Aggressive Tumor Research Articles

High Caveolin-1 mRNA expression in triple-negative breast cancer is associated with an aggressive tumor microenvironment, chemoresistance, and poor clinical outcome.

Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC. CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells. In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression. CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target.

An Update on the Genetic Drivers of Corticotroph Tumorigenesis.

The genetic landscape of corticotroph tumours of the pituitary gland has dramatically changed over the last 10 years. Somatic changes in the USP8 gene account for the most common genetic defect in corticotrophinomas, especially in females, while variants in TP53 or ATRX are associated with a subset of aggressive tumours. Germline defects have also been identified in patients with Cushing's disease: some are well-established (MEN1, CDKN1B, DICER1), while others are rare and could represent coincidences. In this review, we summarise the current knowledge on the genetic drivers of corticotroph tumorigenesis, their molecular consequences, and their impact on the clinical presentation and prognosis.

FDG PET/CT in Staging and Response Evaluation of Primary Urothelial Carcinoma of the Urethra.

Primary urethral urothelial carcinoma is a rare aggressive tumor with a high propensity for local invasion and regional and distal metastases. We describe the usefulness of FDG PET/CT in management of a patient with primary urethral urothelial carcinoma. FDG PET/CT at initial staging showed FDG-avid primary tumor and lymph node metastasis of the left groin, and mild or no activity of the lung metastases due to small size. FDG PET/CT after 4 cycles of chemotherapy showed progression of the primary tumor and lung metastases, partial response of the left inguinal lymphadenopathy, and multiple new sites of FDG-avid metastases.

Evaluation of the Prognostic Role of D-dimer in Egyptian Hepatocellular Carcinoma Patients Undergoing Locoregional Treatment

Abstract Background The blood coagulation function is often abnormal in HCC patients due to hypercoagulatory state, hyperfibrinolytic state, and increased plasma D-dimer. HCC patients treated with locoregional treatment may show changes of D-dimer levels. Several studies explored the validity of D-dimer levels during locoregional treatment in HCC but definitive data are still lacking. Aim of the Work Determination of the efficacy of D-dimer profile as a prognostic marker regarding tumor features, and post interventional response in HCC subjects undergoing TACE or RFA. Patients and Methods The clinical data of 50HCC patients who underwent TACE or RFA in our hospital from October 2021 to June 2022 were collected, including the CBC, CRP Alfa-fetoproteins and plasma d-dimer level 1 week before TACE or RFA(D0), D-dimer level 1 month (D1) and 4 months(D2) after TACE or RFA. Contrast enhanced CT was performed within 1 week before locoregional treatment and was repeated 1month and 4 months after locoregional treatment to assess for treatment efficacy according to the mRECIST criteria based on change in tumor size as measured by CT scan. One month after TACE or RFA, these patients were divided into four groups according to the mRecist criteria: complete response, partial response, stationary disease and progressive disease. D0, D1 and D2 were compared between the 4 groups and the relation between D-dimer level and the efficacy of locoregional treatment was assessed. Results In patients with negative D-dimer before locoregional treatment (D0), there was no significant difference between D0 and D1 (P > 0.05), while patients with elevated pretreatment D-dimer levels (D0), D1 was significantly higher than D0 (P < 0.05) and the D1 is higher than that in patients with negative Do. Progressive rise of D-dimer levels 4months post locoregional treatment (D2) in HCC was associated with tumor progression suggesting aggressive tumor biology and poor outcome(P = 0.02). Conclusion The changes in plasma D-dimer level can be used as a potential prognostic biomarker in predicting the efficacy of locoregional treatment in HCC patients and thus, elevated D-dimer levels pre and post locoregional treatment may serve as predictors of adverse tumor profile and poor outcome.

Shear Wave Elastography in Breast Cancer: Unveiling Correlations With Histopathological Grades and Subtypes.

