Pathology & Oncology Research最新文献

The establishment of positive and negative controls in immunohistochemistry (IHC) screening for anaplastic lymphoma kinase (ALK) rearrangements is essential in the treatment of lung adenocarcinoma. However, positive control of patient tissue is rare and comes with ethical issues. A novel automated solution for ALK IHC quality control management was investigated by comparison with the established D5F3 antibody on the VENTANA system in 87 lung adenocarcinoma specimens with known ALK status re-analyzed by fluorescence in situ hybridization. The BP6165 concentrated antibody on the LYNX480 PLUS platform demonstrated excellent sensitivity and specificity (98.30% and 100%, respectively) in 87 biopsy specimens. The ALK controls in liquid form (CLFs) applied in an automated way showed a more regular circular shape and better cell distribution than those applied manually. In addition, the novel controls can show changes in the same pattern as tissue controls under different antibody concentrations and antigen retrieval conditions. The automated solution for ALK IHC quality control management provides a convenient solution without the consumption of scarce tissue for IHC testing in day-to-day pathology practice. The availability of standardized protocols for the detection of ALK rearrangements using the BP6165 concentrated antibody on the LYNX480 PLUS platform will expand the number of laboratories that can reliably and consistently determine the eligibility of patients with lung adenocarcinoma for treatment with ALK tyrosine kinase inhibitors.

Introduction: Breast cancer is a leading cause of morbidity and mortality among women. Advances in molecular biology have improved detection and treatment, but conventional histopathological factors remain crucial for prognosis. Tumour budding, defined as clusters of less than 5 tumour cells detached from the main tumour, has been linked to poor prognosis in several cancers. This study explores the association between intra-tumoral budding (ITB) and peripheral tumour budding (PTB) with known prognostic factors in Invasive Breast Carcinoma of no special type (IBC NST).

Materials and methods: This retrospective study analysed 70 cases of IBC NST diagnosed at Kasturba Medical College, Manipal, between January 2020 and December 2021. Tumour budding was classified as high-grade or low-grade based on density, which denotes the number of buds per x20 field. Clinicopathological data, including hormone receptor status, Ki-67 index, lymphovascular invasion (LVI), perineural invasion (PNI), and axillary lymph node involvement, were obtained. Statistical analyses were performed to identify a significant association between tumour budding and these factors. Univariate and multivariate logistic regression analyses were also done to demonstrate the significance of association.

Results: High-grade PTB showed significant associations with LVI (p = 0.046), PNI (p = 0.017), and axillary lymph node involvement (p = 0.021). In contrast, high-grade ITB was only significantly correlated with axillary lymph node involvement (p = 0.044). LVI (p-value = 0.240) and axillary lymph node involvement (p-value = 0.142) did not show any association with PTB on multivariate analysis and PNI (p-value = 0.074) near significant association with PTB). A significant inverse association was observed between PTB and Ki-67 (p = 0.012), which remained significant in univariate and multivariate analysis (p-value = 0.017). No significant associations were found between tumour budding and hormone receptor status or menopausal status.

Conclusion: Peripheral tumour budding (PTB) is significantly associated with several poor prognostic factors in IBC NST, while intra-tumoral budding (ITB) correlates primarily with axillary lymph node involvement. Tumor budding, particularly PTB, could serve as an important prognostic marker in breast cancer. Further research is needed to standardize tumour budding assessment in clinical practice.

Background: Angiogenesis is closely associated with tumor growth and metastasis, and microvascular density (MVD) is currently the clinical standard for evaluating tumor angiogenesis. Thus, the detection of intratumoral MVD is of great significance for understanding disease progression and predicting patient prognosis.

Methods: Tumor tissue sections of 238 patients with lung adenocarcinoma (LUAD) who underwent radical surgery were retrospectively analyzed. Immunohistochemical (IHC) staining was carried out using a CD34 polyclonal antibody to determine intratumoral MVD, and the relationship of CD34-MVD with the clinicopathological characteristics and survival time of LUAD patients was analyzed.

Results: CD34-MVD was associated with tumor size, lymph node metastasis, tumor recurrence, and patient survival status; patients with tumor size ≤3 cm (P = 0.015), negative for lymph node metastasis (P = 0.049), no tumor recurrence (P = 0.021), and survival (P = 0.042) had higher MVD. Survival analysis suggested that patients with high MVD had higher disease-free survival (log-rank P = 0.005) and overall survival (log-rank P = 0.004) compared to patients with low MVD. The Cox proportional hazards model showed that a high MVD (P = 0.022) reduced the risk of postoperative tumor recurrence in patients with LUAD.

Conclusion: Decreased intratumoral CD34 positive microvessels were associated with tumor development in patients with LUAD. CD34-MVD is an independent risk factor affecting postoperative tumor recurrence in patients with LUAD and can be used as a prognostic indicator for this group of patients.

