Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer

Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter- and intra- tumor genetic heterogeneity. A molecular classification should help sort patients into less heterogeneous and more appropriate groups regarding the metastatic risk and the therapeutic response, with the consequences of better predicting evolution and better orienting the treatment. PDAC can be classified based on mutational subtypes and 18gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions.     

胰腺癌的生物学临床诊断研究进展

胰腺癌(pancreatic cancer,PC)是一种发病率接近死亡率、死亡率极高的恶性肿瘤.由于胰腺癌早期无明显病症,许多病人确诊时已是癌症末期,错过了最佳的治疗时期,预后极差,因此,迫切需要高效的胰腺癌早期诊断生物标志物.随着高通量测序技术(next-generation sequencing,NGS)、高分辨质...     

Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers

INTRODUCTION: There is mounting evidence describing the immunosuppressive role of bulky metastatic disease, thus countering the therapeutic effects of tumor vaccine. Therefore, adjuvant immunotherapy may have a better impact on clinical outcome. In this phase II clinical trial, we aimed to test the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients. MATERIALS AND METHODS: Twelve patients with no evidence of disease (NED), five pancreatic and seven colorectal cancer patients were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor's ras mutation. Vaccinations were given every 4 weeks, up to a total of six vaccines. RESULTS: No serious acute or delayed systemic side effects were seen. We detected specific immune responses to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by quantitative real-time PCR. Five out of eleven patients showed a positive immune response. Furthermore, the five pancreatic cancer patients have shown a mean disease-free survival (DFS) of 35.2+ months and a mean overall survival (OS) of 44.4+ months. The seven colorectal cancer patients have shown a mean disease-free survival (DFS) of 27.2+ months and a mean overall survival (OS) of 41.5+ months. CONCLUSION: In this study, we found that it is feasible to use mutant ras vaccine in the adjuvant setting. This vaccine is safe, can induce specific immune responses, and it appears to have a positive outcome in overall survival. Therefore, we believe that such an approach warrants further investigation in combination with other therapies.     

Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers

p53 Mutations are found in up to 30% of breast cancers and peptides derived from over-expressed p53 protein are presented by class I HLA molecules and may act as tumor-associated epitopes in cancer vaccines. A dendritic cell (DC) based p53 targeting vaccine was analyzed in HLA-A2+ patients with progressive advanced breast cancer. DCs were loaded with 3 wild-type and 3 P2 anchor modified HLA-A2 binding p53 peptides. Patients received up to 10 sc vaccinations with 5 x 10(6) p53-peptide loaded DC with 1-2 weeks interval. Concomitantly, 6 MIU/m(2) interleukine-2 was administered sc. Results from a phase II trial including 26 patients with verified progressive breast cancer are presented. Seven patients discontinued treatment after only 2-3 vaccination weeks due to rapid disease progression or death. Nineteen patients were available for first evaluation after 6 vaccinations; 8/19 evaluable patients attained stable disease (SD) or minor regression while 11/19 patients had progressive disease (PD), indicating an effect of p53-specific immune therapy. This was supported by: (1) a positive correlation between p53 expression of tumor and observed SD, (2) therapy induced p53 specific T cells in 4/7 patients with SD but only in 2/9 patients with PD, and (3) significant response associated changes in serum YKL-40 and IL-6 levels identifying these biomarkers as possible candidates for monitoring of response in connection with DC based cancer immunotherapy. In conclusion, a significant fraction of breast cancer patients obtained SD during p53-targeting DC therapy. Data encourage initiation of a randomized trial in p53 positive patients evaluating the impact on progression free survival.     

A systematic assessment of statistics,risk factors,and underlying features involved in pancreatic cancer

Pancreatic cancer remains the fourth leading cause of cancer-related death in the world, and will continue to become the number two cause of cancer-related death unless a remarkable breakthrough is achieved. With a slim chance of early diagnosis, surgery can only provide a median survival of 17–23 months. The presence of a dense stroma makes this cancer resilient to chemotherapy, with very few potent inhibitors like nab paclitaxelin available that can work in combination with chemotherapeutic agents. Survival rates, on the one hand, lie at 8.5%. Variation in types of pancreatic cancer, on the other hand, makes it notoriously difficult to come up with a practical solution for the treatment of this disease. A deeper understanding of the root cause would be beneficial for diagnosis. Advancement in the field of genomics has made the identification of novel biomarkers relatively easier. By coupling this factor with the production of suitable inhibitors, testing in large numbers can be made possible with the help of cell lines. With the combined efforts of biological knowledge and modern technology, the cure for pancreatic cancer could be at hand.     

