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Simple Summary: Perihilar cholangiocarcinoma is a rare biliary cancer with a poor prognosis, even after surgery. This study aimed to assess the impact of perineural (Pn), lymphangio (L), and vascular (V) invasion on overall survival following surgical resection. Data from 214 patients who underwent surgery between 2013 and 2023 were analyzed. Of these, curative intended resection was achieved in 168 patients (78.5%). Perineural, lymphangio and vascular invasion were present in 79.2%, 17.3% and 14.3% of patients, respectively. L1 and V1 were significantly associated with each other. Vascular invasion was associated with a significantly worse overall survival, while perineural invasion showed a trend toward worse overall survival, although this was not statistically significant. In Bismuth type IV tumors, both L1 and V1 were significantly linked to poorer overall survival. Furthermore, the combination of Pn1 with the presence of either L1 or V1 (or both) was associated with worse overall survival, underscoring the prognostic importance of these factors, particularly in Bismuth type IV tumors. Introduction: Perihilar cholangiocarcinoma is a rare malignancy of the biliary tract, for which surgery remains the treatment of choice. However, even after radical resection, the prognosis is poor. In addition to tumor size, depth of invasion and nodal/metastatic status, the TNM classification includes additional parameters such as perineural (Pn), lymphangio (L) and vascular (V) invasion. The prognostic impact of these factors is not yet fully understood. The aim of this study was to investigate the influence of these parameters on overall survival after resection of perihilar cholangiocarcinoma. Material and Methods: Data from all patients who underwent surgical exploration for perihilar cholangiocarcinoma between January 2013 and December 2023 were included into an institutional database. The impact of perineural, lymphangio and vascular invasion on overall survival was analyzed. Results: Over the 11-year period, a total of 214 patients underwent surgical exploration for perihilar cholangiocarcinoma. Curative intended resection was possible in 168 patients (78.5%). Perineural invasion, lymphangio invasion and vascular invasion were present in 79.2%, in 17.3% and in 14.3% of patients, respectively. Cross tabulation revealed a significant association between the presence of L1 and V1 (p = 0.006). There was also a significant association of Pn1, L1, and V1 with R-status (p = 0.010; p = 0.006 and p ≤ 0.001). While V1 was associated with significantly worse overall survival across the entire cohort, Pn1 alone showed only a tendency towards worse overall survival without reaching statistical significance. In Bismuth type IV, both L1 and V1, but not Pn1, were significantly associated with worse overall survival (p = 0.001; p = 0.017 and p = 0.065). Conclusions: Perineural invasion is very common in perihilar cholangiocarcinoma. Although Pn1 was associated with a tendency toward worse survival, it did not reach statistical significance. In contrast, vascular invasion significantly worsened overall survival in the entire cohort, and lymphangio invasion was linked to worse overall survival in Bismuth type IV tumors. The combination of perineural invasion with positivity of more than one additional factor (either L or V) was also associated with worse overall survival. In patients with Bismuth type IV, these pathological markers appeared to have even greater prognostic relevance. [ABSTRACT FROM AUTHOR]

Background: This short review and pictorial essay presents a morphological insight into cancer neuroscience, which is a complex and dynamic area of the pathobiology of tumors. Methods: We discuss the different methods and issues connected with structural research on tumor innervation, interactions between neoplastic cells and the nervous system, and dysregulated neural influence on cancer phenotypes. Results: Perineural invasion (PNI), the most-visible cancer–nerve relation, is briefly presented, focusing on its pathophysiology and structural diversity as well as its clinical significance. The morphological approach to cancer neurobiology further includes the analysis of neural density/axonogenesis, neural network topographic distribution, and composition of fiber types and size. Next, the diverse range of neurotransmitters and neuropeptides and the neuroendocrine differentiation of cancer cells are reviewed. Another morphological area of cancer neuroscience is spatial or quantitative neural-related marker expression analysis through different detection, description, and visualization methods, also on experimental animal or cellular models. Conclusions: Morphological studies with systematic methodologies provide a necessary insight into the structure and function of the multifaceted tumor neural microenvironment and in context of possible new therapeutic neural-based oncological solutions. [ABSTRACT FROM AUTHOR]

Opinion Statement: Cutaneous squamous cell carcinoma (cSCC) stands as the second most prevalent non-melanoma skin cancer worldwide, comprising approximately 20% of all cutaneous malignancies. Determining its precise incidence poses challenges; however, reports indicate a global increase in its prevalence. At the time of diagnosis, the majority of cSCCs are localized, resulting in favorable 5-year cure rates surpassing 90%. Nevertheless, a subset of patients (3–7%) encounters locally advanced or metastatic cSCC, leading to substantial morbidity and mortality. The risk of metastasis ranges from 0.1% to 9.9%, carrying an associated mortality risk of 2.8%. Factors influencing recurrence, metastasis, and disease-specific mortality underscore the significance of perineural invasion (PNI) as a key indicator. Patients with PNI may manifest clinical symptoms and/or radiologic signs of PNI, while the majority remain asymptomatic, and PNI is frequently identified upon histologic examination. Despite its lower frequency compared to other cancer types, PNI serves as a recognized adverse prognostic factor for cSCC. Surgery is the elective treatment for these patients, while the role of adjuvant radiotherapy (ART) is yet contentious and have not been conclusively assessed, particularly in clear surgical margin. Prospective comparative studies are required to comprehensively evaluate the benefit and the risks of ART for cSCC and PNI patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether preoperative spectral CT quantitative parameters can assess perineural invasion (PNI) status in rectal cancer. Methods: Sixty-two patients diagnosed with rectal cancer who underwent preoperative spectral CT were retrospectively enrolled and divided into positive and negative PNI groups according to histopathologic results. The CT attenuation value (HU) of virtual monochromatic images (40–70 keV), spectral curve slope (K(HU)), effective atomic number (Zeff), and iodine concentration (IC) from spectral CT were compared between these two groups using t test or rank sum test. A nomogram was established by incorporating the independent predictors to assess the overall diagnostic efficacy. The area under the ROC curves (AUCs) were compared using the DeLong test. Results: The preoperative spectral CT parameters (40–70 keV attenuation, K(HU), Zeff, and IC) were significantly higher in the PNI-positive group compared to the PNI-negative group (all p < 0.05). The highest predictive efficiency of PNI was observed at 40 keV attenuation, with an area under the curve (AUC), sensitivity, specificity, and accuracy of 0.847, 81.8%, 72.5%, and 75.8%, respectively. Binary logistic regression demonstrated that the clinical feature (cN stage) and 40 keV attenuation were independent predictors of PNI status. The nomogram incorporating these two predictors (cN stage and 40 keV attenuation) exhibited the best evaluation efficacy, with an AUC, sensitivity, specificity, and accuracy of 0.885, 86.4%, 77.5%, and 80.6%. Conclusion: Spectral CT quantitative parameters proved valuable in the preoperative assessment of PNI status in rectal cancer patients. The combination of spectral CT parameters and clinical features could further enhance the diagnostic efficiency. [ABSTRACT FROM AUTHOR]

