Application of Magnetic Resonance Imaging in Neoadjuvant Treatment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors of the human digestive system. Due to its insidious onset, many patients have already lost the opportunity for radical resection upon tumor diagnosis. In recent years, neoadjuvant treatment for patients with borderline resectable PDAC has been recommended by multiple guidelines to increase the resection rate of radical surgery and improve the postoperative survival. However, further developments are required to accurately assess the tumor response to neoadjuvant therapy and to select the population suitable for such treatment. Reductions in drug toxicity and the number of neoadjuvant cycles are also critical. At present, the clinical evaluation of neoadjuvant treatment is mainly based on several serological and imaging indicators; however, the unique characteristics of PDAC and the insufficient sensitivity and specificity of the markers render this system ineffective. The imaging evaluation system, magnetic resonance imaging (MRI), has its own unique imaging advantages compared with computed tomography (CT) and other imaging examinations. One key advantage is the ability to reflect the changes more rapidly in tumor tissue components, such as the degree of fibrosis, microvessel density, and tissue hypoxia. It can also perform multiparameter quantitative analysis of tumor tissue and changes, attributing to its increasingly important role in imaging evaluation, and potentially the evaluation of neoadjuvant treatment of pancreatic cancer, as several current articles have studied. At the same time, owing to the complexity of MRI and some of its limitations, its wider application is limited. Compared with CT imaging, few relevant studies have been conducted. In this review article, we will investigate and summarize the advantages, limitations, and future development of MRI in the evaluation of neoadjuvant treatment of PDAC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Should Positive Cytology Revealed by Intraoperative Lavage Preclude Radical Resection in Resectable Pancreatic Cancer?: A Systemic Review and Meta-analysis.

OBJECTIVES: The aims of this review were to determine whether positive peritoneal lavage cytology (CY+) precludes radical resection in pancreatic cancer and to propose prospections for future studies. METHODS: MEDLINE, Embase, and Cochrane Central were searched for related articles. Dichotomous variables and survival outcomes were analyzed with the estimation of odds ratio and hazards ratio (HR), respectively. RESULTS: A total of 4905 patients were included, of which 7.8% were CY+. Positive peritoneal lavage cytology was correlated with poor overall survival (univariate survival analysis [HR, 2.35; P < 0.00001]; multivariate analysis [HR, 1.62; P < 0.00001]), poor recurrence-free survival (univariate survival analysis [HR, 2.50; P < 0.00001]; multivariate analysis [HR, 1.84; P < 0.00001]), and higher initial peritoneal recurrence rate (odds ratio, 5.49; P < 0.00001). CONCLUSIONS: Although CY+ predicts poor prognosis and a higher risk of peritoneal metastasis after curative resection, it is not sufficient to preclude curative resection based on the current evidence, and high-quality trials should be conducted to assess the prognostic impact of operation among resectable CY+ patients. In addition, more sensitive and accurate methods to detect peritoneal exfoliated tumor cells and more effective comprehensive treatment for resectable CY+ pancreatic cancer patients are clearly warranted.

Analysis of survival factors after hepatic resection for colorectal cancer liver metastases: Does the R1 margin matter?