5-Fu小剂量泵二线治疗晚期胰腺癌的临床研究

目的观察5-Fu小剂量泵二线治疗晚期胰腺癌的疗效和不良反应。方法 13例晚期吉西他滨治疗失败的胰腺癌患者,5-Fu300mg/d,1～14d持续静脉泵入,DDP5mg1～5d,8～12d静点,28d为1周期。观察客观疗效、临床获益率及不良反应。结果部分缓解1例,稳定6例,10例临床获益,中位生存期5.8个月（2.2～8.3个月）,中位疾病进展时间3.0个月（1～4.5个月）,主要不良反应为菌群失调相关性腹泻。结论 5-Fu小剂量泵二线治疗可改善晚期胰腺癌患者生存,耐受性好。     

Functions and clinical implications of exosomes in pancreatic cancer

Pancreatic cancer is one of the most aggressive human malignancies and is associated with a dismal prognosis, which can be contributed to its atypical symptoms, metastatic propensity, and significant chemoresistance. Emerging evidence shows that pancreatic cancer cell-derived exosomes (PEXs) play critical roles in tumorigenesis and tumor development, as they are involved in drug resistance, immune evasion and metabolic reprograming, and distant metastasis of pancreatic cancer. Their numerous differentially expressed and functional contents make PEXs promising screening tools and therapeutic targets, which require further exploration. In this review, we focus on the functions of PEX contents and their clinical implications in pancreatic cancer.     

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I?<?O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8–25.5] for patients with I?<?O above the median value of 97.5% as compared to 11.9 months [10.4–13.3] for those with a lower I?<?O (Log-rank p?<?0.001). Multivariate analyses retained continuous I?<?O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p?<?0.001) and 0.970 (p?<?0.001) for each 1% increase in I?<?O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I?<?O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms.     

Rapid induction of pancreatic cancer cells to cancer stem cells via heterochromatin modulation

Mounting evidence supports that CSCs (cancer stem cells) play a vital role in cancer recurrence. Therefore elimination of CSCs is currently considered to be an important therapeutic strategy for complete remission. A major obstacle in CSC research is the obtainment of sufficient numbers of functional CSC populations. Here, we established a method to induce bulk pancreatic cancer cells to CSCs via heterochromatin modulation. Two pancreatic cancer cell lines Panc1 and Bxpc3 were cultured for 4 days in inducing medium (mTeSR containing FBS, B27, MEK inhibitor, GSK3 inhibitor, and VPA), and another 2 days in sphere culture medium (mTeSR supplemented with B27). Then the induced cells were dissociated into single cells and cultured in suspension in sphere culture medium. It was found that the majority of induced cells formed spheres which could grow larger and be passaged serially. Characterization of Panc1 sphere cells demonstrated that the sphere cells expressed increased pancreatic cancer stem cell surface markers and stem cell genes, were more resistant to chemotherapy, and were more tumorigenic in vivo, indicating that the induced sphere cells acquired CSC properties. Thus, the inducing method we developed may be used to obtain a sufficient number of CSCs from cancer cells, and contribute to the research for CSC-targeting therapy.     

miR-21的高表达与胰腺癌预后关系的meta分析

为评价miR-21的高表达与胰腺癌预后的相关性,通过全面检索Pub Med,EMBASE,Google scholar,维普,CNKI等数据库,收集已公开发表的关于miR-21的高表达与胰腺癌预后相关性的文献,按meta分析的要求对原始文献的质量进行评估,采用STATA V12.0软件对各研究的效应量进行统计分析。结果发现共纳入4篇文献(共300个病例),合并总生存率(OS)HR为1.26(95%CI:1.08~1.47,P0.05)。由此可以推断胰腺癌预后的一个危险因素为miR-21的高表达。     

Death of a tumor: targeting CCN in pancreatic cancer

The matricellular protein CCN2 (connective tissue growth factor, CTGF) has been previously implicated in tumorigenesis. In pancreatic cancer cells, CCN2 expression occurs downstream of ras/MEK/ERK. Direct evidence that CCN2 mediates tumor progression in pancreatic cancer has been lacking. An exciting recent report by Bennewith et al. (Cancer Res 69:775–784, 2009) has used shRNA knockdown of CCN2 to illustrate that CCN2 contributes to growth of pancreatic tumor cells, both in vitro and in vivo. This report briefly summarizes these findings.     

Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in many malignant tumors including urothelial cancer but is hardly detectable in normal, differentiated adult tissues. Previously we reported CD8-positive cytotoxic T-lymphocytes (CTLs) were successfully induced by stimulation with survivin-2B80-88 peptide in vitro. We started a phase I clinical study of survivin-2B80-88 peptide vaccination for advanced urothelial cancer patients to assess the safety and efficacy of this vaccination. Nine patients were received vaccination and were evaluated for immunological evaluation, adverse events, and clinical responses. A total of 46 vaccinations were carried out. There was no severe adverse event. HLA-A24/survivin-2B80-88 peptide tetramer analysis revealed a significant increase in the peptide-specific CTL frequency after the vaccination in five patients. Slight reduction of the tumor volume was observed in one patient. Survivin-2B80-88 peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in urothelial cancer patients.     

Personalized liposome–protein corona in the blood of breast,gastric and pancreatic cancer patients

When nanoparticles (NPs) are dispersed in a biofluid, they are covered by a protein corona the composition of which strongly depends on the protein source. Recent studies demonstrated that the type of disease has a crucial role in the protein composition of the NP corona with relevant implications on personalized medicine. Proteomic variations frequently occur in cancer with the consequence that the bio-identity of NPs in the blood of cancer patients may differ from that acquired after administration to healthy volunteers. In this study we investigated the correlation between alterations of plasma proteins in breast, gastric and pancreatic cancer and the biological identity of clinically approved AmBisome-like liposomes as determined by a combination of dynamic light scattering, zeta potential analysis, one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) and semi-quantitative densitometry. While size of liposome–protein complexes was not significantly different between cancer groups, the hard corona from pancreatic cancer patients was significantly less negatively charged. Of note, the hard corona from pancreatic cancer patients was more enriched than those of other cancer types this enrichment being most likely due to IgA and IgG with possible correlations with the autoantibodies productions in cancer. Given the strict relationship between tumor antigen-specific autoantibodies and early cancer detection, our results could be the basis for the development of novel nanoparticle-corona-based screening tests of cancer.     

A metabolism-relevant signature as a predictor for prognosis and therapeutic response in pancreatic cancer

Although several altered metabolic genes have been identified to be involved in the tumorigenesis and advance of pancreatic cancer (PC), their prognostic values remained unclear. The purpose of this study was to explore new targets and establish a metabolic signature to predict prognosis and chemotherapy response for optimal individualized treatment. The expression data of PC patients from two independent cohorts and metabolism-related genes from KEGG were utilized and analyzed for the establishment of the signature via lasso regression. Then, the differentially expressed candidate genes were further confirmed via online data mining platform and qRT-PCR of clinical specimens. Then, the analyses of gene set enrichment, mutation, and chemotherapeutic response were performed via R package. As results showed, 109 differentially expressed metabolic genes were screened out in PC. Then a metabolism-related five-gene signature comprising B3GNT3, BCAT1, KYNU, LDHA, and TYMS was constructed and showed excellent ability for predicting survival. A novel nomogram coordinating the metabolic signature and other independent prognostic parameters was developed and showed better predictive power in predicting survival. In addition, this metabolic signature was significantly involved in the activation of multiple oncological pathways and regulation of the tumor immune microenvironment. The patients with high risk scores had higher tumor mutation burdens and were prone to be more sensitive to chemotherapy. In summary, our work identified a new metabolic signature and established a superior prognostic nomogram which may supply more indications to explore novel strategies for diagnosis and treatment.     

Are older patients less likely to be treated for pancreatic cancer? A systematic review and meta-analysis

Pancreatic cancer is the seventh commonest cause of cancer-related death worldwide. Although prognosis is poor, both surgery and adjuvant chemotherapy improve survival. However, it has been suggested that not all pancreatic cancer patients who may benefit from treatment receive it. This systematic review and meta-analysis investigated the existence of age-related inequalities in receipt of first-line pancreatic cancer treatment. Medline, Embase, Cochrane Library and grey literature were searched for population-based studies investigating treatment receipt, reported by age, for patients with primary pancreatic cancer from inception until 4th June 2020, and updated 5th August 2021. Studies from countries with universal healthcare were included, to minimise influence of health system-related economic factors. A modified version of the Newcastle-Ottawa Scale was used to assess risk of bias. Random-effects meta-analysis was undertaken comparing likelihood of treatment receipt in older versus younger patients. Sensitivity and subgroup analyses were conducted. Eighteen papers were included; 12 independent populations were eligible for meta-analysis. In most studies, < 10% of older patients were treated. Older age (generally ≥65) was significantly associated with reduced receipt of any treatment (OR=0.14, 95% CI 0.10–0.21, n = 12 studies), surgery (OR=0.15, 95% CI 0.09–0.24, n = 9 studies) and chemotherapy as a primary treatment (OR=0.13, 95% CI 0.07–0.24, n = 5 studies). The effect of age was independent of methodological quality, patient population or time-period of patient diagnosis and remained in studies with confounder adjustment. The mean quality score of included studies was 6/8. Inequalities in receipt of healthcare interventions across social groups is a recognised concern internationally. This review shows that older age is significantly, and consistently, associated with non-receipt of treatment in pancreatic cancer. However, there are risks and side-effects associated with pancreatic cancer treatment. Further research on what influences patient and professional treatment decision-making is required to better understand these apparent inequalities.     