Background: There are no large studies reporting oncological or survival outcomes for patients diagnosed with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC) via the ophthalmic nerve (V1). Where orbital exenteration may be necessary for curative treatment, it is critical to have survival data with which the morbidity associated with surgical treatment can be justified. Furthermore, with the emerging treatment option of immunotherapy, current standard of care outcomes are needed to help guide future trial design and eventually changed management guidelines. Objective: To determine the oncological and survival outcomes observed in patients with PNS of cSCC via V1. Materials and methods: Retrospective analysis of prospectively maintained cohort of patients with PNS of cSCC via V1 treated in a tertiary Australian head and neck oncology/skull base referral center. Consecutive sample of 53 patients managed between March 1, 1999 and April 30, 2020. Follow‐up closure date was September 1, 2021. Curative‐intent surgery, curative‐intent radiotherapy, or palliative care was undertaken. Endpoints included five‐year overall, disease‐specific, and disease‐free survival from the date of treatment. Results: Five‐year Kaplan–Meier overall survival was 61.9% (95% CI 46.2%–74.3%), with disease‐specific survival of 74.6% (95% CI 58.8%–85.3%), and disease‐free survival 62.1% (95% CI 46.5%–74.3%). Survival was superior in patients treated via surgery and adjuvant radiotherapy than in those receiving surgery alone or definitive radiotherapy. Survival was superior among patients with less advanced disease as assessed by the Williams zonal staging system; patients with Zone 1 disease had disease‐specific survival of 94.1% at 5 years with 82.5% disease‐free survival. Discussion: Five‐year oncological and survival outcomes in this cohort were favorable. Superior survival was observed in patients treated with curative‐intent surgery and adjuvant radiotherapy. Less extensive disease as delineated by the Williams zonal staging system was associated with improved survival. Conclusion: Surgical resection with adjuvant radiotherapy confers favourable oncological and survival outcome in patients with V1 PNS, particularly with early disease limited to Zone 1. [ABSTRACT FROM AUTHOR]

Abstract Purpose Lympho-vascular invasion (LVI) and perineural invasion (PNI) have been established as prognostic factors in various types of cancers. The preoperative prediction of LVI and PNI has the potential to guide personalized medicine strategies for patients with esophageal squamous cell cancer (ESCC). This study investigates whether radiomics features derived from preoperative contrast-enhanced CT could predict LVI and PNI in ESCC patients. Methods and materials A retrospective cohort of 544 ESCC patients who underwent esophagectomy were included in this study. Preoperative contrast-enhanced CT images, pathological results of PNI and LVI, and clinical characteristics were collected. For each patient, the gross tumor volume (GTV-T) and lymph nodes volume (GTV-N) were delineated and four categories of radiomics features (first-order, shape, textural and wavelet) were extracted from GTV-T and GTV-N. The Mann–Whitney U test was used to select significant features associated with LVI and PNI in turn. Subsequently, radiomics signatures for LVI and PNI were constructed using LASSO regression with ten-fold cross-validation. Significant clinical characteristics were combined with radiomics signature to develop two nomogram models for predicting LVI and PNI, respectively. The area under the curve (AUC) and calibration curve were used to evaluate the predictive performance of the models. Results The radiomics signature for LVI prediction consisted of 28 features, while the PNI radiomics signature comprised 14 features. The AUCs of the LVI radiomics signature were 0.77 and 0.74 in the training and validation groups, respectively, while the AUCs of the PNI radiomics signature were 0.69 and 0.68 in the training and validation groups. The nomograms incorporating radiomics signatures and significant clinical characteristics such as age, gender, thrombin time and D-Dimer showed improved predictive performance for both LVI (AUC: 0.82 and 0.80 in the training and validation group) and PNI (AUC: 0.75 and 0.72 in the training and validation groups) compared to the radiomics signature alone. Conclusion The radiomics features extracted from preoperative contrast-enhanced CT of gross tumor and lymph nodes have demonstrated their potential in predicting LVI and PNI in ESCC patients. Furthermore, the incorporation of clinical characteristics has shown additional value, resulting in improved predictive performance.

Abstract Cancer cells immediately expand and penetrate adjoining tissues, as opposed to metastasis, that is the spread of cancer cells through the circulatory or lymphatic systems to more distant places via the invasion process. We found that a lack of studies discussed tumor development with the nervous system, by the aspects of cancer‐tissue invasion (biological) and chemical modulation of growth that cascades by releasing neural‐related factors from the nerve endings via chemical substances known as neurotransmitters. In this review, we aimed to carefully demonstrate and describe the cancer invasion and interaction with the nervous system, as well as reveal the research progress and the emerging neuroscience of cancer. An initial set of 160 references underwent systematic review and summarization. Through a meticulous screening process, these data were refined, ultimately leading to the inclusion of 98 studies that adhered to predetermined criteria. The outcomes show that one formidable challenge in the realm of cancer lies in its intrinsic heterogeneity and remarkable capacity for rapid adaptation. Despite advancements in genomics and precision medicine, there is still a need to identify new molecular targets. Considering cancer within its molecular and cellular environment, including neural components, is crucial for addressing this challenge. In conclusion, this review provides good referential data for direct, indirect, biological, and chemical interaction for nerve tissue–tumor interaction, suggesting the establishment of new therapy techniques and mechanisms by controlling and modifying neuron networks that supply signals to tumors.

Treatment of rectal cancer has improved over the years thanks to a multidisciplinary approach. A correct staging has a fundamental role for risk stratification and to define the best treatment for each patient. Unfortunately, approximately 30% of patients with locally advanced rectal cancers will experience tumor recurrence. Thus, the identification of novel clinical-pathological and radiological prognostic factors represents an urgent unmet clinical need. Here we report the case of a patient with radically resected localized rectal cancer who developed an impressive early pelvic recurrence. To better understand the clinical scenario, we have studied the possible factors related to the aggressiveness of the disease. The only poor prognosticfactor that was evidenced at histological report was perineural invasion. Therefore, we questioned whether we could evaluate perineural invasion with imaging, similar to head and neck tumors. Learning from this clinical case, we believe that improving the risk stratification and radiology reporting is necessary to provide the best care for the patient and allow for a better prognosis prediction. Of course, our data should be considered as hypothesis generating and should be further investigated and validated in larger and prospective studies.

Objectives: To clarify whether self-expandable metallic stent (SEMS) placement for obstructive colorectal cancer (CRC) increases perineural invasion (PNI), thereby worsening the prognosis. Methods: In total, 1022 patients with pathological T3 or T4 colon or rectosigmoid cancer who underwent resection were retrospectively reviewed. The study patients were divided into a no obstruction group (n=693), obstruction without stent group (n=251), and obstruction with stent group (n=78), and factors demonstrating an independent association with PNI, the difference in PNI incidence and severity between groups, and the association between PNI and the duration from SEMS placement to surgery were investigated. Survival analysis was performed for each group. Results: On multivariate analysis, SEMS placement (hazard ratio [HR]: 2.08) was independently associated with PNI whereas SEMS placement was not. PNI occurred in 39%, 45%, and 68% of the no obstruction, obstruction without stent, and obstruction with stent group, respectively. In the obstruction with stent group, the proportion of PNI was not associated with the duration from SEMS placement to surgery. Extramural PNI, an advanced form of PNI, demonstrated no increase with increasing interval. The five-year OS was 86.3%, 76.7%, and 73.1% in no obstruction, obstruction without stent, and obstruction with stent group, respectively. On multivariate analysis, obstruction was an independent risk factor of decreased OS (HR: 1.57) whereas SEMS placement was not. Conclusions: The prognosis was comparable between patients with SEMS placement and those with an obstruction who did not undergo SEMS placement, thus demonstrating that SEMS is a viable, therapeutic option for BTS.

