Pancreatic cancer, a common digestive system tumor with high malignancy and a poor prognosis, has several treatment options. However, none of them are particularly effective because understanding the pathogenesis of pancreatic cancer remains a significant clinical challenge. Splicing isoforms mediate various biological phenotypes as an important means of regulating gene expression in eukaryotes, and their abnormalities can lead to a variety of diseases. Numb is an important cell fate determining protein whose alternative splicing has been linked to the development of various cancers. In pancreatic cancer, selective splicing of Numb can result in a variety of Numb protein subtypes, each with a different regulatory effect on the activation of various cancer-related signal pathways and tumor cell biology. This paper reviews the recent progress of Numb protein research in pancreatic cancer, with a focus on the regulatory role of its different isoforms in pathogenesis.

Objective:To evaluate the performance of the European Evidence-based Guidelines on Pancreatic Cystic Neoplasms (EEGPCN)(2018) and International Association of Pancreatology(IAP) Guideline(Version 2017) in predicting high grade dysplasia/invasive carcinoma-intraductal papillary mucinous neoplasm(HGD/INV-IPMN).Methods:A retrospective analysis of 363 patients,who underwent surgical resection in Changhai Hospital affiliated to Navy Medical University from January 2012 to December 2018 and were pathologically identified as (intraductal papillary mucinous neoplasm, IPMN),was performed. The patients,including 230 males and 133 females,aging (61.7±10.1) years(range:19 to 83 years). The proportion of HGD/INV-IPMN who met with the absolute indication(AI) of EEGPCN and high risk stigma(HRS) of IAP were compared. The binary Logistic regression analysis was used to find the independent risk factors of HGD/INV-IPMN.Eight combinations of risk factors derived from relative indication/worrisome feature or risk factors in this study,were made to evaluate the diagnostic efficacy. The area under curve(AUC) of receiver operating characteristics was used to evaluate the the cutoff value of risk factors(①CA19-9≥37 U/ml,②diameter of main pancreatic duct 5.0-9.9 mm,③enhancing mural nodule<5 mm,④(acute) pancreatiti,⑤ acyst diameter ≥40 mm,⑤ bcyst diameter ≥30 mm, ⑥thickened or enhancing cyst walls,⑦neutrophile granulocyte to lymphocyte ratio(NLR)≥2, ⑧cyst located in head, uncinate or neck,⑨carcinoembryonic antigen(CEA) ≥5 μg/L) number for predicting HGD/INV-IPMN.The accuracy,sensitivity,specificity,positive predictive value,negative predictive value,true positive,true negative,false positive,false negative,positive likelihood ratio,negative likelihood ratio,Youden index and F1 score were calculated. Results:Ninety-two patients(49.5%) of 186 ones who met AI and 85 patients(48.3%) of 176 ones who met HRS were respectively confirmed as HGD/INV-IPMN. In those patients who were not met AI,tumor location,thickened/enhancing cyst wall,CA19-9 elevated,NLR≥2 and CEA elevated were significantly ( P<0.05) correlated with HGD/INV-IPMN. And tumor location(head/uncinate/neck vs. body/tail, OR=3.284,95% CI:1.268-8.503, P=0.014),thickened/enhancement cyst wall (with vs.without, OR=2.713,95% CI:1.177-6.252, P=0.019),CA19-9(≥37 U/L vs.<37 U/L, OR=5.086,95% CI:2.05-12.62, P<0.01) and NLR(≥2 vs.<2, OR=2.380,95% CI:1.043-5.434, P=0.039) were the independent risk factors of HGD/INV-IPMN. Patients with ≥4 risk factors of 9 in combination Ⅷ(①②③④⑤ b⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the moderate accuracy(71.0%),moderate sensitivity (62.0%) and moderate specificity (73.0%). Patients with ≥4 risk factors of 9 in Combination Ⅶ(①②③④⑤ a⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the highest specificity(83.0%) and patients with ≥3 risk factors of 8 in combination Ⅵ(①②③④⑤ b⑥⑧⑨) were diagnosed as HGD/INV-IPMN with the highest sensitivity(74.0%). The AUC for diagnosis of HGD/INV-IPMN in combination Ⅵ,Ⅶ and Ⅷ were 0.72,0.75 and 0.75,respectively. Older patients and younger patients could respectively refer to combination Ⅶ and combination Ⅵ to improve the management of IPMN. Conclusions:Patients who meet AI of EEGPCN should undertake resection, otherwise the method we explored is recommended. The method of improvement for diagnosis of HGD/INV-IPMN is relatively applicable and efficient for decision-making of surgery, especially for younger patients with decreasing of missed diagnosis and elder patients with decreasing of misdiagnosis.