Immunotherapy with intralesional and systemic interleukin-2 of patients with non-small-cell lung cancer

Eight patients affected by non-small-cell lung cancer were treated with intralesional and systemic recombinant IL-2(rIL-2) injection with the aim of activating both tumour-infiltrating lymphocytes and circulating cytotoxic or killer cells. The schedule of treatment was as follows: a daily fine-needle transparietal intralesional rIL-2 injection (1×10⁵ Cetus units) from day 1 to day 5 and systemic rIL-2 infusion (1×10⁵ Cetus units kg^–1 day^–1) from day 6 to day 10. One to four cycles of treatment were received by each patient. Clinical and immunological evaluations were performed (a) before treatment, (b) following the intralesional rIL-2 administration, (c) 1 h after the beginning of rIL-2 infusion and (d) at the end of the systemic rIL-2 infusion. No complete remission was achieved, two patients showed a partial remission, three resulted in stable disease and three patients progressed. Natural killer and lymphokine-activated killer cell activity dramatically decreased 1 h after the beginning of rIL-2 infusion and increased at the end of treatment. A progressive increase of circulating CD8⁺ and HLA class II⁺ T cells as well as of CD8⁺ T cell clones, most of which displayed NK activity, was recorded following rIL-2 infusion. Present data indicate that (a) the local administration of rIL-2 coupled with systemic rIL-2 infusion may be suggested as an alternative approach for the immunotherapy of lung cancer, (b) rIL-2 induces different immunological modifications according to the route and the time of its administration and (c) rIL-2 administration increases the amount of circulating immune cells with potential antitumour activity.     

快速康复护理联合益生菌营养疗法对胰腺癌根治术后患者的影响

探讨快速康复护理联合益生菌营养疗法对胰腺癌根治术后患者营养状况和康复情况的影响。

选择2020年1月至2022年2月在我院接受胰腺癌根治术的100例患者作为研究对象,采用随机数表法将其分为对照组（n = 50）和试验组（n = 50）。对照组患者接受胰腺癌根治术常规护理和营养支持,试验组在此基础上施行快速康复护理联合益生菌营养疗法。比较干预前后两组患者转铁蛋白（TRF）、前清蛋白（PAB）、白蛋白（ALB）等营养指标水平,以及免疫球蛋白A（IgA）、免疫球蛋白G（IgG）、免疫球蛋白M（IgM）等免疫功能指标水平。同时记录干预期间两组患者的腹腔感染、消化道出血、吻合口瘘、切口感染等并发症发生情况,以及住院时间、下床活动时间、肛门排气时间和干预满意率,以评价干预效果。

干预前,两组患者TRF、PAB、ALB、IgA、IgG和IgM水平比较差异均无统计学意义（均P＞0.05）。干预后,试验组患者TRF、PAB、ALB、IgA、IgG和IgM水平均高于对照组（均P＜0.05）。干预期间,试验组患者术后并发症总发生率、术后肛门排气时间、下床活动时间和住院时间均低于对照组（均P＜0.05）。此外,试验组患者总干预满意率（96.0%）显著高于对照组（80.0%）,差异有统计学意义（P＜0.05）。

快速康复护理联合益生菌营养疗法可有效降低胰腺癌根治术后患者并发症发生率,保障患者的营养状况,提高免疫功能,促进术后康复,值得在临床推广应用。

     

Synthesis and biological evaluation of isoprenylated coumarins as potential anti-pancreatic cancer agents

A series of isoprenylated coumarins has been designed, synthesized, and evaluated against human pancreatic adenocarcinoma cell line PANC-1 under nutrient-rich and nutrient-deprived conditions. The compounds described investigate the effect of isoprenyl chain length and positioning on cell growth inhibition. The majority of these compounds displayed cytotoxicity against PANC-1 cells selectively in the absence of essential amino acids, glucose, and serum, and showed no cytotoxicity under nutrient-rich conditions. In this study, compound 6 exhibited the highest cytotoxic activity with an LC₅₀ value of 4 μM and induced apoptosis-like morphological changes in PANC-1 cells after a 24-h incubation. The evaluated structure–activity relationships show that substitution at the 6-position and the presence of a farnesyl isoprenyl tail are important structural features for enhanced preferential cytotoxicity. These findings provide important information to designing other structural analogues for potential application as novel pancreatic antitumor agents.