Perineural Invasion Research Articles

POORLY DIFFERENTIATED CLUSTERS IN COLORECTAL CARCINOMA: ASSOCIATION WITH OTHER HISTOPATHOLOGICAL PROGNOSTIC PARAMETERS INCLUDING TUMOUR BUDDING

Objective: In India, colorectal carcinoma (CRC) ranks third in terms of cancer incidence. Pathologists are essential when it comes to determining the stage, examining surgical margins, and recording the histopathologic prognostic factors. A new prognostic grading system is proposed named poorly differentiated clusters (PDCs), which are defined by neoplastic clusters of 5 cells lacking glandular structure in the invasive front of the stroma. It is significant for cancer-specific and recurrence-free survival in CRC patients, reflecting the biological aggressiveness of the tumor. Aim of the study was to analyse of PDCs in colorectal carcinomas and association with other histopathological prognostic factors. Methods: The Hematoxylin and Eosin (HandE)-stained slides of 76 histopathologically diagnosed CRC resection specimens were reviewed. Poorly differentiated clusters (PDC) were assessed into under 200x power. The correlation of PDC with other histopathological prognostic parameters like tumor size, site, grade, laterality, lymphovascular invasion, perineural invasion, T stage, N stage, and tumor budding was analyzed using descriptive statistics and the Chi-square test with SPSS version 26.0. Results: There was no significant association between PDC and age, tumor location, tumor size, histological grade, LVI, PNI, or lymphnode status. Where a significant association was noted between the sex and PDC grade (P value = 0.035), T stage and PDC grade (P value = 0.045), and N stage and PDC grade is significant (P value = 0.001). Conclusion: PDCs may be considered, along with other clinical-pathological parameters, a promising prognostic factor for the management of patients with CRC and should be included in pathological reports, but it still needs standardization and further validation. At the same time, tumor budding can become an irreplaceable histological indicator for identifying a high malignant potential carcinoma and poor prognosis in CRCS, thus indicating the need for aggressive postoperative management to improve the prognosis of the patient. PDC is important for the survival of CRC patients, indicating the aggressiveness of the tumor both in terms of cancer-specific survival and freedom from recurrence. PDC may help to identify patients who need a more intensive postoperative follow-up and the possibility of adjuvant therapy.

Modified Textbook Outcome was a Predictor for Early Mortality After Oral Cancer Surgery.

To explore prognostic factors for early mortality among patients undergoing surgery for oral cavity cancer (OCC) and identify valuable strategies to improve patient outcomes. A total of 397 patients treated by primary tumor resection and neck dissection between 2017 and 2021 were retrospectively analyzed. Univariate and multivariate Cox regression analysis were used to explore the relationships between the study factors and early death (within 12months). Predictors were further incorporated into a nomogram for estimation of 1-year overall survival (OS). The mean age was 57.2 (SD, 9.8)years and 92.9% patients were male. The early death rate was 12.6% overall, 35.6% in patients with pN2-3, 22.3% in patients with tumor size > 3 cm, and 36.2% in patients with lymphovascular invasion. A non-modified textbook outcome (mTO), pN2-3, tumor size > 3 cm, and lymphovascular permeation were independent prognosticators for early mortality. A nomogram with the above-mentioned four factors were created with good discrimination and calibration. Among the pN2-3 or tumor size > 3 cm subgroup, a non-mTO, cancer resource center (CRC) visits, perineural invasion, and lymphovascular permeation were independent prognostic factors for early death. In addition to traditional clinicopathological features, a non-mTO and CRC visits could serve as prognostic factors for early death in OCC. A novel nomogram had good discrimination and calibration. Quality improvements in terms of mTO and patients demanding resource support could improve survival outcomes in OCC.