The current lack of a comprehensive understanding of brain metastasis mechanisms presents a significant gap in cancer research. This review outlines the role that Schwann cells (SCs) have in this process. SCs are already known for their role in myelination and nerve repair within the peripheral nervous system (PNS), but there is less information on their function in facilitating the transport and activation of neoplastic cells to aid in the invasion of the blood–brain barrier and brain. Detailed insights into SCs’ interactions with various cancers, including lung, breast, melanoma, colon, kidney, and pancreatic cancers, reveal how these cells are coerced into repair-like phenotypes to accelerate cancer spread and modulate immune responses. By outlining SCs’ involvement in perineural invasion and BBB modification, this review highlights their functions in facilitating brain metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor with a high metastatic potential. Perineural invasion (PNI) occurs in the early stages of PDAC with a high incidence rate and is directly associated with a poor prognosis. It involves close interaction among PDAC cells, nerves and the tumor microenvironment. In this review, we detailed discuss PNI-related pain, six specific steps of PNI, and treatment of PDAC with PNI and emphasize the importance of novel technologies for further investigation. [ABSTRACT FROM AUTHOR]

Objectives: The presence of lymphovascular invasion (LVI), perineural invasion (PNI) and extranodal extension (ENE) have shown adverse outcomes in oral squamous cell carcinoma (OSCC). This study evaluated the impact of LVI, PNI and ENE, individually and in combination, on survival outcomes in OSCC. Material and Methods: A retrospective analysis of a prospectively maintained oral cancer database was done from January 2017 to March 2023. All consecutive OSCC patients who underwent curative intent surgery were included. The triple-positive group was defined by the presence of all three features (LVI/PNI/ENE), while the double-positive group had the presence of two features. The disease-free survival (DFS) and overall survival (OS) analysis was done between different study groups. Results: A total of 255 patients were included in the analysis. The LVI, PNI and ENE positivity was 13%, 26% and 11%, respectively. There were 19 patients (7%) with double-positive and ten patients (4%) with triple-positive disease. The triple-positive group had lower DFS than non-triple-positive (0% vs 57%, p-value 0.001) and lower OS (0% vs 72%, p-value 0.003). The median DFS and OS of the triple-positive group were eight months and 24 months, respectively. Similarly, the double-positive group also had statistically significant inferior DFS (p-value 0.007) and OS (p-value 0.002) compared to the single-positive/triple-negative group. Conclusion: The triple-positive disease had poor outcomes, with no patients achieving disease-free or overall survival at the 5-year follow-up. The presence of multiple adverse factors necessitates modification of adjuvant therapy and therapeutic strategy, which may enhance survival outcomes. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to analyse the independent prognostic significance of perineural invasion (PNI) on local recurrence (LR) in patients with oral squamous cell carcinoma (OSCC) managed primarily with surgery. Subjects and Methods: Clinical and histopathological data of 195 patients with OSCC were analysed retrospectively to identify risk factors associated with PNI and to evaluate its significant correlation with local recurrence, overall survival (OS) and recurrence free survival (RFS). Results: Patients were followed for a mean period of 39.5 ± 1.376 months and median 35 months. PNI was found in 57 patients (29.2%). PNI correlated with tongue subsite (p = 0.001), nodal metastasis (p < 0.000), depth of invasion (DOI) (p = 0.002), stage (p = 0.013) and adjuvant therapy (p < 0.001). Mean time to recurrence with PNI was significantly shorter (p = 0.002).Multivariate analysis did not establish significant relationship between PNI and LR. Kaplan–Meier curve did not show statistical significance with OS (p = 0.085) or RFS (p = 0.110). Conclusion: PNI remains an aggressive factor for nodal metastasis mandating neck management for regional control. Though PNI showed no statistical significance with LR, time to recurrence in PNI positive patients were significantly shorter. Hence, close follow-up regimen becomes necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Perineural invasion (PNI) is the infiltration of cancer cells into peripheral nerves and is recognized as potential cancer metastasis. The presence of PNI has been extensively studied as a prognostic factor in head and neck squamous cell carcinoma (HNSCC) recently. The aim of this study was to quantitatively assess the prognostic value of PNI in HNSCC. From the results of the systematic review and meta-analysis, we confirmed that PNI is an independent prognostic factor in HNSCC. Specifically, HNSCC patients with PNI have worse survival, and are more likely to relapse locally, regionally, and distantly compared to those without PNI. We hope that these findings can serve as a basis for consideration of PNI as an indicator for more advanced pathological stages and more intensive clinical management for HNSCC patients. The aim of this study was to conduct a comprehensive review of the predictive significance of PNI in HNSCC survival outcomes. A systematic search was conducted across multiple databases, and all studies published in the last decade were screened (Research Registry ID: reviewregistry1853). The included studies were assessed using the Quality in Prognosis Studies tool. Survival outcome data were extracted, combined, and presented as hazard ratios (HR) with a 95% confidence interval (CI). Totally, 74 studies encompassing 27,559 patients were analyzed and revealed a cumulative occurrent rate of 30% for PNI in HNSCC. PNI+ HNSCC patients had a worse overall survival (HR: 1.91, 95% CI: 1.71–2.13), disease-specific survival (HR: 1.79, 95% CI: 1.55–2.07), disease-free survival (HR: 1.82, 95% CI: 1.69–1.96), local recurrence (HR: 2.54, 95% CI: 1.93–3.33), locoregional recurrence (HR: 2.27, 95% CI: 1.82–2.82), locoregional relapse free survival (HR: 1.77, 95% CI: 1.28–2.45), distant metastasis (HR: 1.82, 95% CI: 1.34–2.48), and distant metastasis-free survival (HR: 2.97, 95% CI: 1.82–4.85) compared to those PNI– patients. The available evidence unequivocally establishes PNI as a critical prognostic factor for worse survival in HNSCC patients. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI), the neoplastic invasion of nerves, is an often overlooked pathological phenomenon in cervical cancer that is associated with poor clinical outcomes. The occurrence of PNI in cervical cancer patients has limited the promotion of Type C1 surgery. Preoperative prediction of the PNI can help identify suitable patients for Type C1 surgery. However, there is a lack of appropriate preoperative diagnostic methods for PNI, and its pathogenesis remains largely unknown. Here, we dissect the neural innervation of the cervix, analyze the molecular mechanisms underlying the occurrence of PNI, and explore suitable preoperative diagnostic methods for PNI to advance the identification and treatment of this ominous cancer phenotype. [ABSTRACT FROM AUTHOR]

Background and Objectives: Renal cell carcinomas and upper tract urothelial carcinomas are types of malignancies that originate in the kidneys. Each of these examples shows an increasing trend in the frequency and the mortality rate. This study aims to comprehensively define carcinomas by analyzing clinical, paraclinical, and histological aspects to predict aggressiveness and mortality. Materials and Methods: We conducted a retrospective investigation on a group of patients suspected of kidney cancers. Results: We identified 188 cases. We observed a higher mortality rate and older age in individuals with urothelial carcinomas. Anemia, acute kidney injury, hematuria, and perineural invasion were the main risk factors that predicted their mortality. Tumor size in renal cell carcinomas correlates with the presence of necrosis and sarcomatoid areas. Factors that indicate a higher rate of death are older age, exceeding the renal capsule, a lesion that includes the entire kidney, lymphovascular invasion, acute kidney injury, and anemia. Conclusions: Even if they originate at the renal level, and the clinical–paraclinical picture is similar, the histopathological characteristics make the difference. In addition, to these are added the previously mentioned common parameters that can represent important prognostic factors. In conclusion, the characteristics commonly identified in one type of cancer may act as risk factors for the other tumor. The detected data include threshold values and risk factors, making a significant contribution to the existing literature. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted neurons and their associated Schwann cells (SCs) as key regulators of cancer development. However, the mode of their interaction with tumor cells or other components of the tumor microenvironment (TME) remains elusive. We established an SC-related 43-gene set as a surrogate for peripheral nerves in the TME. Head and neck squamous cell carcinoma (HNSCC) from The Cancer Genome Atlas (TCGA) were classified into low, intermediate and high SC score groups based on the expression of this gene set. Perineural invasion (PNI) and TGF-β signaling were hallmarks of SChigh tumors, whereas SClow tumors were enriched for HPV16-positive OPSCC and higher PI3K-MTOR activity. The latter activity was partially explained by a higher frequency of PTEN mutation and PIK3CA copy number gain. The inverse association between PI3K-MTOR activity and peripheral nerve abundance was context-dependent and influenced by the TP53 mutation status. An in silico drug screening approach highlighted the potential vulnerabilities of HNSCC with variable SC scores and predicted a higher sensitivity of SClow tumors to DNA topoisomerase inhibitors. In conclusion, we have established a tool for assessing peripheral nerve abundance in the TME and provided new clinical and biological insights into their regulation. This knowledge may pave the way for new therapeutic strategies and impart proof of concept in appropriate preclinical models. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI), a particularly insidious form of tumor metastasis distinct from hematogenous or lymphatic spread, has the capacity to extend well beyond the primary tumor site, infiltrating distant regions devoid of lymphatic or vascular structures. PNI often heralds a decrease in patient survival rates and is recognized as an indicator of an unfavorable prognosis across a variety of cancers. Despite its clinical significance, the underlying molecular mechanisms of PNI remain elusive, complicating the development of specific and efficacious diagnostic and therapeutic strategies. In the realm of cancer research, non-coding RNAs (ncRNAs) have attracted considerable attention due to their multifaceted roles and cancer-specific expression profiles, positioning them as promising candidates for applications in cancer diagnostics, prognostics, and treatment. Among the various types of ncRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have emerged as influential players in PNI. Their involvement is increasingly recognized as a contributing factor to tumor progression and therapeutic resistance. Our study synthesizes and explores the diverse functions and mechanisms of ncRNAs in relation to PNI in cancer. This comprehensive review aims to shed light on cutting-edge perspectives that could pave the way for innovative diagnostic and therapeutic approaches to address the challenges posed by PNI in oncology. [ABSTRACT FROM AUTHOR]

