Transforming growth factor beta-1 (TGF-ß1) expression in patients with adenomyosis.

Objective: To compare Transforming growth factor beta-1 (TGF-ß1) expression in patients with and without adenomyosis. Methods: A prospective design was performed including 49 patients submitted to hysterectomy. Immunohistochemistry was performed on anatomopathological samples staged in paraffin blocks from patients with and without adenomyosis. The sample contained 28 adenomyosis cases and 21 controls. Student's t-test and multivariate logistic regression tests were used for statistical analysis. Associations were considered significant at p < 0.05. Results: We found no significant association between adenomyosis and: smoking (p = 0.75), miscarriage (p = 0.29), number of previous pregnancies (p = 0.85), curettage (p = 0.81), pelvic pain (p = 0.72) and myoma (p = 0.15). However, we did find a relationship between adenomyosis and abnormal uterine bleeding (AUB) (p = 0.02) and previous cesarean section (p = 0.02). The mean TGF-ß1 intensity (mean ± SD) in the ectopic endometrium of women with adenomyosis showed no significant association (184.17 ± 9.4 vs.184.66 ± 16.08, p = 0.86) from the topic endometrium of women without adenomyosis. Conclusion: TGF-ß1 expression was not increased in the ectopic endometrium of women with adenomyosis.

Clinical review and literature analysis of hepatic epithelioid angiomyolipoma in alcoholic cirrhosis: A case report.

BACKGROUND: Hepatic epithelioid angiomyolipoma (HEA) has a low incidence and both clinical manifestations and imaging lack specificity. Thus, it is easy to misdiagnose HEA as other tumors of the liver, especially in the presence of liver diseases such as hepatitis cirrhosis. This article reviewed the diagnosis and treatment of a patient with HEA and alcoholic cirrhosis, and analyzed the literature, in order to improve the understanding of this disease. CASE SUMMARY: A 67-year-old male patient with a history of alcoholic cirrhosis was admitted due to the discovery of a space-occupying lesion in the liver. Based on the patient's history, laboratory examinations, and imaging examinations, a malignant liver tumor was considered and laparoscopic partial hepatectomy was performed. Postoperative pathology showed HEA. During outpatient follow-up, the patient showed no sign of recurrence. CONCLUSION: HEA is difficult to make a definite diagnosis before surgery. HEA has the potential for malignant degeneration. If conditions permit, surgical treatment is recommended.

Gigantic laryngeal schwannoma: A case report with literature review.

Laryngeal schwannoma is a rare benign nerve sheath tumor that is slow growing. The diagnosis is made from a combination of clinical, radiological, and histopathological findings, and the main method of treatment is resection. We report a case of a 69-year-old presenting with a neck mass causing stridor, dysphagia, and orthopnea. CT of the neck showed an enhancing mass measuring 6.3 cm and extending superior to the larynx. Emergent tracheostomy and mass resection were performed, and histopathology and immunohistochemical findings were obtained from the specimen supporting schwannoma. In conclusion, while rare, schwannoma should always be considered as a differential diagnosis for a laryngeal mass. More studies are needed to assess the size and prognosis of the tumor.

Risk factors associated with tumor upstaging in melanomas treated with Mohs micrographic surgery with melanocytic immunohistochemistry.

Background: Mohs micrographic surgery with melanocytic immunohistochemistry (MMS-I) is increasingly utilized for special site melanoma treatment. Yet, frequency and risk factors associated with upstaging of all-stage cutaneous melanomas treated with MMS-I remain undefined. Objective: Determine upstaging frequency and factors associated with tumor upstaging for all-stage melanomas treated with MMS-I. Methods: In this retrospective, single-center case series, all cases of invasive and in situ melanoma treated with MMS-I between 2008 and 2018 were reviewed. Patient and tumor characteristics were recorded and compared between tumors that were and were not upstaged from their initial T stage. Results: Of the 962 melanoma MMS-I cases identified, 44 (4.6%) were upstaged, including 5.6% of in situ and 2.5% of invasive tumors. Risk factors for upstaging included lack of excisional intent at the time of initial biopsy (P < .01), nonlentigo maligna subtype (P = .03), female sex (P = .02), and initial in situ diagnosis (P = .03). Nonstatistically significant characteristics evaluated included patient age (P = .97), initial Breslow depth (P = .18), and biopsy type (P = .24). Limitations: Retrospective study design. Conclusions: All-stage cutaneous melanomas treated with MMS-I are associated with low upstaging rates. Tumor upstaging is associated with lack of excisional intent, female sex, and in situ tumors.

Spontaneous splenic rupture as the initial symptom of splenic angiosarcoma: case report and literature review.