HPB SO28 - Pre-operative Biliary Drainage in Pancreatic Adenocarcinoma and its Effect on Surgical Oncological Outcomes

Abstract Background Pre-operative biliary drainage (PBD) in patients undergoing pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) has been associated with a significantly increased risk of serious complications. This retrospective study investigated if PBD has a significant effect on lymphovascular (LVI) or perineural (PNI) invasion compared to direct surgery (DS). Method Data was collected retrospectively from patients undergoing PD for PDAC from 01/01/2014 to 30/12/2022. Patients were grouped according to whether they received any form of PBD or not. Patients’ T and N stage, as well as lymph node ratio (LNR), R status, Mortality, disease free (DFS) and overall survival (OS) were recorded. The primary outcome measure was lymph node ratio. Results A total of 87 patients were identified (48 PBD group vs 39 DS group), with a mean age of 68. The median LNR was 0.2 in PBD vs 0.21 in DS Group (p=0.87). There was no significant difference in median DFS (310 days PBD vs 285 DS p=0.94) or median OS (513 days PBD vs 515 DS p=0.39). PBD was not associated with a greater incidence of LVI (67% PBD vs 69% DS p=0.8), or PNI (94% PBD vs 97% p=0.41). PBD did not have a significant effect on resection margin status (p=0.75). Conclusion Despite evidence in the literature on its effects on the rate of complications, PBD has not been shown to have an effect on LVI or PNI, disease progression, nor overall survival in our patient group.

The epidemiological and histopathological factors for delayed local recurrence in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy in oral cancer. Approximately 26% of OSCC cases recur after initial curative treatment, with over 80% of these recurrences occurring within the first 2years. Delayed local recurrence (DLR) occurring beyond the 2-year period in cases of OSCC is infrequent. The aim of this study is to investigate the histopathological characteristics associated with DLR. This study included 197 patients diagnosed with OSCC who underwent primary surgery from 2006 to 2022. Epidemiological features, such as age and gender, and histopathological features, including primary tumor sites, TNM staging, histopathological grading, depth of invasion, the presence of lymphovascular or perineural invasion, and the utilization of radiation therapy (RT) and neck dissection (ND) were analyzed. The mean interval until local recurrence was 22 ± 27months. There were 10 cases of DLR (20.83%) among 51 patients with local recurrence. The epidemiological and histopathological analysis of these cases is as follows: 10 patients (3 males and 7 females) aged 51-80years (median, 56.5years). Primary tumor sites were tongue (n = 3), maxillary gingiva (n = 1), mandibular gingiva (n = 3), retromolar trigone (n = 1), and buccal mucosa (n = 2). Tumor size was advanced (T3/T4) in 5 cases, while a smaller size (T1/T2) was observed in 5 cases. No lymph node metastasis was 80.0%. Histopathological grading was well differentiated in 9 cases and moderately differentiated in 1 case, with no cases of poorly differentiated tumors. Depth of invasion > 5mm was 70.0% of the cases (n = 7). Lymphovascular invasion and perineural invasion were not present. Three patients received RT, and 8 patients underwent ND. There were 2 patients who consumed alcohol, and 2 patients who smoked tobacco. The results showed that histological differentiation had a significant relationship with the interval (p = 0.031). DLR, occurring more than 2years after the initial tumor resection surgery, is infrequent. Histological differentiation is associated with tumor recurrence intervals. Patients with a higher histological grading require more precise follow-up observation during the initial 2years after surgery.

NCMP-18. A CASE OF METASTATIC GLIOBLASTOMA MULTIFORME

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor and rarely causes metastasis. We present a case of a 43-year-old female who developed tingling and heaviness in her right lower extremity in March 2023. This sensation progressed to involve her entire right hemi-body over the next two months. She presented to the emergency department where an MRI show a large left frontal parietal mass measuring 5.2x3.7x3.7cm with significant mass effect. She underwent surgical resection and surgical pathology showed IDH1-mutant R132H, retained ATRX, MGMT promoter mutation, and ki-67 of 80%. She received 6 weeks chemoradiation and then started maintenance temozolomide at 150mg/m2. Temozolomide was increased to 200mg/m2 for cycle 3 maintenance. In March 2024, she presented to the hospital with pain radiating down her legs and saddle anesthesia. MRI lumbar spine showed infiltrating osseous mass at S1 and S2 and bilateral sacral ala with anterior and posterior extraosseous invasion, invading the spinal canal resulting in moderate to severe spinal canal narrowing and compression of the sacral nerve roots. She underwent biopsy of the lesion which showed IDH wildtype metastatic GBM. She also underwent lumbar puncture and cerebrospinal fluid cytology was negative. She experienced pancytopenia limiting chemotherapy options. In April 2024, she underwent PET scan which showed hypermetabolic epidural soft tissue in spinal canal at L5-S1 level, widespread hypermetabolic skeletal lesions, tiny left cervical level 4 lymph node, small hypermetabolic right hilar, aortocaval, left retroperitoneal nodes and a tiny left common iliac node. The incidence of extracranial metastasis is 0.4-2.0% with less than 25 reported cases of bone marrow spread. This is thought to be rare due to the absence of lymphatics within the brain and the limited survival associated with GBM. This metastasis may occur through vascular invasion, perineural spread, lymphatics, direct invasion, or iatrogenic spread into soft tissues.