The current lack of a comprehensive understanding of brain metastasis mechanisms presents a significant gap in cancer research. This review outlines the role that Schwann cells (SCs) have in this process. SCs are already known for their role in myelination and nerve repair within the peripheral nervous system (PNS), but there is less information on their function in facilitating the transport and activation of neoplastic cells to aid in the invasion of the blood–brain barrier and brain. Detailed insights into SCs' interactions with various cancers, including lung, breast, melanoma, colon, kidney, and pancreatic cancers, reveal how these cells are coerced into repair-like phenotypes to accelerate cancer spread and modulate immune responses. By outlining SCs' involvement in perineural invasion and BBB modification, this review highlights their functions in facilitating brain metastasis. [ABSTRACT FROM AUTHOR]

Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 patients diagnosed with cutaneous melanomas between 2013 and 2018 in order to evaluate progression-free survival and overall survival. Multivariate Cox proportional hazards regression was performed by considering both clinical histopathological and immunohistochemical features. The mitotic rate was significantly independently associated with both outcomes, while the Ki67 index was not an independent prognostic factor. However, the Ki67 predictive accuracy could be improved by establishing both a cut-off value and a standardized protocol for evaluating its expression. Until these desiderata are met, the mitotic rate remains superior to the Ki67 index for predicting prognosis in cutaneous melanomas, as also has the advantage of being easily interpreted in a standard histopathological examination regardless of the pathologist's experience and with no further financial expenses. Importantly, this is one of very few articles that has shown perineural invasion to be an independent prognostic factor for both progression-free survival and overall survival in cutaneous melanomas. As a consequence, this parameter should become a mandatory feature in the histopathological evaluation of cutaneous melanomas as it can improve the identification of patients who are at high risk for disease progression. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system. [ABSTRACT FROM AUTHOR]

Purpose: The histologic finding of perineural invasion is a poor prognostic factor in oral squamous cell carcinoma patients. The aim of this study is to detect factors that influence prognosis in patients operated for oral cancer with perineural invasion in their histopathology report and to propose safer options of treatment with respect to recurrence and survival rates. Patients and methods: We performed a prospective cohort study of all oral squamous cell carcinoma cases operated in our department from January 2018 to January 2022. Overall, 75 cases of patients operated for oral squamous cell carcinoma were included in the study. Of these cases, 14 with perineural invasion were found. We created two groups: one group of patients treated with in-continuity resection and a second group of patients treated with a discontinuous resection between the primary site and the neck. Type of operation was considered the predictor variable and recurrence, survival or death, the outcome variables. Results: Oral cancer patients with known perineural invasion treated with in-continuity resection had a much better overall and disease-specific survival than patients treated with a discontinuous manner (p <.001). The difference in recurrence rate between these two groups of patients was found to be very significant in our study (p <.0005). Conclusion: It is therefore our suggestion that in oral squamous cell carcinoma of the tongue and floor of the mouth with perineural invasion detected in the incisional biopsy, an extended in-continuity resection to include the affected nerves should be performed. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain. Methods We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures. Results PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease. Conclusions Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present.

Introduction: The patterns of microRNA (miRNA) expression have opened up new avenues in the search for prognostic biomarkers and potential therapeutic targets for various tumours. In oral carcinogenesis research, analysing microRNAs expressed in Oral Squamous Cell Carcinoma (OSCC) unveils a complex network of interest. miR-21 is known to be overexpressed in numerous solid tumours and is linked to the progression of malignancies in hepatocellular carcinomas, breast cancer, and colon carcinomas. Aim: To determine the impact of surgical excision on serum miR-21 expression levels in OSCC cases and to establish correlations with clinicopathological parameters. Materials and Methods: The study was an exploratory prospective observational study conducted with proper institutional ethical approval at the Cancer Research Institute (CRI), Himalayan Institute of Medical Sciences (HIMS), Jolly Grant, Dehradun, Uttarakhand, India. Fifty-six histologically confirmed OSCC cases were enrolled along with 25 healthy subjects as controls from May 2021 to June 2023. The relative fold expression change was calculated using the Livak method (2-ΔΔct). Data analysis was performed using software such as Statistical Package for Social Sciences (SPSS) version 20.0 and MS Excel. Non parametric statistical tests such as Wilcoxon signed-rank test, Mann-Whitney test, and Kruskal-Wallis test were utilised. Results: Out of 56 sample included, 28 exhibited high expression of miR-21 (p-value

Abstract Background Perineural invasion (PNI) is the invasion of nerves by cancer cells and is associated with poor survival in stage II colorectal cancer. However, PNI can be further subdivided according to the depth of invasion, and the depth of PNI has not been clearly linked to prognosis. Method This study aimed to assess the prognostic value of different depths of PNI in stage II colorectal cancer. We defined PNI in the submucosal plexus and myenteric plexus as superficial perineural invasion (sup-PNI) and PNI in the subserous plexus as deep perineural invasion (deep-PNI). Patients were divided into three groups based on the depth of PNI: sup-PNI, deep-PNI and non-PNI. Then, univariate and multivariate Cox regression analyses were conducted to evaluate the role of PNI in the prognosis of stage II colorectal cancer. Results This study enrolled 3508 patients with stage II colorectal cancer who underwent resection for primary colorectal lesions between January 2013 and September 2019. Clinicopathological features, including elevated carcinoembryonic antigen (CEA) levels, T4 stage, poor differentiation, deficient DNA mismatch repair (dMMR), and vascular invasion, were correlated with deep-PNI. Multivariate analyses revealed that deep-PNI was associated with worse overall survival (OS; hazard ratio [HR], 3.546; 95% confidence interval [CI], 2.307–5.449; P