Objective This study explores the correlation between shear wave elastography (SWE) features and histopathological grades and subtypes in breast cancer, aiming to enhance diagnostic accuracy andpersonalized treatment strategies. Methods The study retrospectively analyzed 59 consecutive women with breast cancer who underwent breast ultrasound with SWE. SWE parameters and histopathologic information, including histological type and grade, were recorded. Qualitative and quantitative SWE findings were analyzed, and B-mode findings wereevaluated. Sociodemographic and clinical factors and B-mode findings were assessed as predictors of elastography stiffness using logistic regression analysis. Results Of the 59 participants diagnosed with breast cancer,invasive ductal carcinoma of no special type (IDC-NST) was predominantly found in 50 (84.7%) cases, followed by invasive medullary carcinoma in 5 (8.5%) cases. The majority of participants belonged to the 50-59 age group, comprising 19 (32.2%) patients. Histopathological grading revealed grade II tumors in 27 (45.8%) cases and grade III tumors in 24 (40.7%) cases. Notably, grade III tumors exhibited higher tissue stiffness compared to grade II tumors. Out of 36 stiff lesions, 30 (83.3%%) were IDC-NST while 3 (8.3%) wereinvasive medullary carcinoma. A significant association was observed between higher histopathological grade (grade III) and increased tissue stiffness (p < 0.05). Furthermore, among participants with stiff lesions, 21 (58.3%) exhibited color defectswhile 4 (23.5%) cases with soft lesions also displayed color defects Conclusion The correlation between SWE findings and histopathological grades and subtypes underscores the potential of SWE as a valuable tool for predicting tumor aggressiveness and characterizing specific subtypes.SWE enhances diagnostic accuracy and complements traditional imaging modalities, holding promise for personalized treatment strategies.

Collision Tumor of the Ovary: Adult Granulosa Cell Tumor and Mesonephric-like Adenocarcinoma.

Collision tumors of the ovaries are rare, with only a few reports in the literature. Adult granulosa cell tumors are a relatively common primary tumor component of previously reported collision tumors. The combination of serous and mucinous tumors with adult granulosa cell tumors has been reported in several cases. On the other hand, mesonephric-like adenocarcinomas are rare neoplasms that commonly arise in the uterine corpus and ovaries. In this report, we present the case of a collision tumor composed of an adult granulosa cell tumor and mesonephric-like adenocarcinoma of the ovary in a 63-year-old woman. The initial magnetic resonance imaging findings showed a cystic mass with an internal hemorrhage, which suggested an adult granulosa cell tumor, and a solid mass with different enhancements. Microscopically, the tumor had two distinct components: An adult granulosa cell tumor and a mesonephric-like adenocarcinoma. Recognizing collision tumors consisting of slow-growing and aggressive tumors may prove beneficial in future diagnostic and treatment strategies.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Immune cells and checkpoints in pancreatic adenocarcinoma: Association with clinical and pathological characteristics.

Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics. Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma. CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated. PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.

Role of the IL-8/CXCR2 axis in promoting vasculogenic mimicry in triple-negative breast cancer through epithelial-mesenchymal transition

