Preoperative prediction of perineural invasion of rectal cancer based on a magnetic resonance imaging radiomics model:A dual-center study

BACKGROUND Perineural invasion(PNI)has been used as an important pathological indicator and independent prognostic factor for patients with rectal cancer(RC).Preoperative prediction of PNI status is helpful for individualized treatment of RC.Recently,several radiomics studies have been used to predict the PNI status in RC,demonstrating a good predictive effect,but the results lacked generalizability.The preoperative prediction of PNI status is still challenging and needs further study.AIM To establish and validate an optimal radiomics model for predicting PNI status preoperatively in RC patients.METHODS This retrospective study enrolled 244 postoperative patients with pathologically confirmed RC from two independent centers.The patients underwent preoperative high-resolution magnetic resonance imaging(MRI)between May 2019 and August 2022.Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging(T2WI)and contrast-enhanced T1WI(T1CE)sequences.The radiomics signatures were constructed using logistic regression analysis and the predictive potential of various sequences was compared(T2WI,T1CE and T2WI+T1CE fusion sequences).A clinical-radiomics(CR)model was established by combining the radiomics features and clinical risk factors.The internal and external validation groups were used to validate the proposed models.The area under the receiver operating characteristic curve(AUC),DeLong test,net reclassification improvement(NRI),integrated discrimination improvement(IDI),calibration curve,and decision curve analysis(DCA)were used to evaluate the model performance.RESULTS Among the radiomics models,the T2WI+T1CE fusion sequences model showed the best predictive performance,in the training and internal validation groups,the AUCs of the fusion sequence model were 0.839[95%confidence interval(CI):0.757-0.921]and 0.787(95%CI:0.650-0.923),which were higher than those of the T2WI and T1CE sequence models.The CR model constructed by combining clinical risk factors had the best predictive performance.In the training and internal and external validation groups,the AUCs of the CR model were 0.889(95%CI:0.824-0.954),0.889(95%CI:0.803-0.976)and 0.894(95%CI:0.814-0.974).Delong test,NRI,and IDI showed that the CR model had significant differences from other models(P<0.05).Calibration curves demonstrated good agreement,and DCA revealed significant benefits of the CR model.CONCLUSION The CR model based on preoperative MRI radiomics features and clinical risk factors can preoperatively predict the PNI status of RC noninvasively,which facilitates individualized treatment of RC patients.

Preoperative prediction of lymphovascular and perineural invasion in gastric cancer using spectral computed tomography imaging and machine learning

BACKGROUND Lymphovascular invasion(LVI)and perineural invasion(PNI)are important prognostic factors for gastric cancer(GC)that indicate an increased risk of metastasis and poor outcomes.Accurate preoperative prediction of LVI/PNI status could help clinicians identify high-risk patients and guide treatment deci-sions.However,prior models using conventional computed tomography(CT)images to predict LVI or PNI separately have had limited accuracy.Spectral CT provides quantitative enhancement parameters that may better capture tumor invasion.We hypothesized that a predictive model combining clinical and spectral CT parameters would accurately preoperatively predict LVI/PNI status in GC patients.AIM To develop and test a machine learning model that fuses spectral CT parameters and clinical indicators to predict LVI/PNI status accurately.METHODS This study used a retrospective dataset involving 257 GC patients(training cohort,n=172;validation cohort,n=85).First,several clinical indicators,including serum tumor markers,CT-TN stages and CT-detected extramural vein invasion(CT-EMVI),were extracted,as were quantitative spectral CT parameters from the delineated tumor regions.Next,a two-step feature selection approach using correlation-based methods and information gain ranking inside a 10-fold cross-validation loop was utilized to select informative clinical and spectral CT parameters.A logistic regression(LR)-based nomogram model was subsequently constructed to predict LVI/PNI status,and its performance was evaluated using the area under the receiver operating characteristic curve(AUC).RESULTS In both the training and validation cohorts,CT T3-4 stage,CT-N positive status,and CT-EMVI positive status are more prevalent in the LVI/PNI-positive group and these differences are statistically significant(P<0.05).LR analysis of the training group showed preoperative CT-T stage,CT-EMVI,single-energy CT values of 70 keV of venous phase(VP-70 keV),and the ratio of standardized iodine concentration of equilibrium phase(EP-NIC)were independent influencing factors.The AUCs of VP-70 keV and EP-NIC were 0.888 and 0.824,respectively,which were slightly greater than those of CT-T and CT-EMVI(AUC=0.793,0.762).The nomogram combining CT-T stage,CT-EMVI,VP-70 keV and EP-NIC yielded AUCs of 0.918(0.866-0.954)and 0.874(0.784-0.936)in the training and validation cohorts,which are significantly higher than using each of single independent factors(P<0.05).CONCLUSION The study found that using portal venous and EP spectral CT parameters allows effective preoperative detection of LVI/PNI in GC,with accuracy boosted by integrating clinical markers.