Abstract Background We aimed to explore the application value of various machine learning (ML) algorithms based on multicenter CT radiomics in identifying peripheral nerve invasion (PNI) of colorectal cancer (CRC). Methods A total of 268 patients with colorectal cancer who underwent CT examination in two hospitals from January 2016 to December 2022 were considered. Imaging and clinicopathological data were collected through the Picture Archiving and Communication System (PACS). The Feature Explorer software (FAE) was used to identify the peripheral nerve invasion of colorectal patients in center 1, and the best feature selection and classification channels were selected. Finally, the best feature selection and classifier pipeline were verified in center 2. Results The six-feature models using RFE feature selection and GP classifier had the highest AUC values, which were 0.610, 0.699, and 0.640, respectively. FAE generated a more concise model based on one feature (wavelet-HLL-glszm-LargeAreaHighGrayLevelEmphasis) and achieved AUC values of 0.614 and 0.663 on the validation and test sets, respectively, using the “one standard error” rule. Using ANOVA feature selection, the GP classifier had the best AUC value in a one-feature model, with AUC values of 0.611, 0.663, and 0.643 on the validation, internal test, and external test sets, respectively. Similarly, when using the “one standard error” rule, the model based on one feature (wave-let-HLL-glszm-LargeAreaHighGrayLevelEmphasis) achieved AUC values of 0.614 and 0.663 on the validation and test sets, respectively. Conclusions Combining artificial intelligence and radiomics features is a promising approach for identifying peripheral nerve invasion in colorectal cancer. This innovative technique holds significant potential for clinical medicine, offering broader application prospects in the field. Critical relevance statement The multi-channel ML method based on CT radiomics has a simple operation process and can be used to assist in the clinical screening of patients with CRC accompanied by PNI. Key points • Multi-channel ML in the identification of peripheral nerve invasion in CRC. • Multi-channel ML method based on CT-radiomics can detect the PNI of CRC. • Early preoperative identification of PNI in CRC is helpful to improve the formulation of treatment strategies and the prognosis of patients. Graphical Abstract

Abstract Background Perineural invasion (PNI), as the fifth recognized pathway for the spread and metastasis of colorectal cancer (CRC), has increasingly garnered widespread attention. The preoperative identification of whether colorectal cancer (CRC) patients exhibit PNI can assist clinical practitioners in enhancing preoperative decision-making, including determining the necessity of neoadjuvant therapy and the appropriateness of surgical resection. The primary objective of this study is to construct and validate a preoperative predictive model for assessing the risk of perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). Materials and methods A total of 335 patients diagnosed with colorectal cancer (CRC) at a single medical center were subject to random allocation, with 221 individuals assigned to a training dataset and 114 to a validation dataset, maintaining a ratio of 2:1. Comprehensive preoperative clinical and pathological data were meticulously gathered for analysis. Initial exploration involved conducting univariate logistic regression analysis, with subsequent inclusion of variables demonstrating a significance level of p

Objectives: Several studies have evaluated the prognostic significance of Perineural Invasion (IPN) in laryngeal cancer; however, the results are non-conclusive. Therefore, we conducted a meta-analysis aiming to identify the prognostic value of IPN in laryngeal cancer. Methods: A literature review was performed, searching MedLine via PubMed, Scielo, Lilacs, Cochrane and Websco. RevMan 5.4 was used for the statistical analysis. Results: A total of 19 laryngeal cancer studies were included. The results indicate that IPN in laryngeal cancer shows 2-year survival with RR 0.71 (0.59‒0.86); disease-free survival RR 0.51 (0.14–1.95); and locoregional recurrence RR 1.71 (1.25–2.35). Conclusion: IPN is a negative prognostic factor in laryngeal cancer.

Introduction The commonest type of malignancy in the head and neck region is oral squamous cell carcinoma (OSCC). Brandwein provided a risk model that includes scores for the following three factors: worst invasion pattern, lymphocytic host response and perineural invasion. This risk model accounts for overall survival and local recurrence. p53 is considered to be one of the most significant prognostic markers. Objectives To assess and correlate Brandwein-Gensler criteria with p53 immunoexpression in oral squamous cell carcinoma. Methods In this study, a total of 80 samples will be included from histopathologically diagnosed OSCC patients will be taken for the study. H&E-stained slides of all cases will be evaluated using Brandwein-Gensler criteria and then immunostaining will be done for p53 immunoexpression. A correlation between Brandwein-Gensler criteria and p53 immunoexpression will be determined. The present study will assess and correlate Brandwein-Gensler criteria with p53 immunoexpression. If the Brandwein-Gensler criteria score increases, the intensity of p53 immunoexpression will also increase. Conclusions We hypothesize that Brandwein-Gensler criteria may be significantly correlated with p53 immunoexpression in OSCC.

A 74-year-old woman who presented initially with trigeminal neuralgia of the left forehead and scalp was later found to have a poorly differentiated squamous cell carcinoma (SCC) with large-nerve perineural and intraneural invasion of the left supraorbital nerve. Negative histopathologic margins were achieved in three stages of permanent fixed tissue en face processing and the final defect was repaired with a large rotation flap. Approximately one month after repair, the patient presented with new-onset diplopia and was found to have a complete left cranial nerve VI palsy suspicious for continued disease spread. MRI confirmed perineural spread along the ophthalmic branch of the trigeminal nerve through the superior orbital fissure into the cavernous sinus. She was subsequently treated with radiation therapy (66Gy in 33 fractions). The involvement of two distinct cranial nerves by perineural invasion is uncommon and has mostly been described involving branches of the trigeminal and facial nerves. This case highlights the rare presentation of perineural invasion involving both the trigeminal nerve and the abducens nerve. Anatomically, this clinical presentation can be explained by the retrograde perineural spread along the ophthalmic branch of the trigeminal nerve through the supraorbital fossa into the cavernous sinus where these two nerves are in close proximity.

Background: Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain. Methods: We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures. Results: PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease. Conclusions: Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present. [ABSTRACT FROM AUTHOR]

Introduction: The patterns of microRNA (miRNA) expression have opened up new avenues in the search for prognostic biomarkers and potential therapeutic targets for various tumours. In oral carcinogenesis research, analysing microRNAs expressed in Oral Squamous Cell Carcinoma (OSCC) unveils a complex network of interest. miR-21 is known to be overexpressed in numerous solid tumours and is linked to the progression of malignancies in hepatocellular carcinomas, breast cancer, and colon carcinomas. Aim: To determine the impact of surgical excision on serum miR-21 expression levels in OSCC cases and to establish correlations with clinicopathological parameters. Materials and Methods: The study was an exploratory prospective observational study conducted with proper institutional ethical approval at the Cancer Research Institute (CRI), Himalayan Institute of Medical Sciences (HIMS), Jolly Grant, Dehradun, Uttarakhand, India. Fifty-six histologically confirmed OSCC cases were enrolled along with 25 healthy subjects as controls from May 2021 to June 2023. The relative fold expression change was calculated using the Livak method (2-ΔΔct). Data analysis was performed using software such as Statistical Package for Social Sciences (SPSS) version 20.0 and MS Excel. Non parametric statistical tests such as Wilcoxon signed-rank test, Mann-Whitney test, and Kruskal-Wallis test were utilised. Results: Out of 56 sample included, 28 exhibited high expression of miR-21 (p-value<0.001), while 27 cases showed downregulation postsurgery (p-value<0.001), with one sample showing the same level of expression. In cases where the time difference between pre and postsurgery samples was over 25 days, no significant change was observed (p-value=0.06), and similarly, in cases with a time difference below 25 days, no significant difference was noted (p-value=0.14). A significant negative correlation was found between presurgery serum Albumin to Globulin ratio (A:G ratio) and miR-21 expression (p-value <0.05), while no other parameters showed a significant correlation with miR-21. Conclusion: miR-21 expression decreased significantly in some OSCC cases; however, in the majority of cases, it increased postsurgery. A significant correlation was observed between miR-21 expression and the serum A:G ratio. [ABSTRACT FROM AUTHOR]