Background and objectives: This study aims to evaluate the correlation between Tumor-Infiltrating Lymphocyte (TIL) levels and Fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) metabolic parameters, including spleen and bone marrow FDG uptake and tumor heterogeneity in non-luminal breast cancers (NLBC), and to elucidate their association with survival outcomes.

Methods: We retrospectively analyzed data from 100 females with stage 2-4 NLBC who underwent pretreatment ¹⁸F-FDG Positron emission tomography-computed tomography (PET/CT). TIL was scored based on Hematoxylin-Eosin-stained specimens and ¹⁸F-FDG PET metabolic parameters, including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), liver, spleen, and bone marrow FDG uptake were calculated. Heterogeneity Index (HI)1, HI2, and HI3 indices were analyzed with FDG metabolic parameters. The association between these factors and overall survival was analyzed using multivariate Cox regression models.

Results: TIL showed weak negative correlations with tumor size, tumor (T), and metastasis (M) stages. No significant correlation was found between TIL levels and overall SUV values. However, in stage 4, TIL correlated positively with liver, spleen, and bone marrow SUV values and negatively with heterogeneity indices (HI2, HI3). Higher tumor size, HI values, and Bone marrow-to-liver ratio (BLR) SUVmean were associated with increased mortality. A TIL cut-off value of <5 was linked to significantly worse survival.

Conclusion: Our study demonstrates a strong connection between TIL, FDG metabolic parameters, and tumor heterogeneity, particularly in advanced NLBC. Although TIL is not generally associated with SUV values, its association with certain metabolic and heterogeneity indices suggests that it is important in influencing survival. Further research involving larger cohorts and diverse breast cancer subtypes is needed to validate these results.

The neurotrophic tyrosine kinase receptor (NTRK) gene family is of rising importance as their fusions are oncogenic, and specific target drugs are available to inhibit the chimera proteins. Pan-TRK antibody, which shows the overexpression of the NTRK1-2-3 genes, is a useful tool to detect tumors with or without NTRK gene alterations, due to high negative predictive value. Though it is well known that pan-TRK immunopositivity is usually not connected to NTRK fusion, the role of other possible genetic alterations is under-researched. In our previous work, we found 3 NTRK1 amplified cases out of 6 cases with recurrent NTRK1 tyrosine kinase domain mutation pair, so we extended our investigation to a larger series to estimate amplification frequency. Pan-TRK immunopositivity was seen in 76 of the 132 dedifferentiated liposarcomas cases, followed by NTRK1-2-3 break-apart FISH tests in 76 pan-TRK positive cases to detect oncogenic fusions or other copy number alterations of these genes. None of the pan-TRK immunopositive dedifferentiated liposarcomas showed absolutely certain sign of fusion, however, 18 (28%) cases showed amplification of one of the genes, 13 had polysomy, 34 were normal, 11 were not evaluable. The extent of pan-TRK immunoreaction showed a positive correlation (p = 0.002) with the NTRK status found by FISH. Analyzing publicly available data from large series of 265 liposarcoma samples consisting of both well-differentiated and dedifferentiated liposarcoma case, 23 (8.6%) cases showed a mutual exclusive amplification of the NTRK genomic loci in a non-preselected, independent patient population indicating that our findings are presented in other cohorts. Our results underline the so far not revealed frequent occurrence of NTRK amplifications which might be important in the TRK inhibition therapy.

Objectives: Spingosine-1-phosphate (S1P) and ceramides are bioactive sphingolipids that influence cancer cell fate. Anti-ceramide antibodies might inhibit the effects of ceramide. The aim of this study was to assess the potential role of circulating S1P and anti-ceramide antibody as biomarkers in non-small cell lung cancer (NSCLC).

Methods: We recruited 66 subjects (34 controls and 32 patients with NSCLC). Patient history and clinical variables were taken from all participants. Venous blood samples were collected to evaluate plasma biomarkers. If bronchoscopy was performed, bronchial washing fluid (BWF) was also analyzed. We measured the levels of S1P and anti-ceramide antibody with ELISA.

Results: S1P levels were significantly higher in the NSCLC group (3770.99 ± 762.29 ng/mL vs. 366.53 ± 249.38 ng/mL, patients with NSCLC vs. controls, respectively, p < 0.001). Anti-ceramide antibody levels were significantly elevated in the NSCLC group (278.70 ± 19.26 ng/mL vs. 178.60 ± 18 ng/mL, patients with NSCLC vs. controls, respectively, p = 0.007). Age or BMI had no significant effect on anti-ceramide antibody or S1P levels. BWF samples had higher levels of anti-ceramide antibody (155.29 ± 27.58 ng/mL vs. 105.87 ± 9.99 ng/mL, patients with NSCLC vs. controls, respectively, p < 0.001). Overall survival (OS) was 13.36 months. OS was not affected by anti-ceramide antibody or S1P levels.

