent unfavorable prognostic factor (Hazard Ratio 4.84; 95% confidence interval: 1.910-12.262; P=0.001). In patients with increased levels of tumor markers before treatment, the levels of tumor markers decreased after chemotherapy, especially in those with clinical benefit (CEA, CA72.4 reached statistical significance, P=0.013 and P=0.029, respectively). A decrease of CEA ≥35%, CA199 ≥30%, or CA72.4 ≥40% after chemotherapy had positive prediction value for the response to chemotherapy (P=0.016, P=0.029, and P=0.008, respectively). CONCLUSIONS: The results showed that both high pre-chemotherapy serum levels of tumor markers (CA199 ≥80 U/mL or CA72.4 ≥20 U/mL) and a substantial decrease in tumor markers after chemotherapy (CEA ≥35%, CA199 ≥30%, or CA72.4 ≥40%) could predict a higher clinical benefit rate in patients with unresectable advanced or metastatic gastric cancer. However, this advantage in short-term response to chemotherapy failed to convert into prolonged survival benefits.

Prognosis impact of clinical characteristics in patients with inoperable esophageal squamous cell carcinoma.

BACKGROUND: Patients with inoperable esophageal squamous cell carcinoma (ESCC) were not homogeneous and their outcomes were widely divergent. There was a lack of identified clinical factors related to prognosis; and there were no previous studies constructing prognosis score to predict survival and guide treatment. METHODS: In this retrospective cohort study, twelve clinical characteristics of one hundred and twenty inoperable ESCC patients were collected at diagnosis and analyzed by Cox regression model. Various methods including univariate analysis, confounding adjusted multivariate analysis and model selection were applied to determine factors associated with poor prognosis; and prognosis score was built on established factors. RESULTS: Four characters were identified as poor prognosis factors, including mid- and low-thoracic tumor (aHR = 2.20, 95% CI = 1.03, 4.72), abdominal and retroperitoneal lymph node metastasis (aHR = 1.62, 95% CI = 1.00, 2.64), albumin no more than 39g/L (aHR = 2.81, 95% CI = 1.24, 6.41) and hematogenous metastasis (aHR = 1.61, 95% CI = 0.97, 2.69). Patients were stratified into three groups by prognosis score, that was, good survival with none of four identified factors (score zero), poor survival with three to four factors (score three to four) and median with one to two factors (score one to two), survival of three groups were statistically different (ptrend = 0.020). CONCLUSION: Prognosis score based on selected clinical characteristics could predict survival among inoperable ESCC patients, which was critical for individualized treatment and central of precise medicine.

Chest circumference and sitting height among children and adolescents from Lhasa, tibet compared to other high altitude populations.

OBJECTIVES: The adaptation of human beings to a high altitude environment during growth has been reported in several populations but is less known for Tibetans. The objective of this study was to investigate similarities and differences of Tibetans in patterns and characteristics of physical growth and development in comparison to other high altitude populations. METHODS: We measured the stature, weight, chest circumference and sitting height of 2,813 healthy children and adolescents aged 6- to 21-year-old living at 3,658-4,500 m in Tibet, China, and compared them with published data from other high altitude populations. Eligible participants must have been born and raised in Tibet, and both their parents' families have to be Tibetan for at least the past three generations. RESULTS: The physical growth and development of children and adolescents in Tibet and the Andes followed similar patterns, such as delayed growth, short stature and sitting height, and large chest dimensions. Relative to stature, Tibetan sitting heights are similar to Andeans, but chest circumferences are smaller. CONCLUSIONS: Findings from this study reinforce the conclusion that Tibetan and Andean populations have adapted differently to high altitude hypoxia. The physical features of each population may result from unique adaptation to hypoxia, as well as socio-ecological factors, such as poor nutrition.

[Genetic polymorphism of 15 STR loci in Tibetan population].

The polymorphism distributions of 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, VWA, TPOX, D18S51, D5S818, and FGA) were investigated in a Tibetan population by multiplex PCR amplification using five fluorochromes (6FAM, VIC, NED, PET, LIZ). Gene frequency, discrimination power (DP), heterozygosity (H), polymorphism information content (PIC) and probability of paternity exclusion (EPP) were calculated, and all loci were tested for Hardy-Weinberg equilibrium. Results indicate that the gene frequency of these 15 STR loci is in Hardy-Weinberg equilibrium. The DP is at 0.7555-0.9602, H is at 0.5651-0.8530, PIC is at 0.5528-0.8456, and EPP is at 0.3811-0.8549. Cumulative DP of the 15 STR is 0.99999999, and cumulative EPP is 0.999999997. Therefore, these 15 STR loci can be used as genetic markers of Tibetan populations in anthropological studies, linkage analysis of genetic diseases, individual identification and paternity testing in forensic medicine.