Prediction of the lymphatic,microvascular,and perineural invasion of pancreatic neuroendocrine tumors using preoperative magnetic resonance imaging

BACKGROUND Significant correlation between lymphatic,microvascular,and perineural invasion(LMPI)and the prognosis of pancreatic neuroendocrine tumors(PENTs)was confirmed by previous studies.There was no previous study reported the relationship between magnetic resonance imaging(MRI)parameters and LMPI.AIM To determine the feasibility of using preoperative MRI of the pancreas to predict LMPI in patients with non-functioning PENTs(NFPNETs).METHODS A total of 61 patients with NFPNETs who underwent MRI scans and lymphadenectomy from May 2011 to June 2018 were included in this retrospective study.The patients were divided into group 1(n=34,LMPI negative)and group 2(n=27,LMPI positive).The clinical characteristics and qualitative MRI features were collected.In order to predict LMPI status in NF-PNETs,a multivariate logistic regression model was constructed.Diagnostic performance was evaluated by calculating the receiver operator characteristic(ROC)curve with area under ROC,sensitivity,specificity,positive predictive value(PPV),negative predictive value(NPV)and accuracy.RESULTS There were significant differences in the lymph node metastasis stage,tumor grade,neuron-specific enolase levels,tumor margin,main pancreatic ductal dilatation,common bile duct dilatation,enhancement pattern,vascular and adjacent tissue involvement,synchronous liver metastases,the long axis of the largest lymph node,the short axis of the largest lymph node,number of the lymph nodes with short axis>5 or 10 mm,and tumor volume between two groups(P<0.05).Multivariate analysis showed that tumor margin(odds ratio=11.523,P<0.001)was a predictive factor for LMPI of NF-PNETs.The area under the receiver value for the predictive performance of combined predictive factors was 0.855.The sensitivity,specificity,PPV,NPV and accuracy of the model were 48.1%(14/27),97.1%(33/34),97.1%(13/14),70.2%(33/47)and 0.754,respectively.CONCLUSION Using preoperative MRI,ill-defined tumor margins can effectively predict LMPI in patients with NF-PNETs.

Pleiotrophin promotes perineural invasion in pancreatic cancer

Perineural invasion(PNI)in pancreatic cancer is an important cause of local recurrence,but little is known about its mechanism.Pleiotrophin(PTN)is an important neurotrophic factor.It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer.PTN strongly presents in the cytoplasm of pancreatic cancer cells,and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer.Correspondingly,PNI is prone to happen in PTN-positive tumors.We thus hypothesize that,as a neurite growth-promoting factor,PTN may promote PNI in pancreatic cancer.PTN is released at the time of tumor cell necrosis,and binds with its highaffinity receptor,N-syndecan on pancreatic nerves,to promote neural growth in pancreatic cancer.Furthermore,neural destruction leads to a distorted neural homeostasis.Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves.However,the abundance of N-syndecan attracts further PTN-positive cancer cells to the site of injury,creating a vicious cycle.Ultimately,increased PTN and N-syndecan levels,due to the continuous nerve injury,may promote cancer invasion and propagation along the neural structures.Therefore,it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer,which may lead to a better understanding of the mechanism of PNI in pancreatic cancer.

Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer

AIM To investigate the relationship between autophagy and perineural invasion(PNI), clinical features, and prognosis in patients with pancreatic cancer. METHODS Clinical and pathological data were retrospectively collected from 109 patients with pancreatic ductal adenocarcinoma who underwent radical resection at the First Affiliated Hospital of Zhengzhou University from January 2011 to August 2016. Expression levels of the autophagy-related protein microtubuleassociated protein 1 A/1 B-light chain 3(LC3) and PNI marker ubiquitin carboxy-terminal hydrolase(UCH) in pancreatic cancer tissues were detected by immunohistochemistry. The correlations among LC3 expression, PNI, and clinical pathological features in pancreatic cancer were analyzed. The patients were followed for further survival analysis. RESULTS In 109 cases of pancreatic cancer, 68.8%(75/109) had evidence of PNI and 61.5%(67/109) had high LC3 expression. PNI was associated with lymph node metastasis, pancreatitis, and CA19-9 levels(P < 0.05). LC3 expression was related to lymph node metastasis(P < 0.05) and was positively correlated with neural invasion(P < 0.05, r = 0.227). Multivariate logistic regression analysis indicated that LC3 expression, lymph node metastasis, pancreatitis, and CA19-9 level were factors that influenced neural invasion, whereas only neural invasion itself was an independent factor for high LC3 expression. Univariate analysis showed that LC3 expression, neural invasion, and CA19-9 level were related to the overall survival of pancreatic cancer patients(P < 0.05). Multivariate COX regression analysis indicated that PNI and LC3 expression were independent risk factors for poor prognosis in pancreatic cancer(P < 0.05). CONCLUSION PNI in patients with pancreatic cancer is positively related to autophagy. Neural invasion and LC3 expression are independent risk factors for pancreatic cancer with a poor prognosis.

Radiomics for predicting perineural invasion status in rectal cancer

BACKGROUND Perineural invasion(PNI),as a key pathological feature of tumor spread,has emerged as an independent prognostic factor in patients with rectal cancer(RC).The preoperative stratification of RC patients according to PNI status is beneficial for individualized treatment and improved prognosis.However,the preoperative evaluation of PNI status is still challenging.AIM To establish a radiomics model for evaluating PNI status preoperatively in RC patients.METHODS This retrospective study enrolled 303 RC patients in a single institution from March 2018 to October 2019.These patients were classified as the training cohort(n=242)and validation cohort(n=61)at a ratio of 8:2.A large number of intraand peritumoral radiomics features were extracted from portal venous phase images of computed tomography(CT).After deleting redundant features,we tested different feature selection(n=6)and machine-learning(n=14)methods to form 84 classifiers.The best performing classifier was then selected to establish Rad-score.Finally,the clinicoradiological model(combined model)was developed by combining Rad-score with clinical factors.These models for predicting PNI were compared using receiver operating characteristic curve(ROC)analysis and area under the ROC curve(AUC).RESULTS One hundred and forty-four of the 303 patients were eventually found to be PNIpositive.Clinical factors including CT-reported T stage(cT),N stage(cN),and carcinoembryonic antigen(CEA)level were independent risk factors for predicting PNI preoperatively.We established Rad-score by logistic regression analysis after selecting features with the L1-based method.The combined model was developed by combining Rad-score with cT,cN,and CEA.The combined model showed good performance to predict PNI status,with an AUC of 0.828[95%confidence interval(CI):0.774-0.873]in the training cohort and 0.801(95%CI:0.679-0.892)in the validation cohort.For comparison of the models,the combined model achieved a higher AUC than the clinical model(cT+cN+CEA)achieved(P<0.001 in the training cohort,and P=0.045 in the validation cohort).CONCLUSION The combined model incorporating Rad-score and clinical factors can provide an individualized evaluation of PNI status and help clinicians guide individualized treatment of RC patients.

Perineural invasion of hilar cholangiocarcinoma in Chinese population: One center’s experience

BACKGROUND Hilar cholangiocarcinoma(HCCA)often produces perineural invasion(PNI)extending to extra-biliary sites,while significant confusion in the incidence of PNI in HCCA has occurred in the literature,and the mechanism of that procedure remains unclear.AIM To summarize the incidence of PNI in HCCA and to provide the distribution of nerve plexuses around hepatic portal to clinical surgeons.METHODS Reported series with PNI in HCCA since 1996 were reviewed.A clinicopathological study was conducted on sections from 75 patients with HCCA to summarize the incidence and modes of PNI.Immunohistochemical stains for CD34 and D2-40 in the cancer tissue were performed to clarify the association of PNI with microvessel and lymph duct.Sections of the hepatoduodenal ligament from autopsy cases were scanned and handled by computer to display the distribution of nerve plexuses around the hepatic portal.RESULTS The overall incidence of PNI in this study was 92%(69 of 75 patients),while the rate of PNI in HCCA in the literature ranging from 38%to 100%.The incidence of PNI did not show any remarkable differences among various differentiated groups and Bismuth-Corlette classification groups.Logistic regression analysis identified the depth of tumor invasion was the only factor that correlated significantly with PNI(P<0.01).In spite of finding tumor cells that could invade microvessels and lymph ducts in HCCA,we did not find tumor cells invaded nerves via microvessels or lymph ducts.Three nerve plexuses in the hepatoduodenal ligament and Glisson’s sheath were classified,and they all surrounded the great vessels very closely.CONCLUSION The incidence of PNI of HCCA in Chinese population is around 92%and correlated significantly with a depth of tumor invasion.It also should be considered when stratifying HCCA patients for further treatment.