Introduction: The effect of liver margin on colorectal cancer liver metastases (CRLM) after hepatectomy has been controversial. In this study, we conducted a postoperative follow-up study of 205 patients with CRLM to clarify whether a positive margin is significant and to define the risk factors affecting CRLM survival. Methods: The data of 205 patients with CRLM who underwent surgical treatment at the Third Hospital of Peking University in the Department of General Surgery from January 2009 to December 2020 were retrospectively analyzed. The general data, surgical data and postoperative follow-up of the patients were statistically analyzed. Results: There were 130 cases (63.4%) of R0 resection and 75 cases (36.6%) of R1 resection. There were 136 males and 69 females, age 61 ± 11 years, and body mass index (BMI 24.5 ± 3.3 kg/m2). The overall survival rates at 1, 3, and 5 years for the entire cohort were 93.4%, 68.4%, and 45.5% in the R0 resection group vs. 93.2%, 53.7%, and 42% in the R1 resection group, respectively, which were not statistically significant (P = 0.520). The 1-, 3-, and 5-year disease-free survival rates of 63.2%, 33.3%, and 29.7% were significantly better in the R0 resection group than in the R1 resection group of 47.9%, 22.7%, and 17.7% (P = 0.016), respectively. After multivariable analysis, carbohydrate antigen 19-9 (CA19-9) > 39 U/ml (HR = 2.29, 95% CI: 1.39-3.79, P = 0.001), primary tumor perineural invasion (HR = 1.78, 95% CI: 1.01-3.13, P = 0.047), and BMI > 24 kg/m2 (HR = 1.75, 95% CI: 1.05-2.93, P = 0.033) were independently associated with poorer overall patient survival. The number of liver metastases >2 (HR = 1.65, 95% CI: 1.10-2.47, P = 0.016), the maximum diameter of metastases ≥50 mm (HR = 1.67, 95% CI: 1.06-2.64, P = 0.026), and vascular invasion of the primary tumor (HR = 1.65, 95% CI: 1.03-2.64, P = 0.038) were also independently associated with poorer disease-free survival. Conclusion: In patients undergoing hepatectomy for CRLM, the negative effect of the R1 margin should be downplayed, and although the disease-free survival of the R1 margin is shorter than that of the R0 margin, it has no impact on overall survival. To improve overall survival, extra attention should be given to the factors of preoperative BMI, preoperative CA19-9, and the presence of perineural invasion of the primary tumor.

Nomogram and competing risk model to predict recurrence after curative surgical resection of PDAC.

BACKGROUND: Surgical resection remains the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). However, a number of patients get disease recurred in a short time post-operation. Few studies have focused on the predictors of different recurrence patterns of PDAC. OBJECTIVE: To try to establish and verify a nomogram to predict recurrence free survival (RFS) in PDAC patients, and to distinguish the risk factors of local recurrence first and distant metastasis first via competing risk model. METHODS: Patients who underwent radical pancreatectomy for PDAC in our center from 2010 to 2018 were reviewed retrospectively. Kaplan-Meier methods and multivariate Cox regression analyses were used to identify the clinicopathological predictors of recurrence post-operation. And then, a nomogram was constructed and validated. Competing risk regression model was used to compare the predictors between local recurrence group and distant metastasis group. RESULTS: A total of 200 patients were included into the final analysis, and 153 patients got disease relapsed post-operation. CA19-9 level, vascular resection, tumor differentiation, lymph node ratio (LNR) and adjuvant chemotherapy were identified as independent risk factors for recurrence free survival (RFS) and incorporated into the nomogram. The C-index of the nomogram was 0.650. Competing risk model indicated that the status of lymph-node metastasis was significantly associated the patterns of first relapse. CONCLUSIONS: Nomogram and competing risk model were constructed to quantify the risk of recurrence following surgery for PDAC. Our findings may be useful for predicting RFS and recurrence pattern in clinical work.

Establishment of a Macrophage Phenotypic Switch Related Prognostic Signature in Patients With Pancreatic Cancer.

INTRODUCTION: Macrophage phenotype switch plays a vital role in the progression of malignancies. We aimed to build a prognostic signature by exploring the expression pattern of macrophage phenotypic switch related genes (MRGs) in the Cancer Genome Atlas (TCGA)-pancreatic adenocarcinoma (PAAD), Genotype-Tissue Expression (GTEx)-Pancreas, and Gene Expression Omnibus (GEO) databases. METHODS: We identified the differentially expressed genes between the PAAD and normal tissues. We used single factor Cox proportional risk regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox proportional hazard regression analysis to establish the prognosis risk score by the MRGs. The relationships between the risk score and immune landscape, "key driver" mutations and clinicopathological factors were also analyzed. Gene-set enrichment analysis (GSEA) analysis was also performed. RESULTS: We detected 198 differentially expressed MRGs. The risk score was constructed based on 9 genes (KIF23, BIN1, LAPTM4A, ERAP2, ATP8B2, FAM118A, RGS16, ELMO1, RAPGEFL1). The median overall survival time of patients in the low-risk group was significantly longer than that of patients in the high-risk group (P < 0.001). The prognostic value of the risk score was validated in GSE62452 dataset. The prognostic performance of nomogram based on risk score was superior to that of TNM stage. And GSEA analysis also showed that the risk score was closely related with P53 signaling pathway, pancreatic cancer and T cell receptor signaling pathway. qRT-PCR assay showed that the expressions of the 9 MRGs in PDAC cell lines were higher than those in human pancreatic ductal epithelium cell line. CONCLUSIONS: The nine gene risk score could be used as an independent prognostic index for PAAD patients. Further studies validating the prognostic value of the risk score are warranted.

KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages.

Tumor microenvironment (TME) exerts key roles in pancreatic ductal adenocarcinoma (PDAC) development. However, the factors regulating the cross-talk between PDAC cells and TME are largely unknown. In the present study, we identified a long noncoding RNA (lncRNA) KLHDC7B divergent transcript (KLHDC7B-DT), which was up-regulated in PDAC and correlated with poor survival of PDAC patients. Functional assays demonstrated that KLHDC7B-DT enhanced PDAC cell proliferation, migration, and invasion. Mechanistically, KLHDC7B-DT was found to directly bind IL-6 promoter, induce open chromatin structure at IL-6 promoter region, activate IL-6 transcription, and up-regulate IL-6 expression and secretion. The expression of KLHDC7B-DT was positively correlated with IL-6 in PDAC tissues. Via inducing IL-6 secretion, KLHDC7B-DT activated STAT3 signaling in PDAC cells in an autocrine manner. Furthermore, KLHDC7B-DT also activated STAT3 signaling in macrophages in a paracrine manner, which induced macrophage M2 polarization. KLHDC7B-DT overexpressed PDAC cells-primed macrophages promoted PDAC cell proliferation, migration, and invasion. Blocking IL-6/STAT3 signaling reversed the effects of KLHDC7B-DT on macrophage M2 polarization and PDAC cell proliferation, migration, and invasion. In conclusion, KLHDC7B-DT enhanced malignant behaviors of PDAC cells via IL-6-induced macrophage M2 polarization and IL-6-activated STAT3 signaling in PDAC cells. The cross-talk between PDAC cells and macrophages induced by KLHDC7B-DT represents potential therapeutic target for PDAC.

Does Prior Cancer Have an Influence on the Survival Outcomes of Patients with Localized Pancreatic Neuroendocrine Tumors?

Objective To investigate the impact of prior non-pancreatic cancer on the survival outcomes of patients with localized pancreatic neuroendocrine tumors (PanNETs). Methods We reviewed the Surveillance, Epidemiology, and End Results database and selected patients with localized PanNETs diagnosed between 1973 and 2015. We divided the patients into two groups according to the presence or absence of prior non-pancreatic malignancy. Before and after propensity score matching, we compared the clinicopathological characteristics and studied the overall survival and cancer-specific survival. Results A total of 357 (12.9%) of 2778 patients with localized PanNETs had prior cancer. A total of 1211 cases with only a localized PanNET and 133 cases with a localized PanNET and prior cancer had complete data and met the inclusion criteria of the current study. Patients with prior cancer were associated with advanced age (>65 years, 57.9% prior cancer vs. 31.0% no prior cancer, P<0.001), later year of diagnosis (87.2% vs. 80.2%, P=0.049), a higher proportion of poorly differentiated/undifferentiated grade tumors (4.5% vs. 1.5%, P=0.025), and a higher proportion of no primary site surgery (19.5% vs. 10.4%, P=0.003). Prostate (29.32%), breast (18.05%), other genitourinary and retroperitoneal (16.54%), and gastrointestinal (12.78%) cancers were the most common prior cancer types. Most of the prior cancers (95.49%) were localized and regional, and only 4.51% of the prior cancers were distant. Patients with interval periods between the prior cancer and PanNET of ≤36 months, 36-60 months, 60-120 months, and >120 months accounted for 33.08%, 13.53%, 24.06%, and 29.32% of all cases with prior cancers, respectively. Univariate and multivariate Cox proportional hazards analyses were performed. The presence/absence of prior cancers did not impact survival outcomes of patients with localized PanNETs before and after propensity score matching (PSM). Further subgroups analysis showed that, patients with localized PanNETs and prior distant cancer had worse cancer-specific survival than patients with prior local/regional cancer or patients without prior cancer (P<0.001). No significant differences in cancer-specific survival were observed in terms of the different sites of the prior cancers and the different interval periods of prior cancers and PanNETs (P<0.05). Conclusions Patients with localized PanNETs and a history of prior cancer had survival outcomes that were comparable to those of patients with no history of prior cancer. Patients with localized PanNETs and prior cancer could be candidates for clinical trials if they satisfy all other conditions; aggressive and potentially curative therapies should be offered to these patients.