Preoperative Prediction of Perineural Invasion in Pancreatic Ductal Adenocarcinoma Using Machine Learning Radiomics Based on Contrast-Enhanced CT Imaging.

The objective of the study is to assess the clinical value of machine learning radiomics based on contrast-enhanced computed tomography (CECT) images in preoperative prediction of perineural invasion (PNI) status in pancreatic ductal adenocarcinoma (PDAC). A total of 143 patients with PDAC were enrolled in this retrospective study (training group, n = 100; test group, n = 43). Radiomics features were extracted from CECT images and selected by the Mann-Whitney U-test, Pearson correlation coefficient, and least absolute shrinkage and selection operator (LASSO). The logistic regression (LR), support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and decision tree (DT) algorithms were trained to build radiomics models by radiomic features. Multivariate logistic regression was employed to identify independent predictors and establish clinical models. A combined model was constructed by integrating clinical and radiomics features. Model performances were assessed by receiver operating characteristic curves (ROCs) and decision curve analyses (DCAs). A total of 788 radiomics features were extracted from CECT images, of which 14 were identified as significant through the three-step selection process. Among the machine learning models, the SVM radiomics model exhibited the highest predictive performance in the test group, achieving an area under the curve (AUC) of 0.831, accuracy of 0.698, sensitivity of 0.677, and specificity of 0.750. After logistic regression screening, the clinical model was established using carbohydrate antigen 19-9 (CA199) levels as one independent predictor. In the test group, the clinical model demonstrated an AUC of 0.644, accuracy of 0.744, sensitivity of 0.871, and specificity of 0.417. The combined model showed improved performance compared to both the clinical and radiomics models in the test group, with an AUC of 0.844, accuracy of 0.767, sensitivity of 0.806, and specificity of 0.667. Subsequently, DCA of the combined model indicated optimal clinical value for predicting PNI status. Machine learning radiomics models can accurately predict PNI status in patients with pancreatic ductal adenocarcinoma. The combined model, which incorporates clinical and radiomics features, enhances preoperative diagnostic performance and aids in the selection of treatment methods.

Frequent Occurrence of High-Risk Basal Cell Carcinoma in Xeroderma Pigmentosum: A Histopathological Insight From an Indian Cohort.

Xeroderma pigmentosum (XP) is a genodermatosis, characterized both by premature aging and significantly increased risk of non-melanoma and melanoma skin cancers at an early age. However, limited literature is available on the common histopathological subtypes of basal cell carcinoma (BCC) in these patients. In this ambispective case series, we recruited patients of XP who had either a currently present skin tumor or previously excised one, provided their histopathological sections were available. Cytogenetic analysis was performed in all the patients. The histopathological findings were recorded by two trained dermatopathologists. Of 22 recruited patients with XP, 12 patients had 41 BCCs, and 23 (56.09%) of them showed a high-risk histopathological subtype. Basosquamous carcinoma (10, 24.39%) was the most frequent high-risk tumor followed by infiltrative variant (7, 17.07%). Mixed-histopathological subtypes were noted in six (14.63%) cases, and all of them had a high-risk component. The low-risk subtypes included nodular (n = 17, 41.46%) and superficial BCC (1, 2.43%). Though a deep dermal involvement was seen in 27 (65.85%) lesions, none showed a perineural invasion or necrosis. Three (7.31%) lesions showed ulceration, while 10 (24.39%) showed presence of pigmentation. A frequent occurrence of high-risk basal cell carcinoma was noted in patients with XP-mandating creation of appropriate treatment and follow-up strategies in these patients.