Preliminary study correlating CX3CL1/CX3CR1 expression with gastric carcinoma and gastric carcinoma perineural invasion

AIM:To study the relationship between the CX3CL1chemokine,its receptor CX3CR1,and gastric carcinoma/gastric carcinoma perineural invasion(PNI).METHODS:Thirty cases of gastric carcinoma were surgically resected(radical resection or palliative resection)between February 2012 and July 2012.Tumour and tumour-adjacent tissues were evaluated for the presence of CX3CL1(ELISA)and CX3CR1(immunohistochemistry and Western blotting)in an effort to analyse the relationship between CX3CL1/CX3CR1 and gastric carcinoma/gastric carcinoma PNI.RESULTS:Of these 30 cases,14 were PNI-positive(46.7%).No significant differences in CX3CL and CX3CR1 expression in tumour-adjacent tissues were found between the PNI positive and negative groups.Expression levels of CX3CL and CX3CR1 in tumour tissues were significantly higher than those in adjacent tissues(P<0.01),and were significantly higher in tumour tissues from the PNI-positive group compared to the PNI-negative group(P<0.01).CONCLUSION:CX3CL1/CX3CR1 expression may be associated with the occurrence and development of gastric carcinoma as well as gastric carcinoma PNI.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer

AIM To detect the expression of pleiotrophin(PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion(PNI).METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis.RESULTS The expression rates of PTN and N-syndecan proteinswere 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI(P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites(P = 0.009), liver metastasis(P = 0.035), and decreased survival time(P = 0.022). N-syndecan expression was significantly associated with tumor size(P = 0.025), but not with survival time(P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

Muscarinic acetylcholine receptor M3 in proliferation and perineural invasion of cholangiocarcinoma cells

BACKGROUND:Cholangiocarcinoma,a type of malignant tumor,originates from epithelial cells of the bile duct.Perineural invasion is common path for cholangiocarcinoma metastasis,and it is highly correlated with postoperative recurrence and poor prognosis.It has been reported that muscarinic acetylcholine receptor M3(mAChR M3) is widely expressed in digestive tract cancer,and may play an important role in the proliferation,differentiation,transformation and carcinogenesis of tumors.This study was to explore the effect of mAChR M3 on the growth of cholangiocarcinoma cells in vitro and provide a new approach to the pathogenesis and treatment of cholangiocarcinoma.METHODS:Streptavidin-biotin complex immunohistochemistry was carried out to assess the expression of mAChR M3 in surgical specimens of cholangiocarcinomas(40 cases) and normal bile duct tissues(9),as well as to investigate nerve infiltration.The cholangiocarcinoma cells were treated with different concentrations of selective M-receptor agonist pilocarpine and M-receptor blocker atropine sulfate to induce changes in cell proliferation.The experimental data were analyzed by the Chi-square test.RESULTS:The strongly-positive expression rate of mAChR M3 was much higher in poorly-differentiated(69%,9/13) than in well-and moderately-differentiated cholangiocarcinomas(30%,8/27)(χ 2 =5.631,P<0.05).The strongly-positive mAChR M3 expression rate in hilar cholangiocarcinoma(50%,14/28) was higher than that in cholangiocarcinomas from the middle and lower common bile duct(25%,3/12)(χ 2 =2.148,P<0.05).Cholangiocarcinomas with distant metastasis had a stronglypositive expression rate(75%,9/12),which was much higher than those without distant metastasis(29%,8/28)(χ 2 =7.410,P<0.01).The absorbance value in the pilocarpine+atropine group was significantly higher than the corresponding value in the pilocarpine group.CONCLUSIONS:The expression of mAChR M3 is influenced by the extent of differentiation,distant metastasis and the site of cholangiocarcinoma.It also plays a key role in the proliferation and metastasis of cholangiocarcinoma.