Vasculogenic mimicry (VM) &amp;mdash; a phenomenon where tumor cells form de novo vascular networks independent of endothelial cells &amp;mdash; supports the growth of highly aggressive tumors, including triple-negative breast cancer (TNBC). Evidence indicates that the interleukin 8 (IL-8)/CXCR2 axis and epithelial-mesenchymal transition (EMT) independently promote VM in TNBC. This study tested the hypothesis that the IL-8/CXCR2 axis promotes VM via EMT. Tissue samples from 71 female breast cancer cases (age range: 50 &amp;ndash; 55 years), comprising 37 TNBC and 34 non-TNBC cases, were retrieved from the Department of Pathology at the University of Ghana Medical School. Out of the 37 TNBC tissues, 10 expressed either IL-8, CXCR2, or vimentin exclusively; three expressed all three markers; and 14 did not express any of these markers. For the non-TNBC tissues, 31 expressed CXCR2 (alone or co-expression with IL-8 and/or vimentin), 27 co-expressed IL-8 with CXCR2 and/or vimentin, and two expressed all three markers. Notably, 24 of the 37 non-TNBC tissues co-expressed IL-8 and CXCR2. A phi coefficient analysis displayed an inverse relationship between CXCR2 or IL-8 expression and TNBC and a positive correlation between vimentin expression and TNBC. Inhibiting the IL-8/CXCR2 axis with the CXCR2 antagonist SB225002 suppressed VM in MDA-MB-231 breast cancer cells. In addition, inhibiting the IL-8/CXCR2 axis using SB225002 and siRNA-mediated CXCR2 knockdown suppressed EMT by upregulating E-cadherin expression and downregulating N-cadherin and vimentin expression. Our findings suggest that the IL-8/CXCR2 signaling axis promotes VM in TNBC by facilitating EMT. Therefore, therapies targeting IL-8/CXCR2 may be used to suppress EMT and VM in TNBC simultaneously.

Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours.

The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.

A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer.

Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and invivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.

Prospective study of successful autologous dendritic cell therapy in dogs with splenic stage II hemangiosarcoma

Hemangiosarcoma is an aggressive tumour that most frequently occurs in larger, middle-aged dogs of certain breeds. The spleen is the most commonly affected organ. The aim of this prospective therapy study was to evaluate the clinical effect of autologous, monocyte-derived dendritic cell (DC) therapy in canine hemangiosarcoma stage II after splenectomy. Dogs (n=452) diagnosed with splenic hemangiosarcoma that underwent splenectomy were enrolled. Of these, 42 dogs with stage II entered the DC therapy study. The median survival time for the total group of 42 dogs was 203 days. The median survival for the group (n=34) that received the full DC therapy (≥3 vaccines) was 256 days, with a 29 % one-year survival rate and a hazard ratio of 0.30, adjusted to age and bodyweight (P=0.010). We further observed a significant increase in DC yield after each application and demonstrated that DC yield at the beginning of treatment is significantly related to patient survival. While further evidence is needed, we conclude that autologous, monocyte-derived DC therapy is a viable alternative to standard treatment methods of canine splenic stage II hemangiosarcoma.

Primary Ewing sarcoma/primitive neuroectodermal tumors of the kidney: Case series of eight cases from a single center with follow-up details.

We aim to share the experience of a single center in the management of eight cases of renal primitive neuroectodermal tumor (PNET) which are uncommon, aggressive tumors. The objectives were to study the presentation of the disease, the treatment offered and its outcomes, and the comparison of the treatment with published literature. The single-center renal PNET data of all patients were retrospectively reviewed from 2011 to 2022. Renal PNET was seen in eight patients. Minimum follow-up period of 1 year was required. Male-to-female ratio was 7:1. The mean age was 26.5 years. All were locally advanced tumors on presentation. One patient had an inferior vena cava thrombus, one patient had metastases on presentation, and two patients had tumor extending to paranephric space. The diagnosis was made by histopathology supported by immunohistochemistry showing CD99 positivity. All patients were treated with radical nephrectomy, followed by chemotherapy in all and radiotherapy in three patients. Two patients expired at 3½ and 6 years after surgery, the remaining six are alive at a median follow-up period of 34.5 months. Renal PNET is an uncommon renal tumor which is aggressive and requires multimodal therapy for prolonged survival.