Objective: Current guidelines indicate postoperative radiotherapy (PORT) in oral squamous cell carcinoma (OSCC) with perineural invasion (PNI), however, its real benefit has never been proven. The aim of our study is to investigate the benefit of PORT in OSCC patients with PNI in terms of survival and disease control. Data Sources: The Pubmed/MEDLINE, Cochrane Library, and Scopus databases. Review Methods: Patients with PNI + OSCC treated with primary surgery were extracted from the included studies. The pooled logHR was calculated by comparing patients who underwent PORT to those who underwent only observation for overall survival (OS), disease‐specific survival (DSS), disease‐free survival (DFS), and locoregional control (LRC). Results: About 690 patients with primary OSCC and PNI were included from nine studies. 374 (54.2%) patients underwent PORT, while 316 (45.8%) underwent observation. Analyses showed non‐significant difference between the two groups for OS (HR: 1.01; 95% CI: 0.38–2.69), DSS (HR: 2.03; 95% CI: 0.54–7.56), and LRC (HR: 0.89; 95% CI: 0.53–1.50). They showed a significant difference in terms of DFS (HR: 0.86; 95% CI: 0.77–0.97). Conclusion: The real benefit of PORT in OSCC patients with PNI is still unclear, although it may have a positive impact on DFS. Clinicians should consider individual patient's characteristics, tumor factors, and treatment goals when deciding whether to recommend PORT. Further studies are needed to clarify which entity of PNI really benefits from PORT. Level of Evidence: NA Laryngoscope, 134:2019–2027, 2024 [ABSTRACT FROM AUTHOR]

Background: Perineural invasion (PNI) is the invasion of nerves by cancer cells and is associated with poor survival in stage II colorectal cancer. However, PNI can be further subdivided according to the depth of invasion, and the depth of PNI has not been clearly linked to prognosis. Method: This study aimed to assess the prognostic value of different depths of PNI in stage II colorectal cancer. We defined PNI in the submucosal plexus and myenteric plexus as superficial perineural invasion (sup-PNI) and PNI in the subserous plexus as deep perineural invasion (deep-PNI). Patients were divided into three groups based on the depth of PNI: sup-PNI, deep-PNI and non-PNI. Then, univariate and multivariate Cox regression analyses were conducted to evaluate the role of PNI in the prognosis of stage II colorectal cancer. Results: This study enrolled 3508 patients with stage II colorectal cancer who underwent resection for primary colorectal lesions between January 2013 and September 2019. Clinicopathological features, including elevated carcinoembryonic antigen (CEA) levels, T4 stage, poor differentiation, deficient DNA mismatch repair (dMMR), and vascular invasion, were correlated with deep-PNI. Multivariate analyses revealed that deep-PNI was associated with worse overall survival (OS; hazard ratio [HR], 3.546; 95% confidence interval [CI], 2.307–5.449; P < 0.001) and disease-free survival (DFS; HR, 2.921; 95% CI, 2.032–4.198; P < 0.001), compared with non-PNI. Conversely, no significant difference in OS or DFS was observed between the sup-PNI and non-PNI groups in multivariate analyses. Conclusions: The study demonstrated that the depth of PNI was an independent prognostic factor for patients with stage II colorectal cancer, and patients with deep PNI had a worse prognosis. Thus, patients with PNI require further subdivision according to the depth of invasion. [ABSTRACT FROM AUTHOR]

Background: We aimed to explore the application value of various machine learning (ML) algorithms based on multicenter CT radiomics in identifying peripheral nerve invasion (PNI) of colorectal cancer (CRC). Methods: A total of 268 patients with colorectal cancer who underwent CT examination in two hospitals from January 2016 to December 2022 were considered. Imaging and clinicopathological data were collected through the Picture Archiving and Communication System (PACS). The Feature Explorer software (FAE) was used to identify the peripheral nerve invasion of colorectal patients in center 1, and the best feature selection and classification channels were selected. Finally, the best feature selection and classifier pipeline were verified in center 2. Results: The six-feature models using RFE feature selection and GP classifier had the highest AUC values, which were 0.610, 0.699, and 0.640, respectively. FAE generated a more concise model based on one feature (wavelet-HLL-glszm-LargeAreaHighGrayLevelEmphasis) and achieved AUC values of 0.614 and 0.663 on the validation and test sets, respectively, using the "one standard error" rule. Using ANOVA feature selection, the GP classifier had the best AUC value in a one-feature model, with AUC values of 0.611, 0.663, and 0.643 on the validation, internal test, and external test sets, respectively. Similarly, when using the "one standard error" rule, the model based on one feature (wave-let-HLL-glszm-LargeAreaHighGrayLevelEmphasis) achieved AUC values of 0.614 and 0.663 on the validation and test sets, respectively. Conclusions: Combining artificial intelligence and radiomics features is a promising approach for identifying peripheral nerve invasion in colorectal cancer. This innovative technique holds significant potential for clinical medicine, offering broader application prospects in the field. Critical relevance statement: The multi-channel ML method based on CT radiomics has a simple operation process and can be used to assist in the clinical screening of patients with CRC accompanied by PNI. Key points: • Multi-channel ML in the identification of peripheral nerve invasion in CRC. • Multi-channel ML method based on CT-radiomics can detect the PNI of CRC. • Early preoperative identification of PNI in CRC is helpful to improve the formulation of treatment strategies and the prognosis of patients. [ABSTRACT FROM AUTHOR]

To investigate the value of computed tomography (CT) radiomics nomogram in the preoperative prediction of perineural invasion (PNI) in oesophageal squamous cell carcinoma (ESCC) through a multicenter study. We retrospectively collected postoperative pathological data of 360 ESCC patients with definite PNI status (131 PNI-positive and 229 PNI-negative) from two centres. Radiomic features were extracted from the arterial-phase CT images, and the least absolute shrinkage and selection operator and logistic regression algorithm were used to screen valuable features for identifying the PNI status and calculating the radiomics score (Rad-score). A radiomics nomogram was established by integrating the Rad-score and clinical risk factors. A receiver operating characteristic curve was used to evaluate model performance, and decision curve analysis was used to evaluate the predictive performance of the radiomics nomogram in the training, internal validation, and external validation sets. Twenty radiomics features were extracted from a full-volume tumour region of interest to construct the model, and the radiomics nomogram combined with radiomics features and clinical risk factors was superior to the clinical and radiomics models in predicting the PNI status of ESCC patients. The area under the curve values of the radiomics nomogram in the training, internal validation, and external validation sets were 0.856 (0.794–0.918), 0.832 (0.742–0.922), and 0.803 (0.709–0.898), respectively. The radiomics nomogram based on CT has excellent predictive ability; it can non-invasively predict the preoperative PNI status of ESCC patients and provide a basis for preoperative decision-making. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf‐1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1‐overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K–AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1‐overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease‐free probability at 3 and 5 years. In summary, DKK1 can promote the PI3K–AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer is the fifth most common cancer today. It is the third most common cause of cancer-related death because it is usually at an advanced stage at the time of diagnosis. Several factors affect the prognosis of gastric cancer. In this study, we examined various factors affecting the prognosis in gastric cancer and evaluated their effects on the prognosis. Methods: Between 2011 and 2016, 146 patients who underwent resection with the diagnosis of curative gastric cancer in Haydarpaşa Numune Training and Research Hospital General Surgery Clinic were included in the study. A total of 146 gastric cancer patients who underwent curative surgery were retrospectively analyzed. Age, gender, type of operation, preoperative albumin and tumor markers, tumor stage, lymph node involvement, histological type, tumor localization, tumor differentiation, lymphovascular and perineural invasion, and Her-2 immunohistochemical features were examined, and survival analyses were performed. Results: Age, stage, lymph node involvement, and perineural-lymphovascular invasion were found to be statistically significant. Discussion and Conclusion: It was concluded that the determination of these prognostic factors will have an important place in the planning of the treatment. However, the subject should be supported by randomized clinical studies involving more patients. [ABSTRACT FROM AUTHOR]

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below. [ABSTRACT FROM AUTHOR]