Objective:To evaluate the performance of the European Evidence-based Guidelines on Pancreatic Cystic Neoplasms (EEGPCN)(2018) and International Association of Pancreatology(IAP) Guideline(Version 2017) in predicting high grade dysplasia/invasive carcinoma-intraductal papillary mucinous neoplasm(HGD/INV-IPMN).Methods:A retrospective analysis of 363 patients,who underwent surgical resection in Changhai Hospital affiliated to Navy Medical University from January 2012 to December 2018 and were pathologically identified as (intraductal papillary mucinous neoplasm, IPMN),was performed. The patients,including 230 males and 133 females,aging (61.7±10.1) years(range:19 to 83 years). The proportion of HGD/INV-IPMN who met with the absolute indication(AI) of EEGPCN and high risk stigma(HRS) of IAP were compared. The binary Logistic regression analysis was used to find the independent risk factors of HGD/INV-IPMN.Eight combinations of risk factors derived from relative indication/worrisome feature or risk factors in this study,were made to evaluate the diagnostic efficacy. The area under curve(AUC) of receiver operating characteristics was used to evaluate the the cutoff value of risk factors(①CA19-9≥37 U/ml,②diameter of main pancreatic duct 5.0-9.9 mm,③enhancing mural nodule<5 mm,④(acute) pancreatiti,⑤ acyst diameter ≥40 mm,⑤ bcyst diameter ≥30 mm, ⑥thickened or enhancing cyst walls,⑦neutrophile granulocyte to lymphocyte ratio(NLR)≥2, ⑧cyst located in head, uncinate or neck,⑨carcinoembryonic antigen(CEA) ≥5 μg/L) number for predicting HGD/INV-IPMN.The accuracy,sensitivity,specificity,positive predictive value,negative predictive value,true positive,true negative,false positive,false negative,positive likelihood ratio,negative likelihood ratio,Youden index and F1 score were calculated. Results:Ninety-two patients(49.5%) of 186 ones who met AI and 85 patients(48.3%) of 176 ones who met HRS were respectively confirmed as HGD/INV-IPMN. In those patients who were not met AI,tumor location,thickened/enhancing cyst wall,CA19-9 elevated,NLR≥2 and CEA elevated were significantly ( P<0.05) correlated with HGD/INV-IPMN. And tumor location(head/uncinate/neck vs. body/tail, OR=3.284,95% CI:1.268-8.503, P=0.014),thickened/enhancement cyst wall (with vs.without, OR=2.713,95% CI:1.177-6.252, P=0.019),CA19-9(≥37 U/L vs.<37 U/L, OR=5.086,95% CI:2.05-12.62, P<0.01) and NLR(≥2 vs.<2, OR=2.380,95% CI:1.043-5.434, P=0.039) were the independent risk factors of HGD/INV-IPMN. Patients with ≥4 risk factors of 9 in combination Ⅷ(①②③④⑤ b⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the moderate accuracy(71.0%),moderate sensitivity (62.0%) and moderate specificity (73.0%). Patients with ≥4 risk factors of 9 in Combination Ⅶ(①②③④⑤ a⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the highest specificity(83.0%) and patients with ≥3 risk factors of 8 in combination Ⅵ(①②③④⑤ b⑥⑧⑨) were diagnosed as HGD/INV-IPMN with the highest sensitivity(74.0%). The AUC for diagnosis of HGD/INV-IPMN in combination Ⅵ,Ⅶ and Ⅷ were 0.72,0.75 and 0.75,respectively. Older patients and younger patients could respectively refer to combination Ⅶ and combination Ⅵ to improve the management of IPMN. Conclusions:Patients who meet AI of EEGPCN should undertake resection, otherwise the method we explored is recommended. The method of improvement for diagnosis of HGD/INV-IPMN is relatively applicable and efficient for decision-making of surgery, especially for younger patients with decreasing of missed diagnosis and elder patients with decreasing of misdiagnosis.