Conclusion: Higher levels of S1P and anti-ceramide antibody were associated with active cancer. These results suggest that sphingolipid alterations might be important features of NSCLC.

Objective: Recently, several non-conventional variants of IBD-associated dysplasia have been described; however, their prevalence in Central-Eastern Europe is unknown. We aimed to perform a retrospective pilot study by re-evaluating several IBD-associated adenocarcinoma cases to survey the incidence of adjacent non-conventional dysplasia and validate that recent North American findings may apply to a European population.

Methods: Retrospectively, 28 randomly chosen cases of IBD-associated adenocarcinomas diagnosed between 2010 and 2022 were re-evaluated. The patient's sex, age (at the diagnosis of IBD and neoplasia), type of IBD, type of specimen [biopsy (n = 8)/surgical specimen (n = 20)], histological type, grade, localisation, stage, disease-free (DFS) and overall survival (OS) were obtained. Statistical analyses were carried out by using Mann-Whitney (continuous variables), Fisher's exact (categorical variables), Kaplan-Meier (DFS/OS curves), and logrank test (survival curves).

Results: Exclusively, conventional dysplasia was observed in 11, and non-conventional dysplasia in 8 patients. Combined conventional and non-conventional dysplasia was detected in 9 patients. Non-conventional dysplasia showing a combination of multiple subtypes was noted in 10 cases. Altogether, 25 non-conventional dysplastic foci were identified, which were diagnosed as hypermucinous (n = 9), goblet cell-deficient (n = 6), serrated not otherwise specified (NOS) (n = 6), and traditional serrated adenoma-like (n = 4). The majority of non-conventional dysplasias were associated with ulcerative colitis (n = 12). Mucinous adenocarcinoma was exclusively associated with non-conventional dysplasia, while medullary carcinoma was only with conventional dysplasias (p = 0.014 and 0.041).

Conclusion: Based on our results, non-conventional dysplasia is common (60%) adjacent to IBD-associated adenocarcinomas in a Central-Eastern European population and may be detected in biopsies. As multiple recent publications reported evidence of a worse prognosis and more common flat morphology compared to conventional dysplasias, their recognition is of great importance, and stricter follow-up with random biopsy samples may be considered.

[This retracts the article DOI: 10.3389/pore.2021.588084.].

Invasive micropapillary carcinoma of the breast is characterized by clusters of cells presenting with inverted polarity. Although the apico-basal polarity is a fundamental property of the epithelium, the biological alterations leading to the inside-out pattern observed in invasive micropapillary carcinoma (IMPC) remain mostly unknown. The regulation of tight junctions in polarity formation and maintenance is acknowledged. By using immunohistochemistry, we have analysed claudin-1, -3, -4, and -7 tight junction proteins expression and their prognostic value on IMPCs and compared them to invasive breast carcinomas of no special type (IBC-NST) tumors. Our cohort consisted of 37 IMPCs, 36 IBC-NST and 9 mixed IMPC/IBC-NST tumors. Two scoring systems were used to quantify protein expression: a 4-tier scoring system and the H-score method. Distant metastasis free survival (DMFS) intervals and overal survival (OS) data were used for prognosis evaluation. The analysed samples were characterized mainly by low or no claudin-1 expression whereas claudins-3, -4 and -7 showed variable positivity. We have found no significant differences in claudin-3 and -4 protein expression between IMPC and IBC-NST groups with either scoring methods, however high claudin-7 expression was found in significantly more IMPCs than IBC-NST tumors according to the H-score system (p = 0.02). The 4-tier scoring method revealed association of claudin-7 expression with molecular tumor subtypes (p = 0.001). IMPC and IBC-NST tumors did not show difference in DMFS (p = 0.70). In the analysis of pure IMPC and IBC-NST tumors, positive/high claudin-4 protein expression was significantly associated with shorter DMFS (p = 0.02/p = 0.008, respectively according to the two scoring methods). Claudin-3 and claudin-7 expression showed no association with DMFS or OS. Changes in epithelial polarity seem not to be related to claudin-1, -3, and -4 expression. Increased claudin-4 expression may have a role in breast cancer progression.

Pancreatic adenocarcinoma is one of the deadliest forms of cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a milestone in the history of KRAS mutant tumors; however, therapeutic resistance limits their efficacy. Thus, new therapeutic options, including combination therapies, are urgently needed. Recently, we have shown that KRAS G12C inhibitors in combination with farnesyl-transferase inhibitors exert synergistic antitumor effects. Here, we provide evidence for the feasibility of this combinational approach to break down resistance in KRAS G12D mutant pancreatic cancer. Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.