DPC4蛋白在胆道恶性肿瘤中的缺失表达

Objective To clarify the relationship between loss of expression of DPC4 proteins and pathogenesis of biliary tract carcinoma. Methods 71 primary biliary tract carcinomas (BTCa), including 38 common bile duct (CBD) carcinomas, 18 gallbladder carcinomas, and 15 hilar bile ducts (HBD) carcinomas were examined by immunohistochemical staining. In addition, the CBD carcinomas were divided into two groups, a tumor group with metastasis (M+ group, 27 cases) and a tumor group without metastasis (M− group, 11 cases). Results The frequency of loss expression of DPC4 protein was 32.8% in BTCa, 47.3% in CBD carcinoma, 11% in gallbladder carcinoma and 13% in HBD carcinoma. A comparison of the frequency of loss expression of DPC4 showed significantly statistical difference in the CBD carcinoma versus gallbladder carcinoma and HBD carcinoma (P<0.01). The frequency of loss expression of DPC4 was 48.1% in the M⁺ group and 45.4% in the M⁻ group. There was no significantly statistical difference between them (P>0.05). Conclusion There is a close relationship between the pathogenesis of BTCa and inactivation of DPC4 with different frequencies of DPC4 gene alteration in various locations of the biliary tract, but inactivation of DPC4 is not related with tumor metastasis in BTCa.     

Detection of K-ras Point Mutations at Codon 12 in Pancreatic Juice for the Diagnosis of Pancreatic Cancer by Hybridization Protection Assay: A Simple Method for the Determination of the Types of Point Mutations

The present study was undertaken to detect K- ras oncogene point mutations at codon 12 in pure pancreatic juice (PPJ) by the hybridization protection assay (HPA) method for the diagnosis of pancreatic cancer (PC). This assay can be carried out within 30 min and can determine not only the presence of a mutation, but also the mutational type of K- ras at codon 12. The minimal ratio of mutant DNA detectable by the HPA was 5–10% of the total DNA. PPJ was collected through a cannula under duodenal fiberscope control from 20 patients with PC and 20 patients with chronic pancreatitis (CP). Analysis of PPJ by the HPA revealed that the incidence of K- ras point mutations at codon 12 was 55% (11/20) in patients with PC and 0% (0/20) in those with CP. Mutational types of K- ras at codon 12 in PC were aspartic acid (Asp) in nine cases, both Asp and cysteine in one case, and arginine in one case. Analysis of K- ras point mutations at codon 12 in PPJ using the HPA method seems promising as a new genetic test for the diagnosis of PC, because the HPA method is simple, and can easily determine the mutational type.     

Dynamics of CXCR4 positive circulating tumor cells in prostate cancer patients during radiotherapy

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases-directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n = 24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy-number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4-expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem-like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK⁺CXCR4⁺ CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis-directed radiotherapy.     

Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.     

Identification of K-ras Oncogene Mutations in the Pure Pancreatic Juice of Patients with Ductal Pancreatic Cancers

Pancreatic cancer is detected on the basis of morphological changes delineated by means of various image-diagnostic methods. However, differentiation between chronic pancreatitis and pancreatic cancer, especially at the early stage, is not always simple when based upon the morphological changes alone. Therefore, we attempted to elucidate K- ras mutations in the sediment of pure pancreatic juice (PPJ) containing exfoliated ductal pancreatic cancer cells. PPJ was collected endoscopically from 20 patients with pancreatic cancer (PC) and 18 patients with chronic pancreatitis (CP). Polymerase chain reaction and allele specific oligonucleotide dot blot hybridization for K- ras mutations were performed with the DNA extracted from these samples. A K- ras mutation at codon 12 was identified in the PPJ of 11/20 (55%) of the patients with PC. On the other hand, the same mutation was not identified in the PPJ of any patient with CP. Moreover, K- ras mutations at codons 13 and 61 were not recognized in the PPJ of any patient with either PC or CP. These findings suggested that the presence of a K- ras mutation at codon 12 in PPJ would be useful in confirming the diagnosis of PC.     