Individualized prediction of perineural invasion in colorectal cancer: development and validation of a radiomics prediction model

Objective： To develop and validate a radiomics prediction model for individualized prediction of perineural invasion（PNI） in colorectal cancer（CRC）.Methods： After computed tomography（CT） radiomics features extraction, a radiomics signature was constructed in derivation cohort（346 CRC patients）. A prediction model was developed to integrate the radiomics signature and clinical candidate predictors [age, sex, tumor location, and carcinoembryonic antigen（CEA） level]. Apparent prediction performance was assessed. After internal validation, independent temporal validation（separate from the cohort used to build the model） was then conducted in 217 CRC patients. The final model was converted to an easy-to-use nomogram.Results： The developed radiomics nomogram that integrated the radiomics signature and CEA level showed good calibration and discrimination performance [Harrell＇s concordance index（c-index）： 0.817; 95% confidence interval（95% CI）： 0.811–0.823]. Application of the nomogram in validation cohort gave a comparable calibration and discrimination（c-index： 0.803; 95% CI： 0.794–0.812）.Conclusions： Integrating the radiomics signature and CEA level into a radiomics prediction model enables easy and effective risk assessment of PNI in CRC. This stratification of patients according to their PNI status may provide a basis for individualized auxiliary treatment.

Perineural invasion as a prognostic factor in patients with stage Ⅰ-Ⅲ rectal cancer –5-year follow up

BACKGROUND Rectal cancer(RC)is one of the most common diagnosed cancers,and one of the major causes of cancer-related death nowadays.Majority of the current guidelines rely on TNM classification regarding therapy regiments,however recent studies suggest that additional histopathological findings could affect the disease course.AIM To determine whether perineural invasion alone or in combination with lymphovascular invasion have an effect on 5-years overall survival(OS)of RC patients.METHODS A prospective study included newly diagnosed stage I-III RC patients treated and followed at the Digestive Surgery Clinic,Clinical Center of Serbia,between the years of 2014–2016.All patients had their diagnosis histologically confirmed in accordance with both TMN and Dukes classification.In addition,the patient’s demographics,surgical details,postoperative pathological details,differentiation degree and their correlation with OS was investigated.RESULTS Of 245 included patients with stage Ⅰ-Ⅲ RC,lymphovascular invasion(LVI)was identified in 92 patients(38%),whereas perineural invasion(PNI)was present in 46 patients(19%).Using Kaplan-Meier analysis for overall survival rate,we have found that both LVI and PNI were associated with lower survival rates(P<0.01).Moreover when Cox multiple regression model was used,LVI,PNI,older age,male gender were predictors of poor prognosis(HR=5.49;95%CI:2.889-10.429;P<0.05).CONCLUSION LVI and PNI were significant factors predicting worse prognosis in early and intermediate RC patients,hence more aggressive therapy should be reserved for these patients after curative resection.

Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma

BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma(PDAC).The rapid disease progression and patient deterioration seems related to perineural invasion,but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied.As perineural invasion is difficult to be highlighted,a biomarker such as the neurotrophic factor Midkine(MK)which promotes the neuronal differentiation and the cell migration could be helpful.Also,Activin(ACV)has been described as cachexia related to PDAC.However,their role for assessing and predicting the disease course in daily practice is not known.AIM To assess the relationship between perineural invasion and cachexia and their biomarkers,MK and ACV,respectively,and their prognostic value.METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies.Patients with other causes of malnutrition were excluded.The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data.These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease.RESULTS The study comprised 114 patients with PDAC,125 controls and a supplementary group of 14 benign pancreatic tissue samples.ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls(63% vs 32% for ACV,P<0.001;47%vs 16%for MK,P<0.001),with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage(P=0.006),the presence of metastasis(P=0.04),perineural invasion(P=0.03)and diabetes(P=0.002),but with no influence on survival.No correlation between clinicopathological factors and ACV expression was noted.Cachexia,present in 19%of patients,was unrelated to ACV or MK level.Higher ACV expression was associated with a shorter survival(P=0.008).CONCLUSION The MK was a biomarker of perineural invasion,associated with tumor stage and diabetes,but without prognostic value as ACV.Cachexia was unrelated to perineural invasion,ACV level or survival.