The eighth version of American Joint Committee on Cancer nodal classification for high grade pancreatic neuroendocrine tumor should be generalized for the whole population with this disease.

Several indexes evaluating the lymph node metastasis of pancreatic neuroendocrine tumor (pNET) have been raised. We aimed to compare the prognostic value of the indexes via the analysis of Surveillance, Epidemiology, and End Results (SEER) database.We identified pNETs patients from SEER database (2004-2015). The prognostic value of N classification which adopted the 8th American Joint Committee on Cancer (AJCC) N classification for well differentiated pNET, revised N classification (rN) which adopted the AJCC 8th N classification for exocrine pancreatic cancer (EPC) and high grade pNET, lymph node ratio and log odds of positive nodes were analyzed.A total of 1791 eligible patients in the SEER cohort were included in this study. The indexes N, rN, lymph node ratio, and log odds of positive nodes were all significant independent prognostic factors for the overall survival. Specifically, the rN had the lowest akaike information criterion of 4050.19, the highest likelihood ratio test (χ) of 48.87, and the highest C-index of 0.6094. The rN was significantly associated with age, tumor location, tumor differentiation, T classification and M classification (P < .05 for all).The 8th version of AJCC N classification for high grade pNET could be generalized for the pNET population.

Nomograms predict survival outcomes for distant metastatic pancreatic neuroendocrine tumor: A population based STROBE compliant study.

As a rare malignant tumor, pancreatic neuroendocrine tumor (pNET) has very low incidence. However, most of the pNET patients would develop the distant metastasis, which significantly reduces patients' survival rate. Therefore, it is very important to construct a prognostic model of pNET patients with distant metastasis based on a large database to guide clinical application and treatment. The aim of this study is to establish nomograms for cancer-specific survival (CSS) and overall survival (OS) of patients with distant metastatic pNET based on the Surveillance, Epidemiology, and End Results (SEER) database.SEER were reviewed and the patients with pNET diagnosed between 1973 and 2015 were selected. After screening, a total of 624 cases were included in the study. Patients were randomly divided into a training cohort (n = 416) and a validation cohort (n = 208). Cox proportional hazard analysis revealed that age at diagnosis of ≥80 years, year of diagnosis, histological grade, and primary site surgery were independent factors both for CSS and OS. The nomograms indicated good accuracy in predicting 1-, 3-, and 5-year survival, with a C-index of 0.777 (95% confidence interval [CI], 0.743-0.811) for CSS and 0.772 (95% CI 0.738-0.806) for OS in training cohort. In the validation cohort, the C-index was 0.798 (95% CI 0.755-0.841) for CSS and 0.797 (95% CI 0.753-0.841) for OS. The calibration curves showed satisfactory consistency between predicted and actual survival.The study establishes excellent prognostic nomograms for CSS and OS for pNET patients with distant metastasis. They can be used to accurately predict survival rate, and provide useful information to physicians and patients.

Shark mouth pancreaticojejunostomy: a new enteric reconstruction procedure of pancreatic stump.