Background: Forkhead box C2 gene (FOXC2) acts as an epithelial-mesenchymal transition (EMT) inducer while Prospero homeobox 1 gene (PROX-1) function as a regulator of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma (OSCC). It is presumed that PROX-1 has both tumour-suppressive and oncogenic effects. The main aim of this study is to evaluate the role of PROX-1 and FOXC2 in the invasion and progression of OSCC cases and to correlate their expression with various histopathological parameters. Materials and Methods: A prospective cohort study was conducted in a total sample size of 52 OSCC tissues and histologically tumour-free margins of 20. mRNA expression and protein levels of FOXC2 and PROX-1 were evaluated using real-time PCR and sandwich enzyme-linked immunosorbent assay techniques. Chi-square analysis and correlation analysis were done. Kaplan-Meier analysis evaluated the survival rate. Results: Mean Ct values of FOXC2 were 1.915 ± 0.519 and PROX-1 was 0.061 ± 0.173. There was a significant 2-fold increase in the FOXC2 expression and a 0.5-fold decrease in the PROX-1 expression in OSCC tissue. Increased levels of FOXC2 protein and decreased levels of PROX-1 with a mean difference of 1.64 ± 0.73 ng/ml and 1.27 ± 0.33 ng/ml were observed in OSCC compared to histologically tumour-free margins. A significant positive correlation was found between the FOXC2 expression and clinicopathological parameters such as staging, perineural invasion (PNI) and lymphovascular invasion (LVI) whereas PROX-1 showed a significant negative correlation with histopathological parameters such as staging, PNI, LVI and tumour staging. There was a significant positive correlation between the PROX-1 and histologically tumour-free margins in disease-free survival patients (P-value = 0.03). Conclusion: FOXC2 and PROX-1 expressions were correlated with lymphovascular invasion, OSCC tumour staging and PNI. Thus, FOXC2 and PROX-1 could be possible therapeutic targets in the treatment of OSCC that can inhibit the EMT in OSCC and thereby favouring a better prognosis. [ABSTRACT FROM AUTHOR]

Periampullary cancer is a malignant tumor occurring around the ampullary region of the liver and pancreas, encompassing a variety of tissue types and sharing numerous biological characteristics, including interactions with the nervous system. The nervous system plays a crucial role in regulating organ development, maintaining physiological equilibrium, and ensuring life process plasticity, a role that is equally pivotal in oncology. Investigations into nervetumor interactions have unveiled their key part in controlling cancer progression, inhibiting anti-tumor immune responses, facilitating invasion and metastasis, and triggering neuropathic pain. Despite many mechanisms by which nerve fibers contribute to cancer advancement still being incompletely understood, the growing emphasis on the significance of nerves within the tumor microenvironment in recent years has set the stage for the development of groundbreaking therapies. This includes combining current neuroactive medications with established therapeutic protocols. This review centers on the mechanisms of Periampullary cancer's interactions with nerves, the influence of various types of nerve innervation on cancer evolution, and outlines the horizons for ongoing and forthcoming research. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether subcategorization of perineural invasion (PNI) improves the prognostic resolution of the American Joint Committee on Cancer, Eighth Edition (AJCC8) staging system in oral cavity squamous cell carcinoma (OCSCC). Methods: OCSCC tumor specimens from patients seen at a tertiary care institution who underwent primary surgical resection between January 2019 and June 2021 were sorted into four PNI categories: negative, intratumoral, peripheral, and extratumoral. The prognostic effect of these PNI categories were assessed through Kaplan–Meier, Cox regression, and log‐rank testing using recurrence‐free survival (RFS) and overall survival (OS) as primary and secondary outcomes respectively. Results: A total of 158 patients were examined. The median follow‐up time was 21 months. PNI subcategorization further stratified RFS (p = 0.007) and OS (p = 0.002). Extratumoral PNI was associated with a 4.5‐fold increase in recurrence risk (adjusted hazards ratio [aHR]: 4.53; 95% confidence interval [CI]: 1.1–18.66) and worse OS when compared with PNI negative disease (aHR: 5.71; 95% CI: 1.0–32.67). Peripheral PNI was associated with worse OS (aHR: 5.7; 95% CI: 1.35–24.08) but not worse RFS (p = 0.18) when compared with PNI negative disease. Interestingly, intratumoral PNI was not associated with significant differences in RFS (p = 0.087) or OS (p = 0.22) when compared with PNI negative disease. Conclusions: Subcategorization of OCSCC tumors into extratumoral, peripheral, and intratumoral PNI stratifies RFS and OS when compared with patients with PNI negative disease in an incremental fashion. This pilot study suggests that there may be added benefit in subcategorization of PNI in the prognostic evaluation of OCSCC. Level of Evidence: 4 Laryngoscope, 134:1656–1662, 2024 [ABSTRACT FROM AUTHOR]

Background: Perineural invasion (PNI), as the fifth recognized pathway for the spread and metastasis of colorectal cancer (CRC), has increasingly garnered widespread attention. The preoperative identification of whether colorectal cancer (CRC) patients exhibit PNI can assist clinical practitioners in enhancing preoperative decision-making, including determining the necessity of neoadjuvant therapy and the appropriateness of surgical resection. The primary objective of this study is to construct and validate a preoperative predictive model for assessing the risk of perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). Materials and methods: A total of 335 patients diagnosed with colorectal cancer (CRC) at a single medical center were subject to random allocation, with 221 individuals assigned to a training dataset and 114 to a validation dataset, maintaining a ratio of 2:1. Comprehensive preoperative clinical and pathological data were meticulously gathered for analysis. Initial exploration involved conducting univariate logistic regression analysis, with subsequent inclusion of variables demonstrating a significance level of p < 0.05 into the multivariate logistic regression analysis, aiming to ascertain independent predictive factors, all while maintaining a p-value threshold of less than 0.05. From the culmination of these factors, a nomogram was meticulously devised. Rigorous evaluation of this nomogram's precision and reliability encompassed Receiver Operating Characteristic (ROC) curve analysis, calibration curve assessment, and Decision Curve Analysis (DCA). The robustness and accuracy were further fortified through application of the bootstrap method, which entailed 1000 independent dataset samplings to perform discrimination and calibration procedures. Results: The results of multivariate logistic regression analysis unveiled independent risk factors for perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). These factors included tumor histological differentiation (grade) (OR = 0.15, 95% CI = 0.03–0.74, p = 0.02), primary tumor location (OR = 2.49, 95% CI = 1.21–5.12, p = 0.013), gross tumor type (OR = 0.42, 95% CI = 0.22–0.81, p = 0.01), N staging in CT (OR = 3.44, 95% CI = 1.74–6.80, p < 0.001), carcinoembryonic antigen (CEA) level (OR = 3.13, 95% CI = 1.60–6.13, p = 0.001), and platelet-to-lymphocyte ratio (PLR) (OR = 2.07, 95% CI = 1.08–3.96, p = 0.028).These findings formed the basis for constructing a predictive nomogram, which exhibited an impressive area under the receiver operating characteristic (ROC) curve (AUC) of 0.772 (95% CI, 0.712–0.833). The Hosmer–Lemeshow test confirmed the model's excellent fit (p = 0.47), and the calibration curve demonstrated consistent performance. Furthermore, decision curve analysis (DCA) underscored a substantial net benefit across the risk range of 13% to 85%, reaffirming the nomogram's reliability through rigorous internal validation. Conclusion: We have formulated a highly reliable nomogram that provides valuable assistance to clinical practitioners in preoperatively assessing the likelihood of perineural invasion (PNI) among colorectal cancer (CRC) patients. This tool holds significant potential in offering guidance for treatment strategy formulation. [ABSTRACT FROM AUTHOR]