Treatment Recommendations among Radiation Oncologists in the Treatment of Cutaneous Squamous Cell Carcinoma with Perineural Invasion

Purpose: Post-operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to review treatment recommendations among Radiation Oncologists (ROs) in the management of CSCC with PNI. Materials & Methods: In March 2011, we contacted all ROs and trainees in the US through email addresses listed in the 2009 ASTRO directory. Our web-based survey presented clinical vignettes involving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical PNI (cPNI). For each vignette, ROs were asked to indicate if PORT was appropriate and to further specify the dose and volume to treat. Results: Three hundred fifty two responses were completed and analyzed. The majority of ROs (72%) had over 10 years of post residency experience. 64% of the sampled ROs had a special interest in treating head and neck cancers, and 64% treated 4 or more cases per year. Approximately 95% recommended PORT for cPNI whereas 59% recommended PORT for mPNI. Post residency experience (10+ yrs vs. <10 yrs) was associated with a greater propensity to recommend PORT for mPNI (48% vs. 30%, p = 0.005) and for mPNI of deep subcutaneous non-named nerve involvement (80% vs. 60%, p = 0.001). ROs treating 8 or more cases per year (vs. <7) were more likely to recommend PORT for mPNI in immunocompromised patients (74% vs. 57%, p = 0.01). Conclusions: Our study demonstrates significant variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority recommended PORT. In cases of mPNI, there was no consensus for recommending PORT, although experienced practitioners had a lower threshold for offering treatment. These results indicate the need for prospective clinical studies to clarify the role of PORT in CSCC patients with mPNI.

Current status of nerve infiltration by skip metastases in colorectal cancer

Colorectal cancer(CRC)is a prevalent malignant tumor,with the global new cases reaching 1.9316 million and deaths reaching 935,200 in 2022.In China,therewere 555,500 new cases of CRC,with an age-standardized incidence rate of 24.07 per 10million,and 286,200 deaths.China accounts for approximately 30%of new cases and deaths from CRC worldwide,with East Asia accounting for over 75%.Initially,CRC presents as local tumor growth,but it has the potential to spread to other body parts over time.Perineural infiltration(PNI)is a relatively less discussed route of diffusion,yet it plays a crucial role in the progression and prognosis of CRC.PNI often occurs alongside local lymph nodes and distant metastases,posing challenges for treatment and management.Clinical symptoms,radiographic findings,and histopathological examination can be used to diagnose PNI with skipmetastasis.Symptoms commonly include local pain,paresthesia,andmotor impairment.Imaging helps identify the mass’s location and relationship to nerves,whereas histopathological examination confirms the diagnosis.Treatment of PNI skipmetastases is similar to other CRC metastases,including surgical resection,chemotherapy,radiotherapy,and targeted therapy.Surgical resection is the primary therapeutic approach,but the wider range of metastasis in PNI skip transfer may limit its feasibility.In cases where surgical resection is not possible,chemotherapy,radiotherapy,and targeted therapy are used to control tumor metastasis.In conclusion,PNI skip metastases increase the risk of poor prognosis for CRC,requiring a comprehensive approach with multiple treatments to prevent disease progression.Early detection and treatment are vital to improving prognosis.

Perineural invasion status, Gleason score and number of positive cores in biopsy pathology are predictors of positive surgical margin following laparoscopic radical prostatectomy

This study was designed to define possible preoperative predictors of positive surgical margin after laparoscopic radical prostatectomy. We retrospectively analyzed the records of 296 patients with prostate cancer diagnosed by prostate biopsy, and eventually treated with laparoscopic radical prostatectomy. The prognostic impact of age, prostate volume, preoperative prostate-specific antigen, biopsy Gleason score, maximum percentage tumor per core, number of positive cores, biopsy perineurat invasion, capsule invasion on imaging, and tumor laterality on surgical margin was assessed. The overall positive surgical margin rate was 29.1%. Gleason score, number of positive cores, perineural invasion, tumor laterality in the biopsy specimen, and prostate volume significantly correlated with risk of positive surgical margin by univariate analysis （P 〈 0.05）. Gleason score （odds ratio [OR] = 2.286, 95% confidence interval [95% CI] = 1.431-3.653, P= 0.001）, perineural invasion （OR = 4.961, 95% CI = 2.656-9.270, P〈 0.001）, and number of positive cores （OR = 4.403, 95% CI = 1.878-10.325, P = 0.001） were independent predictors of positive surgical margin at the multivariable logistic regression analysis. Patients with perineural invasion, higher biopsy Gleason scores and/or a large number of positive cores in biopsy pathology had more possibility of capsule invasion. The positive surgical margin rate in patients with capsule invasion （49.5%） was much higher than that with localized disease （17.8%）. In contrast, prostate volume showed a protective effect against positive surgical margin （OR = 0.572, 95% CI = 0.346-0.945, P = 0.029）. Gleason score, perineural invasion, and number of positive cores in the biopsy specimen were preoperative independent predictors of positive surgical margin after laparoscopic radical prostatectomy while prostate volume was a protective factor against positive surgical margin.