BACKGROUND: The enteric reconstruction procedure of pancreatic stump after pancreaticoduodenectomy remains to be the critical factor influencing the mortality and morbidity. No widely accepted surgical procedure for the pancreaticojejunostomy has been erected yet. We have developed a new technique of pancreaticojejunostomy named "shark mouth pancreaticojejunostomy." The aim of this study is to assess the efficacy of "shark mouth pancreaticojejunostomy." METHODS: This is a prospective single-arm observational study to evaluate the clinical efficacy of "shark mouth pancreaticojejunostomy." Patients with diseases, in whom a pancreaticoduodenectomy is indicated, would be recruited from Peking University Third Hospital. The hypothesis to be tested is that a "shark mouth pancreaticojejunostomy" will reduce fistula rate from around 20% to less than 10%. A sample size of 120 patients will be needed. The primary endpoint is the incidence rate of postoperative pancreatic fistula (POPF). The secondary endpoints of the study are anastomosis time, postoperative hospital stay, and morbidities besides the POPF such as the hemorrhage. Enrolled patients will undergo pancreaticoduodenectomy and be followed up for 3 months. The relevant data will be monitored and recorded. CONCLUSIONS: The current trial will explore the therapeutic value of the newly raised pancreaticojejunostomy procedure as the "shark mouth pancreaticojejunostomy." Its theoretical base and pragmatic feature will promise high external validity. TRIAL REGISTRATION: Clinical Trials.gov: NCT03366038; https://www.clinicaltrials.gov.

Clinicopathological features and prognosis factors for survival in elderly patients with pancreatic neuroendocrine tumor: A STROBE-compliant article.

To investigate the features and prognosis of the elderly patients with pancreatic neuroendocrine tumor (pNET).The patients diagnosed with pNETs between 2004 and 2014 were identified from the Surveillance Epidemiology and End Results database. The ethical approval was waived because the present study was analysis of the data from Surveillance Epidemiology and End Results database.A total of 4608 patients with "one primary only" histologically pNETs were confirmed and 653 were older than 75 years. Cancer-specific survival (CSS) and overall survival (OS) were examined. The elderly patients (≥75 years) have disadvantage in CSS and OS compared with younger cohort. Multivariate logistic regression revealed that the elderly patients have increased poorly differentiated composition, and decreased proportion of Black patients, receipt of surgery, married status, and number of removed lymph node. Multivariate Cox regression analysis demonstrated worse differentiation. Patients of T3-4 and M1 stage were associated with poor CSS, while patients of being female, tumor locating at pancreatic body/tail, receipt of surgery, and being married were associated with better CSS in the elderly patients. Meanwhile, patients with higher histological grade and M1 stage have poor OS, while patients with the characteristics of female, being married, tumor location at pancreatic body/tail and tumor surgery have better OS. Distant metastatic elderly patients underwent primary site surgery had better CSS and OS than the patients without surgery.The elderly patients have increased possibility of poorly differentiated tumor, and decreased proportion of Black patients, surgery of primary site, number of removed lymph node and married status. Worse differentiation and tumor metastasis were independent risk factors for both CSS and OS, while primary tumor located in body/tail of pancreas, female patients, surgery of tumor primary site, and being married were protective factors.

[Ultrasound guided ablation therapy of hepatic colorectal metastases: initial experience of real time virtual sonography navigation system].