Objective: Perineural invasion (PNI) is a histopathological finding which represents invasion of the nerves and surroundings by cancer cells. Several studies have reported that PNI in prostate cancer (PCa) is a poor prognostic factor. However, there are insufficient data in literature related to the use of PNI status in the biopsy at the stage of making a decision for nerve-sparing surgery. This research aimed to investigate the impact of PNI identified in prostate biopsies on the biochemical recurrence-free survival (RFS) in individuals who underwent nerve-sparing radical prostatectomy (RP) for PCa. Materials and Methods: The data of 972 patients who underwent nerve-sparing RP due to a clinically localized PCa diagnosis were retrospectively examined. Patients were divided into two groups as PNI (+) and PNI (-) according to PRI status in prostate biopsy pathology. Results: Evaluation was made of 747 patients with suitable data for analysis. PNI was determined in the prostate biopsy of 162 patients and not in the biopsies of 585 patients. The 5-year biochemical RFS rates were 90% for PNI (+) patients and 89.6% for the PNI (-) group, and the difference between the two groups was not statistically significant. When the PNI positive and negative groups were compared in respect of surgical margin positivity, the surgical margin was determined as positive in 42 (25.9%) of the group with PNI and in 84 (14.4%) of the group without PNI. Surgical margin positivity was determined to be statistically significantly greater in the PNI (+) group. Biochemical RFS rates were compared according to the surgical margin positivity status, and 5-year biochemical RFS was found to be 81.5% in those with surgical margin positivity and 91.6% in those with surgical margin negativity, no statistically meaningful distinction was found between the groups Conclusions: The findings of this study indicated that PNI determined in prostate biopsy did not affect 5-year RFS following nerve-sparing RP. [ABSTRACT FROM AUTHOR]

Aim. Endometriosis is an inflammatory condition that shares a number of similarities with malignant diseases, such as an abnormal morphology, migration along the nerve bundles and metastatic spread to lymph nodes and distant organs. Endometriotic lesions are associated with oestrogen and progesterone imbalance which seems to play a key role in the pathogenesis of endometriosis. The aim of this study was to compare the status of both oestrogen and progesterone receptors in tissue of deep infiltrating endometriosis, lymph node endometriosis and atypical ovarian endometriosis using immunohistochemical methods, as well as to investigate the relationship between endometriosis and protein p53. Methods. A total of 40 cases with deep infiltrating endometriosis were included in our study. Based on histopathological analysis of resected specimens, the cases were divided into 2 groups: group 1 - lymph node endometriosis (cases with lymph node involvement; n=12) and group 2 - deep infiltrating endometriosis (cases without lymph node involvement; n=28). As a control group, eutopic endometrium of adenomyosis- and endometriosis-free women were used (n=16). Five cases of atypical ovarian endometriosis as well as descriptions of the nerve involvement in endometriosis were also included. Immunohistochemical staining with a total of 4 markers was performed - oestrogen and progesterone receptors (ER, PR), p53 and Ki-67 (proliferation index). Results. The immunophenotype of the cases in groups 1 and 2 and in the control group was virtually identical in the proliferative phase - strong nuclear ER and PR expression in more than 90% of endometrial glandular and stromal cells. In the early and mid secretory phase, ER expression only slightly decreased (80%) in endometrial glandular cells in group 2 and the control group, whereas in the late secretory phase, significant decrease of ER expression only in the control group was observed (15-50%; P<0.001). In group 2 and the control group, significant decrease of PR expression only in endometrial glandular cells was observed in the mid and late secretory phase (less than 15%; P<0.001). Differences in receptor content were found only in isolated cases in group 2. In group 1, no secretory changes were found. In all three groups, sporadic and weak nuclear p53 expression in less than 3% in both endometrial glandular and stromal cells was detected (regardless of the phase of the menstrual cycle). In atypical ovarian endometriosis, higher and strong p53 expression (on average 26%) and decrease in ER (on average 56%) and PR (less than 1%) expression was observed; compared to the control group and groups 1 and 2, the differences for all 3 markers were highly significant (P<0.001). In all groups, the proliferation index (Ki-67) reached the highest values in the proliferation phase and decreased during the cycle. However, in endometriotic tissue, it was widely variable in the individual phases of the cycle. Perineural spread of endometriosis with significant neural hypertrophy, hyperplasia and involvement of the ganglia of the autonomic nervous system was detected in 5 cases (12.5%). Conlusion. From a histological and immunohistochemical point of view, deep infiltrating endometriosis and lymph node endometriosis appear to represent the same entity. For the first time, a simple immunohistochemical panel with antibodies against ER, PR and p53 useful in diagnosing atypical endometriosis has been described. The marked endometriosis-associated neural changes (endometriotic neuropathy) could be one of the causes of impaired function of the affected organs after debulking surgery with macroscopic negative resection margins as well as pain symptomatology in macroscopic inapparent endometriotic lesions. [ABSTRACT FROM AUTHOR]

Introduction: Surgery represents the primary treatment option for cutaneous squamous cell carcinoma (cSCC) aiming for complete tumor resection (R0). Recurrence and metastasis significantly affect survival and outcomes, and poorly differentiated (G3) cSCC is associated with a higher risk of recurrence. However, the specific clinical and histopathological features that predict recurrence and progression in G3-cSCC remain unclear. Methods: A retrospective analysis was conducted on a series of patients with primary G3-cSCC diagnosed at the Turin University Hospital between January 2016 and January 2021. After independent histological revision, logistic regression models were used to identify clinico-pathological predictors of cutaneous recurrence, lymphnode/metastatic progression, and both types of progression. Results: Among the 161 G3-cSCC patients, 80.1% (129/161) showed no signs of local recurrence or metastatic progression, while 19.9% (32 patients) had progressed. In the univariate logistic regression, tumor clinical diameter, depth of infiltration (DOI), and lymphovascular invasion (LVI) were identified as significant predictors across the various types of progression (p < 0.05). In the context of multivariate logistic regression, distinct models proved to be significant. For skin recurrence, a 3-variable model incorporating DOI (OR 1.16, 95% CI, 1.01–1.35, p = 0.050), LVI (OR 3.61, 95% CI, 1.11–11.8, p = 0.034), and desmoplasia (OR 3.45, 95% CI, 1.25–9.5, p = 0.017) was selected. Regarding lymphnode/metastatic progression, a 3-variable model combining pT2 (OR 6.10, 95% CI, 1.15–32.35, p = 0.034), pT3 (OR 14.33, 95% CI, 2.79–73.63, p = 0.001), and LVI (OR 3.86, 95% CI, 1.10–13.62, p = 0.036) was identified. Lastly, a 2-variable model for both types of progression consisted of vertical tumor thickness (OR 5.45, 95% CI, 1.11–27.32, p = 0.039) and LVI (OR 1.15, 95% CI, 1.04–1.26, p = 0.006). Conclusion: Tumor size, DOI, and LVI were significant predictors of recurrence and metastatic progression. Notably, the size of histologically defined tumor-free margins did not affect the risk of recurrence, whilst LVI emerged as a key predictor of all forms of progression. These findings provide insights into risk stratification and suggest that close monitoring and potential adjuvant therapies, such as radiation therapy, may be necessary especially for patients with lymphovascular involvement. [ABSTRACT FROM AUTHOR]

Background and objectives: Perineural invasion (PNI) refers to the invasion, encasement, or penetration of tumor cells around or through nerves. Various malignant tumors, including pancreatic cancer, head and neck tumors, and bile duct cancer, exhibit the characteristic of PNI. Particularly, in head and neck-skull base tumors such as adenoid cystic carcinoma (ACC), PNI is a significant factor leading to incomplete surgical resection and postoperative recurrence. Methods: Spatial transcriptomic and single-cell transcriptomic sequencing were conducted on a case of ACC tissue with PNI to identify potential probes targeting PNI. The efficacy of the probes was validated through in vivo and in vitro experiments. Results: Spatial transcriptomic and single-cell RNA sequencing revealed phenotypic changes in Schwann cells within the PNI region of ACC. Peptide probes were designed based on the antigen-presenting characteristics of Schwann cells in the PNI region, which are dependent on Major Histocompatibility Complex II (MHC-II) molecules. Successful validation in vitro and in vivo experiments confirmed that these probes can label viable Schwann cells in the PNI region, serving as a tool for dynamic in vivo marking of tumor invasion into nerves. Conclusions: Peptide probes targeting Schwann cells' MHC-II molecules have the potential to demonstrate the occurrence of PNI in patients with ACC