Pedunculated Angiomyofibroblastoma of Labia Minora: A Case Report and Review of the Literature

Background: Angiomyofibroblastoma was first described by Fletcher et al. in the year 1992. It is a distinctive benign tumor that most often occurs in the superficial area of the vulva and is rarely reported in men in the inguinoscrotal region. Case Presentation: A 23-year-old female presented with a painless pedunculated labial mass which was initially pea-sized and reached 7 cm in maximum dimension over four months. The case was diagnosed on morphology, IHC and the patient was treated surgically. The interesting feature of the case was the rarity of its incidence at labia minora and pedunculated form and its resemblance to other benign and more aggressive tumours. To the best of our knowledge, the extensive English literature search revealed only seven cases of pedunculated angiomyofibroblastoma at labia majora in middleaged female and one case of labia minora in a young female. Conclusion: The lesion must be differentiated from another benign mesenchymal tumor of vulva which requires extensive surgical management.

Fluorine-18 Prostate-Specific Membrane Antigen–1007 PET/CT vs Multiparametric MRI for Locoregional Staging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) demonstrates overexpression in prostate cancer and correlates with tumor aggressiveness. PSMA positron emission tomography (PET) is superior to conventional imaging for the metastatic staging of prostate cancer per current research but studies of second-generation PSMA PET radioligands for locoregional staging are limited. To determine the accuracy of fluorine-18 PSMA-1007 PET/computed tomography (18F-PSMA-1007 PET/CT) compared to multiparametric magnetic resonance imaging (MRI) in the primary locoregional staging of intermediate-risk and high-risk prostate cancers. The Next Generation Trial was a phase 2 prospective validating paired cohort study assessing the accuracy of 18F-PSMA-1007 PET/CT and MRI for locoregional staging of prostate cancer, with results of histopathologic examination as the reference standard comparator. Radiologists, nuclear medicine physicians, and pathologists were blinded to preoperative clinical, pathology, and imaging data. Patients underwent all imaging studies and radical prostatectomies at 2 tertiary care hospitals in Alberta, Canada. Eligible participants included men with intermediate-risk or high-risk prostate cancer who consented to radical prostatectomy. Participants who underwent radical prostatectomy were included in the final analysis. Patients were recruited between March 2022 and June 2023, and data analysis occurred between July 2023 and December 2023. All participants underwent both 18F-PSMA-1007 PET/CT and MRI within 2 weeks of one another and before radical prostatectomy. The primary outcome was the correct identification of the prostate cancer tumor stage by each imaging test. The secondary outcomes were correct identification of the dominant nodule, laterality, extracapsular extension, and seminal vesical invasion. Of 150 eligible men with prostate cancer, 134 patients ultimately underwent radical prostatectomy (mean [SD] age at prostatectomy, 62.0 [5.7] years). PSMA PET was superior to MRI for the accurate identification of the final pathological tumor stage (61 [45%] vs 38 [28%]; P = .003). PSMA PET was also superior to MRI for the correct identification of the dominant nodule (126 [94%] vs 112 [83%]; P = .01), laterality (86 [64%] vs 60 [44%]; P = .001), and extracapsular extension (100 [75%] vs 84 [63%]; P = .01), but not for seminal vesicle invasion (122 [91%] vs 115 [85%]; P = .07). In this phase 2 prospective validating paired cohort study, 18F-PSMA-1007 PET/CT was superior to MRI for the locoregional staging of prostate cancer. These findings support PSMA PET in the preoperative workflow of intermediate-risk and high-risk tumors.

New ALKBH2 and ALKBH5 inhibitors for treating glioblastoma

PurposeGlioblastoma is an aggressive brain tumor with high mortality and a median survival of about 15 months. Starting from our previous published compound, MV1035 that inhibited migration and invasiveness of glioblastoma U87 cells, and also exhibited a synergic effect in combination with the alkylating agent Temozolomide, we identified new active molecules, with the aim to understand the key motifs responsible for MV1035 activity against the DNA repair protein ALKBH2 and the RNA demethylase ALKBH5. Materials and methodsWe modified the original structure of MV1035, synthesizing new molecules that have been tested through MTT assay, cell-free ALKBH2 assay and cell-free ALKBH5 assay. ResultsWe found that compound 6 is able to reduce the activity of both ALKBH2 and ALKBH5. ConclusionWe obtained important information about the key motifs responsible for the activity of these inhibitors. However, considering the complexity, heterogeneity and plasticity of GBM and GSC cells, the new identified compound will need to be validated in vivo.