OBJECTIVE: To evaluate the feasibility, accuracy and efficacy of the real time virtual sonography navigation and planning system in radio frequency ablation (RFA) of hepatic colorectal metastases. METHODS: Seventeen hepatic colorectal metastases lesions in 12 patients diagnosed pathologically or clinically in Peking University Third Hospital from Oct. 2011 to Apr. 2013 were enrolled, and all the lesions were diagnosed by CT/MRI but invisible in B-mode ultrasound. The patients included 9 males and 3 females, who were 45-82 years old, with an average age of (64.6±19.2) years. Before RFA, the puncture ablation plan of each lesion was made in the planning system, and during RFA the lesion and the 5 mm ablative margin around were ablated according to the puncture ablation plan. After the image fusion between the ultrasound and CT/MRI, the navigation system could decide the location and boundary of the hepatic colorectal metastases in the ultrasound image. Navigation assisted contrast-enhanced ultrasound (CEUS) was employed right after ablation to decide whether the area of the ablative zone had covered the whole tumor. Additional puncture was applied if the ablative zone had not completely covered the tumor. All the patients received CT/MRI one month after ablation to decide whether the carcinoma had been completely ablated. RESULTS: The image fusion was successfully applied in all the 17 hepatic colorectal metastases, and on average, 12 min (8-21 min) was spent in the image fusion. One tumor (1/17, 14.3%) received extra one puncture after navigation assisted CEUS. No severe complications and death occurred in all the 12 patients. Complete ablation of the 17 lesions were observed through CT or MRI scan one month after RFA, showing that all the 17 lesions had been completely ablated. CONCLUSION: The real time virtual sonography navigation system had high detection rate for invisible focal liver lesions in B-mode ultrasound. Navigation assisted CEUS could decide whether the area of the ablative zone had covered the whole tumor. Ultrasound CT or MRI navigation and planning system is safe, feasible and accurate in assisting ablation of hepatic colorectal metastases lesions with satisfactory clinical efficacy.

NT-3-secreting human umbilical cord mesenchymal stromal cell transplantation for the treatment of acute spinal cord injury in rats.

An animal model for clip spinal cord injury (SCI) was used to determine whether Neurotrophin-3 (NT-3) genetically modified human umbilical mesenchymal stem cells (NT-3-HUMSCs) could promote the morphologic and functional recovery of injured spinal cords. Using the Basso, Beattie, and Bresnahan scores and a grid test, the rats in the HUMSC-treated and NT-3-HUMSCs groups had significantly improved locomotor functional recovery more than the control group. In comparison, the NT-3-HUMSCs group achieved better functional recovery than the HUMSCs group at the end of 12 weeks after SCI. The functional recovery was accompanied by increased intensity of 5-HT fibers, increased volume of spared myelination, and decreased area of the cystic cavity in the NT-3-HUMSCs group compared with the HUMSCs group. Moreover, transplanted NT-3-HUMSCs survived and produced larger amounts of NT-3 than the HUMSCs in the host spinal cord. These results show that NT-3 enhanced the therapeutic effects of HUMSCs after clip injury of the spinal cord.

Coagulation function in patients with pancreatic carcinoma.

BACKGROUND: The coagulation function in patients with pancreatic carcinoma is abnormal and the reason is not very clear. In this study, we retrospectively analyzed the coagulation function in patients with pancreatic carcinoma. METHODS: From June 2004 to December 2007, 132 patients received diagnosis and treatment in our hospital. The coagulative parameters including the prothrombin time, activated partial thromboplastin time, and fibrinogen levels were collected and studied retrospectively. RESULTS: The average fibrinogen levels in patients with pancreatic carcinoma, (476.21 +/- 142.05) mg/dl, were significantly higher than in patients with cholangiolithiasis, (403.28 +/- 126.41) mg/dl (P < 0.05). In patients with pancreatic carcinoma, the levels of fibrinogen in the group with jaundice were significantly higher than in patients without jaundice (P < 0.05). In patients who received Pancreaticoduodenectomy, Whipple's operation, the level of fibrinogen in the group with local invasiveness was significantly higher than in the group without invasiveness. The group with lymphatic metastasis had higher levels than the group without lymphatic metastasis (P < 0.05). There was no significant difference of intraoperative blood loss between patients with vitamin K, (748.27 +/- 448.51) ml, and those without vitamin K, (767.31 +/- 547.89) ml (P > 0.05). CONCLUSIONS: The level of fibrinogen in patients with pancreatic carcinoma was elevated. The elevated fibrinogen level may be associated with invasiveness and lymphatic metastasis. Using vitamin K in perioperation management did not reduce intraoperative blood loss.