Proteomic biomarkers profiling in Pakistani pancreatic ductal adenocarcinoma population: a retrospective cohort study.

Aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers. Research in various cancers suggests that investigating target biomarkers may provide directions to precision medicine. However, expression of biomarkers varies across different populations. The biomarker profile of Pakistani patients with PDAC remains unexplored.Materials & methods: We conducted a study on 109 patients to analyze a panel of four proteins (KRAS, p53, BRCA1 and APC) using formalin-fixed paraffin-embedded tumor samples. After confirmation of diagnosis and appropriate tumor content, tissues were processed with antibody specific immunohistochemistry experiments. Subsequently, independent microscopic observation was conducted by two pathologists using scoring criteria specific for each antibody.Results: Statistical analysis showed that negative expression of p53 was significantly associated with positive expression of BRCA1 (p=0.000) and APC (p=0.007). The expression of BRCA1 was also found significantly associated with APC (p=0.028). None of the protein showed association with overall survival or patient demographics. Moreover, KRAS expression was shown to be significantly associated with perineural invasion (p=0.005).Conclusion: This is the first study that investigates protein biomarker expression in a large cohort of Pakistani PDAC patients. The findings from the study may provide directions about the population specific biomarkers and targeted therapies for these patients.

Diagnostic value of the flare sign in predicting extracapsular extension in metastatic axillary lymph nodes and nodal status on breast magnetic resonance imaging.

This study aimed to evaluate the diagnostic performance of breast magnetic resonance imaging (MRI) in predicting extracapsular extension (ECE) and axillary nodal status in the axillary metastatic lymph nodes of patients with breast cancer. The preoperative MRI scans of 92 patients with breast cancer and axillary metastases who did not receive neoadjuvant treatment between January 2018 and January 2024 were retrospectively examined. The presence of an increased signal in the axillary fatty tissue surrounding the lymph node (flare sign) on T2-weighted images, irregular nodal contour (shaggy margin), axillary asymmetry (difference in the number and size of lymph nodes compared with the unaffected axilla), loss of the fatty hilum in the most suspicious lymph node, and morphological features on T1-weighted images were assessed. Each dissected axillary lymph node was examined for ECE, and the histopathological results were recorded. Axillary flare sign was significantly associated with the presence of ECE (P < 0.001), number of lymph nodes with ECE (P < 0.001), the presence of ≥4 axillary metastatic lymph nodes (P < 0.001), size of the primary tumor (P = 0.033), lymphovascular invasion in the primary tumor (P < 0.001), and presence of perineural invasion (P = 0.001). The flare sign exhibited 65.7% sensitivity, 96% specificity, 97.8% positive predictive value, 51.1% negative predictive value, and 73.9% accuracy in predicting ECE. Additionally, the receiver operating characteristic curve analysis revealed an area under the curve of 0.808 (95% confidence interval: 0.719-0.898). The flare sign has high performance in predicting ECE and axillary nodal status and is associated with primary tumor aggressiveness, indicating its potential utility in preoperative evaluation. The flare sign on breast MRI may play a crucial role in preoperative planning, surgical decision-making, and axillary status assessment by accurately predicting ECE.

CT-based radiomics model for predicting perineural invasion status in gastric cancer.

Perineural invasion (PNI) is an independent risk factor for poor prognosis in gastric cancer (GC) patients. This study aimed to develop and validate predictive models based on CT imaging and clinical features to predict PNI status in GC patients. This retrospective study included 291 GC patients (229 in the training cohort and 62 in the validation cohort) who underwent gastrectomy between January 2020 and August 2022. The clinical data and preoperative abdominal contrast-enhanced computed tomography (CECT) images were collected. Radiomics features were extracted from the venous phase of CECT images. The intraclass correlation coefficient (ICC), Pearson correlation coefficient, and t-test were applied for radiomics feature selection. The random forest algorithm was used to construct a radiomics signature and calculate the radiomics feature score (Rad-score). A hybrid model was built by aggregating the Rad-score and clinical predictors. The area under the receiver operating characteristic curve (ROC) and decision curve analysis (DCA) were used to evaluate the prediction performance of the radiomics, clinical, and hybrid models. A total of 994 radiomics features were extracted from the venous phase images of each patient. Finally, 5 radiomics features were selected and used to construct a radiomics signature. The hybrid model demonstrated strong predictive ability for PNI, with AUCs of 0.833 (95% CI: 0.779-0.887) and 0.806 (95% CI: 0.628-0.983) in the training and validation cohorts, respectively. The DCA showed that the hybrid model had good clinical utility. We established three models, and the hybrid model that combined the Rad-score and clinical predictors had a high potential for predicting PNI in GC patients.