Immunological checkpoint inhibitors of anti-programmed cell death-1 and programmed cell death ligand-1(PD-L1)have already demonstrated remarkable clinical efficacy for solid tumors,however,the effectiveness of single drug therapy in immunotherapy is not very high. Therefore,exploring the appropriate therapeutic predictive biomarkers so as to accurately identify the potential patients suitable for this therapy has become a research hotspot. Studies have shown that biomarkers such as PD-L1,tumor mutation burden and mismatch repair deficiency may be related to the efficacy of immunotherapy. In-depth analysis and exploration of these markers may provide a basis for determining those patients who are more likely to benefit from check-point inhibitor.

Objective To investigate the potential dosimetric advantages of half jaw volumetric modulated arc therapy ( H-VMAT) applied to the Oropharyngeal Cancer, comparing with full jaw VMAT (F-VMAT) and intensity modulated radiotherapy ( IMRT ). Methods Planning CT images of 10 oropharyngeal cancer patients were retrospectively chosen and transferred to Eclipse treatment planning system v. 11. 0 (Varian Medical Systems, Pala Alto, USA), based on which H-VMAT, W-VMAT, and IMRT plans were created. Two full arcs (360°) were adopted for VMAT planning, and the 7 beams were equally distributed for IMRT planning. The optimization constraints remained the same for the three kinds of plans. The dosimetric parameters such as D2 , D98 , D50 , HI, and CI were evaluated for PGTV, PCTV1, PCTV2, PGTVln, and PCTVln. In addition, the maximum dose (Dmax) and D1 cc(minimum dose received by 1cc) of the brainstem and spinal cord were analyzed respectively. The mean dose ( Dmean ) to the parotids, oral cave, larynx, and cervical normal tissues were also reviewed. The monitor units ( MU) for all treatment plans were recorded. Results Comparisons of the three planning techniques showed that H-VAMT improved the HI and CI of the targets (except PCTV2) significantly (HI: F =3. 959, 6. 764, 10. 581, 6. 770, 13. 040, P<0. 05;CI:F=6. 594, 4. 138, 0. 842, 4. 031, 5. 388, P<0. 05);reduced Dmax(F=4. 509, 20. 331, P<0. 05) and D1 cc for brainstem and spinal cord (F=27. 432, 26. 314, P<0. 05) significantly;reduced Dmean(F=4. 279, 29. 498, 19. 295, P<0. 05) to the normal tissues of the mouth, throat and neck significantly. The V50 of the mouth and throat were slightly lower in IMRT plans (F=8. 140, P<0. 05). IMRT was slightly better than W-VMAT in sparing oral cavity and larynx, but the dose distribution was the worst. The H-VMAT plans showed the best dose distribution in the cervical normal tissues, especially for the lower and posterior parts, where IMRT plans displayed high dose curves. Conclusions H-VMAT is dosimetrically superior than W-VMAT and IMRT for oropharyngeal cancer, which could be considered for clinical applications.

γδ T cells have been well recognized as a unique cell population that is actively involved in both innate and adoptive immunity of bodies. The features of γδ T cells, such as their major histocompatibility complex independent antigen recognition and their cytotoxic effects to tumor cells, make them as promising candidates used for cancer immunotherapy. There is a strong interest in developing γδ T cell-based immunotherapy for clinical application in treating cancer patients. This review discusses the progress of recent studies related to the γδ T cells and cancer immunotherapy, with an emphasis on the main characteristics of γδ T cells in several types of gynecologic tumors.

Primary pulmonary carcinoid tumors are a group of relatively rare lung neoplasms.In the 2015 World Health Organization classification of lung tumors,lung carcinoid tumors(including both the classical and atypical types)were included in the category of pulmonary neuroendocrine tumors along with large cell neuroendocrine carcinomas and small cell lung carcinomas.Due to the low in-cidence and lack of specific clinical manifestations,the diagnosis and management of pulmonary carcinoid tumors remain relatively challenging.Current consensus supports surgery as the only curative option for localized,resectable pulmonary carcinoid tumors.How-ever,some inconsistencies exist between the guideline recommendations for systemic therapies that have resulted in a lack of consen-sus in regard to the standardized treatment for the metastatic or unresectable disease.This review intends to summarize the latest rec-ommendations for the diagnosis and multidisciplinary treatment of pulmonary carcinoid tumors.