Infiltration of Common Myeloid Progenitor (CMP) Cells is Associated With Less Aggressive Tumor Biology, Lower Risk of Brain Metastasis, Better Response to Immunotherapy and Higher Patient Survival in Breast Cancer.

To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME). The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells. Total of 5,176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using xCell algorithm. High group was defined as more than two thirds of CMP score in each cohort. CMP cells consist of 0.07-0.25% of bulk breast tumor cells, more in Estrogen Receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1-0.75%, 0.18-0.33% of immune cells, respectively). CMP cells did not correlate with any of myeloid lineage nor stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with lower risk of brain metastasis and with better survival, particularly in ER+/HER2- . High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration, and cytolytic activity (P<0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively). CMP in BC is inversely associated with cell-proliferation and brain metastasis, better response to immunotherapy and survival. This is the first to report the clinical relevance of CMP infiltration in BC.

Peer-to-peer validation of Ki-67 scoring in a pathology quality circle as a tool to assess interobserver variability: are we better than we thought?

Ki-67, a nuclear protein expressed in all stages of cellular proliferation, is a valuable tool to assess tumor proliferation and has been linked to more aggressive tumor behavior. However, interlaboratory staining heterogeneity and inter-observer variability challenge its reproducibility. Round Robin tests are a suitable tool to standardize and harmonize immunohistochemical and molecular analyses in histopathology. The study investigates the interrater and interlaboratory reproducibility of Ki-67-scoring using both manual and automated approaches. Unstained TMA slides comprising diverse tumor types (breast cancer, neuroendocrine tumors, lymphomas, and head and neck squamous cell carcinoma) were distributed to six pathology laboratories, each employing their routine staining protocols. Manual and automated scoring methods were applied, and interrater and interlaboratory agreement assessed using intraclass correlation coefficients (ICC). The results highlight good-to-excellent reliability overall, with automated scoring demonstrating higher consistency (ICC 0.955) than manual scoring (ICC 0.871). Results were more variable when looking at the individual entities. Reliability remained good for lymphomas (ICC 0.878) and breast cancer (ICC 0.784) and was poor in well-differentiated neuroendocrine tumors (ICC 0.354). This study clearly advocates standardized practices and training to ensure consistency in Ki-67-assessment, and it demonstrates that this can be achieved in a peer-to-peer approach in local quality-circles.

The immunomodulatory ballet of tumour-derived extracellular vesicles and neutrophils orchestrating the dynamic CD73/PD-L1 pathway in cancer.

Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with a 5-year overall survival rate of around 50%, stagnant for decades. A tumour-induced immunosuppressive microenvironment contributes to HNSCC progression, with the adenosine (ADO) pathway and an upregulated expression of inhibitory immune checkpoint regulators playing a key role in this context. The correlation between high neutrophil-to-lymphocyte ratio (NLR) with advanced tumour staging suggests involvement of neutrophils (NØ) in cancer progression. Interestingly, we associated a high NLR with an increased intracellular PD-L1 localization in primary HNSCC samples, potentially mediating more aggressive tumour characteristics and therefore synergistically favouring tumour progression. Still, further research is needed to harness this knowledge for effective treatments and overcome resistance. Since it is hypothesized that the tumour microenvironment (TME) may be influenced by small extracellular vesicles (sEVs) secreted by tumours (TEX), this study aims to investigate the impact of HNSCC-derived TEX on NØ and blockade of ADO receptors as a potential strategy to reverse the pro-tumour phenotype of NØ. UMSCC47-TEX exhibited CD73 enzymatic activity involved in ADO signalling, as well as the immune checkpoint inhibitor PD-L1. Data revealed that TEX induce chemotaxis of NØ and the sustained interaction promotes a shift into a pro-tumour phenotype, dependent on ADO receptors (P1R), increasing CD170high subpopulation, CD73 and PD-L1 expression, followed by an immunosuppressive secretome. Blocking A3R reduced CD73 and PD-L1 expression. Co-culture experiments with HNSCC cells demonstrated that TEX-modulated NØ increase the CD73/PD-L1 axis, through Cyclin D-CDK4/6 signalling. To support these findings, the CAM model with primary tumour was treated with NØ supernatant. Moreover, these NØ promoted an increase in migration, invasion, and reduced cell death. Targeting P1R on NØ, particularly A3R, exhibited potential therapeutic strategy to counteract immunosuppression in HNSCC. Understanding the TEX-mediated crosstalk between tumours and NØ offers insights into immunomodulation for improving cancer therapies.