Spectrum of Gastric Carcinoma in a Tertiary Care Centre with Special Reference to PDL1 and Cyciln D1

Introduction: Gastric carcinoma is the fifth most frequently diagnosed tumor and the fourth leading cause of death. They represent a heterogenous group of tumors with multifactorial etiologies, both environmental and genetic. PD-L1 is a transmembrane protein, and a positive PD-L1 expression in gastric carcinoma may be a predictive biomarker of the response to PD-1/PD-L1 immune checkpoint inhibitors. Cyclin D1 is an important cell cycle regulatory protein and involved in the carcinogenesis of various cancers including gastric cancer. Aims: The aim of this study is to find out the clinicopathological spectrum of gastric carcinoma and to show the immunohistochemical expression of Cyclin D1 and PD-L1 to evaluate their prognostic importance and their therapeutic impact. Study Design: It is an observational cross-sectional study conducted in the Department of Pathology in collaboration with the Department of Surgery, in a tertiary care hospital. Partial and total gastrectomies were selected from January 2021 to July 2022 in a tertiary care hospital. Clinical history was collected in the study proforma. Immunohistochemical staining for Cyclin D1 and PD-L1 was performed. Material and Methods: The clinicopathological parameters like age, gender, histological type, regional lymph node status, lymphovascular invasion, perineural invasion, and pathological stage were compared and correlated with Cyclin D1 and PD-L1 expression. Results: Positive Cyclin D1 and PDL1 expression were found in 50% and 70% cases of gastric carcinoma, respectively. Cyclin D1 expression showed statistically significant correlation with anemia, regional lymph node status, and lymphovascular invasion. PD-L1 and Cyclin D1 expression showed statistically significant association between them (p value-0.0006). Conclusion: Cyclin D1 and PDL1 are important biomarkers in gastric carcinoma. Their contribution towards prediction of progression and prognosis, along with newer therapeutic modalities, is of immense importace in these patients. A statistically significant correlation was found between these two markers.

Immunomorphological specifcity of HER2-low breast cancer

Assessment of tumor infltrating lymphocytes (TiLs) has been recognized as an additional tool for predicting survival in triple negative (TN) and HER2/neu positive (HER2+) subtypes of breast cancer (BC). Recently, BC, including the above-mentioned subtypes and characterized by low/undefined expression of HER2/neu, has been isolated into a separate group, designated HER2-low BC. The relationship between clinical and morphological parameters of HER2-low breast cancer and infiltration by immunocompetent cells, including tumor associated macrophages (TAM), has not been studied to date. The purpose of the study was to identify significant relationships between the level of subpopulations of immunocompetent cells (Tils + TAM) and the clinical and morphological parameters of HER2-low BC.Material and Methods. The study examined the surgical specimens of 33 patients with HER2-low BC. Visual counting of TILs and assessment (IHC) of the level of T-helpers, T-killers, M1 and M2 macrophages were carried out in intratumor sites and the invasive edge of the primary tumor.Results. The study of mastectomy specimens showed that infiltration of Tils (Me=5 [5; 10] %) was observed in all 33 patients. The level of M2 of macrophages was found to be the highest both in the invasive margin and in the intratumor sites (CD163inv: Me=20 [10; 40] %; CD163c: Me=15 [7; 30] %, respectively). In patients with high (≥20 %) levels of M2 macrophages in the invasive margin, there was also a high level of other immunocompetent cells, and perineural invasion was detected significantly more often (р=0.019).Conclusion. A high level of infiltration by M2 macrophages of the invasive margin is combined with the detection of perineural invasion in primary HER2-low breast cancer, which is one of the predictors of a high risk of progression. In combination with other clinical and morphological parameters, the level of M2 macrophages in HER2-low breast cancer may become another factor in predicting disease prognosis.