Continuous Low-dose-rate Irradiation of Iodine-125 Seeds Inhibiting Perineural Invasion in Pancreatic Cancer

Background：Perineural invasion （PNI） is a histopathological characteristic of pancreatic cancer （PanCa）.The aim of this study was to observe the treatment effect of continuous low-dose-rate （CLDR） irradiation to PNI and assess the PNI-related pain relief caused by iodine-125 （125I） seed implantation.Methods：The in vitro PNI model established by co-culture with dorsal root ganglion （DRG） and cancer cells was interfered under 2 and 4 Gy of 125I seeds CLDR irradiation.The orthotopic models of PNI were established,and 125I seeds were implanted in tumor.The PNI-related molecules were analyzed.In 30 patients with panCa,the pain relief was assessed using a visual analog scale （VAS）.Pain intensity was measured before and 1 week,2 weeks,and 1,3,and 6 months after 125I seed implantation.Results：The co-culture of DRG and PanCa cells could promote the growth of PanCa cells and DRG neurites.In co-culture groups,the increased number of DRG neurites and pancreatic cells in radiation group was significantly less.In orthotopic models,the PNI-positive rate in radiation and control group was 3/11 and 7/11;meanwhile,the degrees of PNI between radiation and control groups was significant difference （P 〈 0.05）.At week 2,the mean VAS pain score in patients decreased by 50% and significantly improved than the score at baseline （P 〈 0.05）.The pain scores were lower in all patients,and the pain-relieving effect was retained about 3 months.Conclusions：The CLDR irradiation could inhibit PNI of PanCa with the value of further study.The CLDR irradiation could do great favor in preventing local recurrence and alleviating pain.

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells.Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion(PNI),a clinical pathological feature of PDAC.The formation and function of PNI are dually regulated by molecular(e.g.,involving neurotrophins,cytokines,chemokines,and neurotransmitters),metabolic(e.g.,serine metabolism),and cellular mechanisms(e.g.,involving Schwann cells,stromal cells,T cells,and macrophages).Such integrated mechanisms of PNI not only support tumor development,growth,invasion,and metastasis but also mediate the formation of pain,all of which are closely related to poor disease prognosis in PDAC.This review details the modulation,signaling pathways,detection,and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

Magnetic resonance imaging evaluation of head and neck involvement in IgG4-related disease

Objective:To evaluate the radiological features of IgG4-related disease(IgG4-RD)in the head and neck region.Methods:In this radiology-based study,radiological features,clinical,laboratory,pathological findings,and prognosis of nine patients with head and neck involvement diagnosed with IgG4-RD were investigated retrospectively.Results:The median age of the patients was 38 years(range:2.5-79 years),and there were six males and three females.The most common symptoms and clinical findings of the patients were eyelid and lacrimal gland swelling,painless exophthalmos,and ophthalmoplegia.The most common site of involvement on MRI was the orbit.Orbital involvement was followed by branches of the trigeminal nerve,sinonasal cavity,cervical lymph nodes,and dural involvement.The most common and remarkable imaging features were T2 hypointensity and diffuse homogeneous contrast enhancement.Conclusions:Head and neck involvement of the IgG4-RD,has specific imaging features that can help with diagnosis.Thus,early diagnosis and better outcomes can be achieved with increasing awareness of these features of this relatively new pathology.

NGF及其受体在肿瘤生长及侵袭中的作用

神经生长因子（NGF）的受体分为高亲和力受体TrkA和低亲和力受体p75。它们对于神经系统的生长发育以及神经元特性的维持有着不可替代的作用。NGF和非神经源性肿瘤的发生发展及生物学特性方面也有着密切的关系。NGF和TrkA结合可以促进某些肿瘤细胞的生长，而且这种作用主要是通过MAPK这一信号通路；而p75则可以诱导肿瘤细胞的凋亡。NGF及其受体通过不同机制在肿瘤的嗜神经侵袭中也发挥着重要作用。