Function of phosphorylation of NF-kB p65 ser536 in prostate cancer oncogenesis

Majority of prostate cancer (PCa) patients carry TMPRSS2/ERG (T/E) fusion genes and there has been tremendous interest in understanding how the T/E fusion may promote progression of PCa. We showed that T/E fusion can activate NF-kB pathway by increasing phosphorylation of NF-kB p65 Ser536 (p536), but the function of p536 has never been studied in PCa. We report here that active p536 can significantly increase cell motility and transform PNT1a cells (an immortalized normal cell line), suggesting p536 plays a critical role in promoting PCa tumorigenesis. We have discovered a set of p536 regulated genes, among which we validated the regulation of CCL2 by p536. Based on all evidence, we favor that T/E fusion, NF-kB p536 and CCL2 form a signaling chain. Finally, PNT1a cells (not tumorigenic) can form tumors in SCID mice when overexpressing of either wild type or active p65 in the presence of activated AKT, demonstrating synergistic activities of NF-kB and AKT signals in promoting PCa tumorigenesis. These findings indicate that combination therapies targeting T/E fusion, NF-kB, CCL2 and/or AKT pathways may have efficacy in T/E fusion gene expressing PCa. If successful, such targeted therapy will benefit more than half of PCa patients who carry T/E fusions.     

CCR9 mediates PI3K/AKT‐dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9‐CCL25 interaction enhances the cytotoxic effects of etoposide

Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer‐related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo‐resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor‐9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK‐3β) and downregulate activation of caspase‐3 in PCa cells. Significant downregulation of these CCR9‐mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9‐CCL25 interaction was blocked using anti‐CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9‐CCL25 axis mediates PI3K/AKT‐dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9‐CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone.     

Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer

The circulating level of insulin-like growth factor-binding protein-3 (IGFBP-3) is inversely associated with the risk of prostate cancer (PCa) and its progression and may be modulated by the A/C polymorphism at position -202 in the promoter region of IGFBP-3. This study was conducted to evaluate the role of the A/C polymorphism as a genetic modifier in the etiology of PCa and its disease status. The polymorphism was analyzed by a PCR restriction fragment-length polymorphism technique in 307 PCa patients, 221 benign prostatic hyperplasia (BPH) patients, and 227 male controls. No significant difference in the genotype frequency was found between the PCa or BPH patients and controls (PCa versus control, P = 0.316; BPH versus control, P = 0.964). Regarding the tumor stage, the C allele was more frequently observed in patients having tumors with higher stage (P for trend = 0.002). When the PCa patients with localized disease (stage A + B + C) were considered as reference, those with CC and AC genotype had a significantly increased risk of metastatic disease (stage D) compared with those with AA genotype [age-adjusted odds ratio (aOR) = 3.89, 95% confidence interval (CI) = 1.42-10.64, P = 0.008, and aOR = 1.68, 95% CI = 1.01-2.79, P = 0.044, respectively]. The presence of the C allele appeared to be associated with an increased risk of metastatic PCa with a gene dosage effect (aOR = 1.82, 95% CI = 1.23-2.68, P = 0.002). Similarly, significant findings were also observed when PCa patients were compared between those with organ-confined disease (stage A + B) and those with extra-prostatic extension (stage C + D). Furthermore, the C allele was present more frequently in patients with higher tumor grade. In conclusion, the IGFBP-3 -202 A/C polymorphism was not associated with susceptibility to PCa and BPH in Japanese men, but the presence of the C allele may cumulatively increase the risk for tumor metastasis and for having tumors with a biologically more aggressive phenotype. Because of the significant differences in incidence of clinically evident PCa according to racial backgrounds, the conjecture should be further examined in different racial populations.     