High α-SMA expression in the tumor stroma is associated with adverse clinical parameters in mismatch repair-proficient colorectal cancers only.

As mismatch repair status confers differential prognosis in colorectal cancers, this study aimed to determine associations of α-smooth muscle actin (α-SMA) protein expression in mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) colorectal tumors with clinicopathologic and prognostic features. Tissue microarrays from patients with colorectal cancer, immunostained with α-SMA, were assessed through digital image analysis. Total (n=962), pMMR (n=782), and dMMR (n=156) stromal H-scores were assessed for associations with clinicopathologic and survival data. Higher α-SMA expression was correlated with pMMR status (P=5.2223×10-8). In the pMMR subgroup, higher α-SMA stromal expression at the tumor periphery was correlated with higher T stage (P=.002), perineural invasion (P=.038), infiltrative tumor edge (P=.01), involved nodal status (P=.036), metastases (P=.013), synchronous metastases (P=.007), recurrence (P=.004), and both 3-year and 5-year survival (P=.018). dMMR tumors showed no significant correlations with α-SMA staining. The findings highlight that immunostaining with α-SMA in pMMR colorectal tumors, especially at the tumor periphery, has the potential to identify patients with adverse prognostic features. Digital assessment of α-SMA may offer improved objectivity, accuracy, economy of time, and risk stratification for management.

Malignant Salivary Gland Neoplasm of the Tongue Base with EWSR1::BEND2 Fusion: An Unusual Case with Literature Review.

Salivary gland malignancies may have overlapping architectural patterns, tumor morphology, and immunohistochemical phenotypes, presenting challenges in precise classification. Molecular phenotyping has become quite useful for providing an additional diagnostic modality, and potential drug targets. Here we reported a young female patient with salivary gland tumor of the tongue base harboring genetic alterations by next generation sequencing (NGS). The morphological, immunohistochemical and molecular features of this case were described, and related literature was reviewed. The tumor showed an epithelial myoepithelial architecture arranged in cords and tubules interwoven with a chondromyxoid stroma, along with perineural invasion and adjacent striated muscle infiltration. Myoepithelial cells were positive for CK5/6, partially positive for P63 and CK7, and sporadically positive for S100. Immunoprofiling revealed a low density of infiltrating lymphocytes and macrophages and the absence of programmed death ligand 1 (PD-L1). Notably, RNA-based NGS showed EWSR1::BEND2 gene fusion in this tumor, and EWSR1 break-apart was confirmed by fluorescence in situ hybridization. This led to a final diagnosis of a minor salivary gland malignancy with EWSR1::BEND2 fusion. Only two other cases of salivary gland tumors with EWSR1::BEND2 fusion had been previously reported, which were also detected via RNA-based NGS. This study emphasized that EWSR1::BEND2 fusion may drive the carcinogenesis in salivary glands neoplasia. In clinic RNA-based NGS could be essential for precise genotyping of EWSR1 fusion in this rare disease.

Endosomal Trafficking Bypassed by the RAB5B-CD109 Interplay Promotes Axonogenesis in KRAS-Mutant Pancreatic Cancer.

Perineural invasion (PNI) represents a unique biological feature associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC), especially in the presence of KRAS mutations. Extracellular vesicle (EV)-packaged circular RNAs (circRNAs) function as essential mediators of tumor microenvironment communication, triggering PDAC cell invasion and distant metastasis. However, the regulatory mechanisms of EV-packaged circRNAs in the PNI of KRAS-mutant PDAC have not yet been elucidated. Herein, a KRASG12D mutation-responsive EV-packaged circRNA, circPNIT, which positively correlated with PNI in PDAC patients is identified. Functionally, KRASG12D PDAC-derived EV-packaged circPNIT promoted axonogenesis and PNI both in vitro and in vivo. Mechanistically, the circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B to the lipid rafts of multivesicular bodies and packaged circPNIT into CD109+ EVs. Subsequently, CD109+ EVs delivered circPNIT to neurons by binding to TRPV1 and facilitating DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating the GFRα1/RET pathway. Importantly, circPNIT-loaded CD109+ EVs are established to dramatically promote PNI in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.