Clinicopathological Profiles of and Patterns of Recurrence in Triple-Negative Breast Cancer Patients at a Cancer Care Center in Southern India.

Triple-negative breast cancer (TNBC) is characterized by the absence of expression of the estrogen receptor and the progesterone receptor by immunohistochemistry and human epidermal growth factor receptor overexpression absence either by immunohistochemistry or absence of amplification by fluorescence in-situ hybridization. TNBCs tend to have rapid growth when compared to other subtypes of breast cancer. TNBC is associated with higher histologic grade and more advanced disease at presentation. TNBC shows aggressive behavior and a high chance of recurrence. The aim was to analyze the clinicopathological profiles of and recurrence patterns in TNBC patients at our institute where most patients are from rural areas. This retrospective study was done at a tertiary cancer care center in Southern India where most patients come from rural backgrounds. Institutional Ethics Committee approval was obtained before the study. Case files of all breast cancer patients registered and treated at our center from 2014 to 2019 were retrieved from the medical record department and reviewed. Data from patients diagnosed with triple-negative breast cancer were identified and analyzed. Among the 841 breast cancer patients registered in our study, 150 (17.8%) were diagnosed with TNBC. The median age of diagnosis was 47 years. The majority of the patients, 89 (59.3%) presented with T2 tumors, and lymph node involvement was observed in 88 (58.6%) cases. Patient distribution based on cancer stage revealed that 77 (51.3%) had early-stage breast cancer (EBC), 70 (46.6%) had locally advanced breast cancer (LABC), and only three patients were categorized as having metastatic breast cancer (MBC). Modified radical mastectomy (MRM) was the preferred surgical approach in 144 (96%) cases, while only four patients underwent breast-conserving surgery (BCS). Adjuvant chemotherapy was administered to 119 (79.3%) patients, with 30 (20%) receiving both neoadjuvant and adjuvant chemotherapy (NACT/ACT). Among those who underwent NACT/ACT, a pathological complete response was observed in five (16.6%) patients out of 30 patients. The median duration of follow-up was 32.8 months. Among all patients, 36 (24%) experienced recurrence, with seven (19.4%) having local recurrence, 24 (66.6%) developing distant metastases, two patients experiencing both local and distant recurrence, and three patients developing contralateral breast cancer. Additionally, three patients experienced a second primary cancer. The most common sites of metastases were the lungs (14), followed by the bone (seven), the liver (four), and the brain (four). Recurrence rates were notably high within the first one to three years post-diagnosis. The median disease-free survival (DFS) of TNBC patients was estimated to be 65.6 months with no statistically significant difference (p=0.174) between EBC and LABC patients. TNBC is known for its heterogeneity. While it is often regarded as being more responsive to chemotherapy compared to other subtypes of breast cancer, TNBCs tend to behave aggressively, basically due to the underlying aggressive tumor biology. Though there are many treatment options for different subtypes of breast cancer, therapeutic modalities are limited for TNBCs. Aggressive tumor biology with limited treatment options denotes a gap in the development of novel strategies to improve outcomes in this subset of breast cancer patients.