Objective To measure and analyze the neutron dose equivalent rate produced by an IORT accelerator with 9 and 12 MeV electron energyies,and compare them with those from a Siemens Primus linear accelerator with the same electron energy,in order to provide data reference for the risk of secondary cancer induced by radiotherapy.Methods Using the neutron detector LB6411,the neutron dose equivalent rates produced by the IORT accelerator of 9 and 12 MeV were measured on some key locations,such as the head of the accelerator,cylinder bottom,patient plane with electron energies 9 and 12 MeV.The similar measurements were also performed on the same locations on a Siemens conventional accelerator.The data were collected and analyzed and the result wer compared between the two accelerators.Results Neutron dose equivalent rates from the IORT accelerator with 9 MeV energy were (51.8±3.1),(45.5 ±1.5),(70.5 ±4.9) and (68.2±3.3) μ Sv/h near the head of the accelerator,cylinder bottom,patient plane,with 5.9％,5.4％,17.8％ and 21.5％ lower than at 12 MeV,respectively.The dose equivalent rates at the similar locations from the Siemens Primus accelerator were (277.3 ±1.2),(285.1 ±1.6),(185.1 ±1.8) and (182.8 ±2.4) μSv/h at 9 MeV,with 48.8％,47.6％,48.7％,52.2％ lower than those at 12 MeV,respectively.At the energy of 12MeV,the neutron equivalent dose rate from the IORT was lower by a factor of about 10 than for Siemens Primus accelerator.Conclusions The neutron dose equivalent rates generaged by both the IORT and the Siemens Primus are higher at 12 MeV than at 9 MeV,which would lead to an increased risk of secondary cancer to patients.The traditional medical accelerator produces much higher neutron dose equivalent rates than the intraoperative electron accelerator,for which the appropriate shielding should be takn.

Objective To compare the neck skin dose between fixed-field dynamic intensity-modulated radiation therapy (dlMRT),volumetric modulated arc therapy (VMAT),and helical tomotherapy (HT) in the treatment of early-stage nasopharyngeal carcinoma.Methods A total of 16 early-stage nasopharyngeal carcinoma patients undergoing radiotherapy were enrolled as subjects.The neck skin was delineated by contraction of the outer edge of neck by 3 mm.Dose planning was made by the traditional method (TP group)and a new method (NP group),in which the neck skin was considered as the organ at risk.Dmean and V5-V70 for the neck skin were recorded.The paired t-test was used to analyze the differences between two plans in each radiotherapy method.An analysis of variance was used to compare the same plan between the three radiotherapy methods.Results The HT group had significantly higher Dmean and V5-V70 for the neck skin than the dIMRT group and the VMAT group (P=0.00,0.00,0.00,0.00,0.00,0.00,0.00,0.02).Using dIMRT,the D and V10-V60 for the neck skin were reduced by 7％,8％,22％,25％,38％,59％,and 85％ in the NP group than in the TP group (P=0.00,0.00,0.00,0.00,0.00,0.00,0.00).Using VMAT,the D and V20-V40 for the neck skin were reduced by 4％,19％,29％,and 34％ in the NP group than in the TP group (P=0.02,0.01,0.02,0.01).Using HT,the V30-V60 for the neck skin were reduced by 20％,29％,50％,and 67％ in the NP group than in the TP group (P=0.00,0.00,0.00,0.00,0.03).Conclusions In the treatment of early-stage nasopharyngeal carcinoma,HT causes a higher radiation dose to the neck skin than dIMRT and VMAT,while dIMRT and VMAT have similar neck skin doses.The neck skin dose can be significantly reduced with the neck skin as the organ at risk.

Objective To explore the effect of peripheral blood genomic DNA methylation on the relationship between methyl donor status and risk of breast cancer.Methods A case-control study was conducted.Each three hundred breast cancer cases and controls were consecutively recruited.Food frequency questionnaire was used to collect dietary information.Amounts on folate,methionine,choline and betaine intake were calculated.Blood samples were collected for DNA extraction.Peripheral blood genomic DNA methylation was measured by using the Methyl FlashTM Methylated DNA Quantification Kit.Pathway analysis was used to examine the effect of genomic DNA methylation on the relations between methyl donor status and risk of breast cancer.Results The genome DNA methylation rates were 0.46％ ± 0.25％ and 0.53％ ± 0.34％,respectively on both cases and controls,with differences statistically significant (P＜0.01).Results from the pathway analysis,results showed that methionine consumption was related to genomic DNA methylation (β=0.065,P＜ 0.05) while genomic DNA methylation was related to the risk of breast cancerk (β =-0.027,P＜ 0.05),respectively.Conclusions The level of peripheral blood genomic DNA methylation in breast cancer cases was significantly lower than that in the controls.Genomic DNA methylation seemed to have played a mediated role between methionine and the risk of breast cancer.