Histopathological Prognostic Factors of Surgically Treated HPV-Associated Oropharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is rising in prevalence and is associated with better survival than HPV-negative OPSCC. In surgically treated HPV-negative OPSCCs, adverse pathologic features such as positive surgical margins, extra-nodal extension (ENE) and perineural invasion are well described to portend worse clinical outcomes. These adverse pathological features, however, are not validated prognostic markers among surgically treated HPV-positive OPSCCs. To that end, we pooled all available evidence to address the prognostic significance of these histologic features. This meta-analysis was performed according to PRISMA guidelines. PubMed, Web of Science and Embase databases were systematically searched for articles evaluating 13 known adverse histopathological prognostic factors of surgically treated HPV-associated OPSCC. Data analysis was done using R v4.0.5. A total of 32 studies (n = 31,535) fulfilled the inclusion criteria. ENE and advanced pT stage were associated with poorer overall survival (OS) [hazard ratio (HR):1.80, 95% confidence interval (CI) [1.59-2.03], p < 0.0001, HR: 3.28, 95% CI [2.20-4.87], p = 0.0025]; disease-specific survival (DSS) (HR: 3.14, 95% CI [1.20-8.26], p = 0.0327, HR: 3.49, 95% CI [2.45-4.96], p = 0.0043) and disease-free survival (DFS) (HR: 2.03, 95% CI [1.05-3.94], p = 0.0397, HR: 3.66, 95% CI [2.81-4.77], p = 0.0001) respectively. The presence of lymphovascular invasion (HR: 1.46, 95% CI [1.22-1.75], p = 0.0018) and positive margins (HR: 1.50, 95% CI [1.185-1.899], p = 0.0069) significantly worsen OS. ENE, advanced pT stage, positive margins and lymphovascular invasion were adverse histologic prognostic marker among surgically treated HPV-positive OPSCC. The presence of these factors should be carefully evaluated in order to select the optimal patients for surgical treatment.

Tumor regression after neoadjuvant hormonal therapy in high risk prostate cancer: pathological outcomes from a randomized phase II trial.

High-risk localized prostate cancer (HRLPC) commonly progresses to metastatic disease after local treatment. Neoadjuvant androgen deprivation therapy (nADT) before radical prostatectomy (RP) has recently been suggested to improve early oncological outcomes in HRLPC. We aimed to perform an exploratory analysis of the pathological outcomes from a prospective trial testing nADT before RP. Prospective, single-centered, phase II, randomized trial performed between October 2018 and July 2021. Random assignment (1:1) for nADT modalities: goserelin (10.8mg) plus abiraterone acetate (1000mg/d) plus prednisone (5mg/d), with or without apalutamide (240mg/d) for 12 weeks, followed by RP (within 30 days) and extended lymph node dissection. Baseline clinical and pathological variables were assessed in needle biopsies before nADT. Tumor regression was histologically evaluated in surgical specimens using the residual cancer burden index (RCB). Sixty-two patients reached the surgical phase. Good response (RCB ≤ 0.25cm³) was achieved in 14 patients (22.5%). Overall stage migration rate between baseline status (MRI before nADT) and final status (after surgery) was 27.4%. Late stage detection (high tumor burden, perineural invasion) and altered PTEN/ERG immunostatus showed significant association with poor response in univariate analysis. Higher baseline tumor burden was the only independent factor related to poor response in multivariate analysis. There are subgroups of patients, such as those with low baseline cancer burden and PTEN/ERG wild-type status, more likely to achieve good response with nADT. In the case of long term oncological benefit to be proven, nADT might be an additional therapeutic resource for these patients.

Perineural Invasion in Head and Neck Cutaneous Squamous Cell Carcinoma.

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14-20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets.

Survival Benefits of Postoperative Chemotherapy in Patients With Colorectal Mucinous Adenocarcinoma: An Analysis Utilizing Propensity Score Matching From the Surveillance, Epidemiology, and End Results Database.