Benefits and risks of using erythropoiesis-stimulating agents (ESAs) in lung cancer patients: study-level and patient-level meta-analyses

In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue. In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69-1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was -0.02 (-0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65-1.09). The ESA odds ratio (95% CI) was 0.34 (0.28-0.41) for transfusion incidence. In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78-1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%). These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.     

Analysis of the interaction of induction regimens with p-glycoprotein expression in patients with acute myeloid leukaemia: results from the MRC AML15 trial

Retrospective analyses in non-randomised cohorts suggest that regimens containing fludarabine/Ara C and/or idarubicin/ara C may be more effective than daunorubicin/AraC (DA)-containing regimens in cases of acute myeloid leukaemia (AML) overexpressing p-glycoprotein (Pgp). We prospectively measured Pgp protein and function by flow cytometry in CD45-gated blasts from 434 AML15 trial patients randomised to remission induction therapy with two courses of FLAG-Ida or DA±etoposide (DA/ADE). In all, 34% were positive for Pgp protein and 38% for function. Pgp protein-positive cases had a higher incidence of resistant disease (14% vs 5%), adjusted odds ratio 2.67 (1.14-6.24). There was a trend towards a higher cumulative incidence of relapse at 5 years for Pgp-positive cases (46% vs 55%), adjusted hazard ratio 1.42 (0.98-2.07) (P=0.06). For patients treated with FLAG-Ida, the complete remission (CR) rate was 86% for both Pgp-positive and Pgp-negative patients. In patients treated with DA/ADE, 78% of Pgp-positive and 90% of Pgp-negative cases achieved CR (P=0.06). In analyses of overall survival, there was no interaction between treatment received and Pgp expression. Data for Pgp function followed similar trends. Our data suggest that FLAG-Ida may improve the remission rate for Pgp-positive AML, but the malignant clone is reduced rather than eradicated such that the relapse rate remains high in Pgp-positive patients.     

Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals

Several infiltrating cells in the tumor microenvironment could influence the cancer progression via secreting various cytokines. Here, we found the CCL5 secreted from BM-MSCs suppressed androgen receptor (AR) signals via enhancing the expression of hypoxia inducible factor 2α (HIF2α) in prostate cancer (PCa) cells. Mechanism dissection revealed that the increased HIF2α might alter the AR-HSP90 interaction to suppress the AR transactivation, and inhibition of HIF2α reversed the BM-MSCs-increased PCa stem cell population and PCa cells invasion. Importantly, CCL5 could suppress the prolyl hydroxylases (PHDs) expression, which might then lead to suppress VHL-mediated HIF2α ubiquitination. Together, these results demonstrated that the CCL5 signals from infiltrating BM-MSC cells to HIF2α signals within PCa cells might play a key role to increase PCa stem cell population and PCa metastasis via altering the AR signals. Targeting this newly identified CCL5/HIF2α/AR axis signal axis may allow us to develop a novel way to suppress PCa metastasis.     

Risk of prostate cancer in low‐dose aspirin users: A retrospective cohort study

A growing body of evidence indicates that use of low‐dose aspirin (LDA) reduces the risk of certain adenocarcinomas. While there are several and consistent findings on the protective effect of LDA on colorectal and other cancers, few and conflicting evidence is available on prostate cancer (PCa). The aim of this study was to assess whether LDA reduces the incidence rate of PCa. We conducted a nationwide, population‐based, retrospective cohort study by using Health Search IMS Health Longitudinal Patient Database (HSD). Patients with ischemic cardio‐ or cerebrovascular disease (index date) were identified. Time‐dependent multivariable Cox proportional hazard models were adopted to estimate Hazard Ratios (HRs) and related 95% confidence intervals (95% CI) of PCa associated with use of LDA. The exposure was lagged by one year to consider the latency of drug effect on the outcome onset. Within a cohort 13,453 patients, the overall incidence rate of PCa was 2.5 per 1,000 person‐years. Use of LDA was associated with a decreased incidence rate of PCa (HR = 0.64; 95% CI: 0.48–0.86), which was primarily driven by a frequency of LDA use equal to or higher than twice per week (HR = 0.60; 95% CI: 0.43–0.83). Such an association was more pronounced (HR = 0.43; 95% CI: 0.21–0.91) when LDA was used for five or more years. Our findings indicate that LDA use might be associated with a reduction of risk of PCa in patients with cardio‐ or cerebrovascular diseases.     