This study aimed to investigate the characteristics of patients with colorectal mucinous adenocarcinoma (MAC) who benefit from postoperative chemotherapy (POCT) and to develop effective postoperative survival nomograms for predicting overall survival (OS) in colorectal MAC patients. Data of colorectal MAC patients who underwent surgery from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2020 were collected. Patients were grouped based on POCT, and intergroup analysis was performed using 1:1 propensity score matching (PSM). Kaplan-Meier (K-M) curves were used to compare the prognosis between the 2 groups. Cox analysis was employed to identify factors associated with OS in patients with colorectal MAC who underwent POCT. The variance inflation factor (VIF) and bilateral stepwise regression were used to determine factors included in the model. Additionally, a nomogram was constructed to predict postoperative survival outcomes for patients. The discriminative ability of the nomograms was evaluated using the C-index and calibration curve analysis, the decision curve analysis (DCA) assessed the clinical utility of the nomogram, and the receiver operating characteristic (ROC) curve evaluated the nomograms' performance. This study encompassed 6829 patients with colorectal MAC, among whom 2258 received POCT, and 4571 did not. Whether pre or post PSM, patients in the POCT group consistently exhibited a superior median OS compared to those in the postoperative non-chemotherapy group (P < .0001). For colorectal MAC patients undergoing POCT, OS was correlated with factors such as patient age, carcinoembryonic antigen levels, tumor deposits, perineural invasion (PNI), lymph node examination count, T staging, and Grade staging. Notably, a significant chemotherapy advantage was observed in patients without perineural invasion, those with lymph node examination counts exceeding 12, and patients with moderately differentiated tumors. The overall colorectal MAC patient postoperative OS predictive nomogram demonstrated a C-index of .74, with a calibration curve near the diagonal and a DCA curve indicating positive net benefits. In comparison to TNM staging, the ROC curves of the nomogram at 1 year, 3 years, and 5 years demonstrated superior predictive capabilities (AUC: .80 vs .71, .78 vs .71, .77 vs .70). This study revealed the characteristics of colorectal MAC patients who benefit from POCT and established effective prognostic nomograms, which can aid clinicians in designing personalized treatment plans for individual patients and promote precision medicine.

CT assessment of liver fat fraction and abdominal fat composition can predict postoperative liver metastasis of colorectal cancer

ObjectiveThe aim of this study is to investigate the clinical value of liver fat fraction assessed by CT(CT-LFF) and abdominal fat components. We focus on predicting liver metastasis (LM) after colorectal cancer (CRC) surgery. MethodsClinical and imaging data from 79 patients who underwent radical CRC surgery between January 2019 and December 2021 were retrospectively collected. Semi-automatic software was used to quantify the area of different body tissues at the level of the third lumbar vertebra, and liver fat fraction was calculated based on the CT values. Patients were grouped according to BMI, tumor grade, T stage, N stage, vascular invasion (VI), perineural invasion (PNI), and preoperative levels of CEA and CA199. A multivariate logistic regression model was used to identify independent risk factors for early LM after surgery. The diagnostic performance was assessed using the receiver operating characteristic analysis with 5-fold cross-validation. The Kaplan-Meier method was used to draw survival curves, and Log-Rank test was used for survival analysis. ResultsThe study found that the occurrence of LM after CRC surgery was significantly associated with CA199 positivity, VI, PNI, N1-2 stage, CT-LFF, VAT index (VATI). Multivariate logistic regression analysis showed that CA199 positivity (OR = 7.659), N1-2 stage (OR = 6.394), CT-LFF (OR = 1.271), VATI (OR = 1.043) were independent risk factors for predicting LM after CRC surgery. The multivariate logistic regression model, constructed using these independent risk factors, demonstrated robust predictive performance across 5-fold cross-validations, with an average AUC of 0.898 (95 % CI: 0.828–0.969). Survival analysis showed a significant difference in liver metastasis-free survival rates between the high-risk and low-risk groups (P < 0.001). ConclusionCT-LFF and VATI assessed by CT are independent risk factors for predicting LM after CRC surgery. The multivariate prediction model combining CA199 and N stage shows high predictive performance.