Diagnostic Role of Serum Free-to-Total Prostate Specific Antigen (PSA) Ratio in Prostate Cancer with Serum Total Concentration of PSA below 4 ng/mL

Purpose: To examine the effectiveness of serum free-to-total prostate specific antigen ratio (%fPSA) forthe detection of prostate cancer (PCa) in men with different serum total PSA (tPSA) categories. Materials andMethods: From January 2010 to December 2013, a total of 225 patients with lower urinary tract symptoms(LUTS) underwent tPSA and %fPSA measurements. Histological examination with calculation of Gleasonscore and whole body bone scans were performed in identified cases of PCa. Results: PCa was diagnosed in 44(19.6%) patients and the remaining 181 patients had benign prostate disease. PCa was detected in 5 (23.8%),13 (8.7%) and 26 (47.3%) cases with tPSA level ranges ≤4 ng/ml, 4 to 10 ng/ml and >10 ng/ml, respectively. Theaverage Gleason score was 7.2±0.2. Some 6 (13.6%) out of 44 PCa patients had bone metastases. The sensitivitywas 80% and specificity was 81.3% at the cut-off %fPSA of 15% in PCa patients with a tPSA level below 4 ng/mL. A lower %fPSA was associated with PCa patients with Gleason score ≥7 than those with Gleason score≤6 (11.7±0.98 vs. 16.5±2.25%, P=0.029). No obvious relation of %fPSA to the incidence of bone metastasis wasapparent in this study. Conclusions: The clinical application of %fPSA could help to discriminate PCa frombenign prostate disease in men with a tPSA concentration below 4 ng/mL.     

Germline Mutations and Polymorphisms of Androgen Receptor in Prostate Cancer Patients: Frequency and Results of in Silico Analysis

Background: Germline and somatic polymorphisms and mutations of the Androgen Receptor (AR) gene are known tobe associated with the incidence of prostate cancer (PCa) in different populations. In this study we assessed germline ARpolymorphisms and mutations in PCa patients with prediction of pathogenicity of the identified mutations by in silicoanalysis. Methods: Diagnosis of PCa was based on histopathology of prostate tissue (Gleason Score criteria) and serumprostate-specific antigen (PSA) levels. Genomic DNA was extracted from peripheral blood of 38 patients. All exons andexon-intron boundaries of AR were amplified using polymerase chain reactions (PCR) followed by Sanger sequencing.In silico analysis was performed using Polyphen-2 and Mutation Taster®. Results: Two polymorphisms, CAG repeatsequence (13-34 repeats in length) and p.Pro214Glu (MAF: 0.0789) located in exon 1 were identified. A missensemutation (c.47C>A/p.Pro146Glu) and in-frame deletion of a CAG sequence leading to loss of Arginine at codon 85(c.252_254delCAG/p.Arg85-) were identified in a 70 year old patient with a Gleason Score and PSA level of 2 and2.4ng/dL, respectively. His PSA level decreased to < 0.5 ng/dL after 9 months of androgen deprivation therapy. Identifiedmutations were predicted to be non-disease causing by Polyphen-2 and Mutation Taster®. Conclusion: Our datademonstrated that the frequency of germline mutations of AR was low in PCa patients in Indonesia (5.26%: 2/38 alleles),so that they are not likely to be major etiological factors. The in silico analysis of identified AR mutations in this studycorroborated the clinopathology features of the patient.     

CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer

It has been reported that an increased population of regulatory T cells (Tregs) is one of the reasons for impaired anti-tumor immunity. Recently, Foxp3 has been reported as a reliable marker of Tregs. The authors investigated the frequency of Foxp3(+) Tregs within CD4(+) cells in TILs, regional lymph nodes and PBLs of gastric cancer patients (n = 45). Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, they evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3(+) Tregs in gastric cancer. CD4(+)CD25(+)Foxp3(+) Tregs as a percentage of CD4(+) cells were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from gastric cancers was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3(+) Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% +/- 7.5% vs. 4.1% +/- 5.3%, p < 0.01). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17(+) or CCL22(+) cells among CD14(+) cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL17(+) or CCL22(+) cells and Foxp3(+) Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3(+) Tregs, with such an observation occurring in early gastric cancer.     

毕Ⅱ式胃切除术后胆道疾病老年患者行内镜逆行胰胆管造影术的风险性及危险因素分析

目的研究对于毕Ⅱ式胃切除术后并发胆道疾病的老年患者行内镜逆行胰胆管造影术（ERCP）辅助治疗的风险及危险因素。方法选取2016年1月至2018年1月在哈尔滨医科大学附属第四医院接受毕Ⅱ式胃切除术后并发胆道疾病经ERCP辅助治疗的60例老年患者。分析ERCP辅助治疗的效果及并发症发生情况，采用多因素Logistic回归分析治疗失败以及术后发生并发症的危险因素。结果ERCP辅助治疗的成功率为6833％(41／60),失败率为3167％(19／60),术后并发症发生率为2167％(13／60),主要包括高淀粉酶血症1500％(9／60),急性胰腺炎500％(3／60),术后出血167％(1／60)。内镜长度较短、反复插管失败、未开展直视镜的ERCP失败率较高,是治疗失败的独立危险因素(均P<005)。年龄≥70岁和采用塑料支架胆管引流的患者经ERCP辅助治疗后并发症的发生率较高,是术后发生并发症的独立危险因素(均P<005)。结论老年患者毕Ⅱ式胃切除术后并发胆道疾病经ERCP辅助治疗的成功率并不理想，且并发症发生风险较高。内镜长度较短、反复插管失败、未能开展直视镜可能增加治疗失败的风险，年龄≥70岁、塑料支架胆管引流可增加术后并发症发生率。     

The CC ligand chemokine family members CCL17/CCL22 predict the survival and response to immune checkpoint blockade therapy of patients with head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is considered an immunosuppressive malignancy. Cross-talk between cancer cells and immune cells is modulated in part by CC ligand (CCL) chemokines, having a major effect on tumor progression. However, the predictive value and function of CCL family members in HNSCC have not been elucidated. Here, the predictive value of CCL members in cancer prognosis and Immune checkpoint blockade therapy response was investigated. CCL17 and CCL22 were screened as the key CCL chemokines in HNSCC through co-expression analysis. Further, the correlation between CCL17/CCL22 expression and cancer immune infiltration were evaluated based on TIMER and were validated by a set of scRNA-seq data. Moreover, the expression level of CCL17/CCL22 we evaluated to predict the response to Immune checkpoint blockade therapy in a panel of cancer types by using the TIDE database. Results indicated that CCL17/CCL22 had a high co-expression correlation and had a marginally statistical significance with the overall survival in HNSCC patients (P value = 0.057 and 0.055, respectively). Our findings showed high expression of CCL17/CCL22 was positively correlated with CD4⁺ T cell infiltration levels in HNSCCs and activate mTORC1 signaling pathway in CD4⁺ T cells. Further analysis from TIDE showed the high expression of CCL17/CCL22 might predict favorable responses to immune checkpoint blockade therapy in HNSCC patients. These findings provide an insight into the predictive roles of CCL17/CCL22 in HNSCC.