Spontaneous splenic rupture is an extremely rare occurrence, often attributed to tumorous pathologies. Among these, primary splenic angiosarcoma stands as a malignancy arising from the endothelial cells within the spleen. While sporadic cases have been reported globally, there remains a lack of comprehensive consensus on standardized approaches for diagnosis and treatment. We report a case of an 83-year-old male who underwent emergency enhanced CT due to sudden shock, revealing significant intra-abdominal fluid accumulation. Emergency surgery revealed splenic rupture necessitating splenectomy. Histopathological examination confirmed the diagnosis of splenic angiosarcoma. Despite successful surgery, the patient succumbed to severe complications two weeks postoperatively.

Immunohistochemical evaluation of osteopontin expression in triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is associated with lack of expression of estrogen and progesterone receptors and HER2 and is the subgroup of breast cancers with the worst prognosis. Osteopontin is a phosphorylated glycoprotein whose overexpression may occur in pathological states such as cancers. The main purpose of our study was to evaluate the immunohistochemical expression of osteopontin in connection with the analysis of recognized clinical and pathological prognostic factors in primary sites of TNBC with and without lymph node metastases. Material and methods: The immunohistochemical evaluation of osteopontin expression in 35 women with TNBC, chosen from a group of 726 patients, was performed. The material came from the excisional biopsies of primary breast cancers and total mastectomies. Results: All patients showed expression of osteopontin, in most cases the expression of osteopontin rated at [+] (57.1%) and [++] (42.9%). Our study analyzed the relationship between the expression of osteopontin and traditional prognostic markers, such as the tumor grade, size, and lymph node involvement. We found a strong relationship only between the expression of osteopontin and the presence of lymph node metastases (p ≤ 0.0001). 93% of patients for whom the expression of osteopontin was determined at [++] had metastasis to lymph nodes and, for comparison, only 15% of women for whom the expression of osteopontin was rated at [+] showed the presence of metastases in the lymphatic nodes. Conclusions: There is a correlation between osteopontin expression and the presence of lymph node metastases in TNBC, suggesting that osteopontin plays an important role in the invasiveness of TNBC.

Claudin-18 status and its correlation with HER2 and PD-L1 expression in gastric cancer with peritoneal dissemination.

BACKGROUND: Gastric cancer with peritoneal dissemination (PD) has a dismal prognosis, and current treatments have shown little efficacy. CLDN18.2-targeted therapies have shown promising efficacy against gastric cancers that express high levels of CLDN18. Because of the limited information regarding CLDN18.2 status in PD, we analyzed PD-positive gastric cancers for CLDN18 status in both primary and PD, along with HER2 and PD-L1 combined positive score (CPS). METHODS: Immunohistochemical analyses were performed on 84 gastric cancer cases using paired primary and PD tissue samples. RESULTS: At 40% cut-off, CLDN18 was positive in 57% (48/84) primary tumors and in 44% (37/84) PDs. At 75% cut-off, 28.6% (24/84) primary tumors and 20.2% (17/84) PDs were CLDN18-positive. The concordance rate between primary tumors and PD was 79.8% at 40% cut-off and 75% at 75% cut-off. When comparing biopsy and surgical specimens, the concordance rates were 87.5% at 40% cut-off and 81.3% at 75% cut-off. Within a tumor, the superficial area tended to have a higher CLDN18-positive rate than the invasive front (P = 0.001). Although HER2 -positivity was only 11.9% in this cohort, CLDN18 positivity in HER2-negative tumors (n = 74) was relatively high: 60.8% at 40% cut-off and 28.4% at 75% cut-off. Among double-negative (HER2 - and PD-L1 CPS < 1) tumors, CLDN18 positivity was 67.6% at 40% cut-off and 26.5% at 75% cut-off. CONCLUSIONS: CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer.

Hepatic Epithelioid Hemangioendothelioma in a Dog.

A 5-year-old spayed female Breton dog was referred for a thyroid nodule. A total body CT scan evidenced multifocal hepatic nodules. Cytological liver samples were hemodiluted and non-diagnostic. Following a thyroidectomy, the histology was consistent with a follicular-compact thyroid carcinoma. On laparoscopy, most hepatic lobes had multifocal dark-red nodules that were biopsied for histology. Microscopically, the hepatic parenchyma in the nodules was substituted by blood channels lined by bland spindle cells but adjacent to epithelioid neoplastic cells, single or in clusters, embedded in a moderate amount of edematous collagen matrix. These cells had optically empty cytoplasmic space, occasionally containing erythrocytes (microlumina). Spindle and epithelioid cells expressed membranous-to-cytoplasmic CD31 and FVIII-RA consistent with endothelial origin. Based on morphology and immunolabelling, a hemangioendothelioma with epithelioid differentiation was diagnosed. Lesions in the liver were initially stable, showing progression with time. The dog was alive with no systemic clinical signs 36 months after laparoscopy.

Primary Cardiac Intimal Sarcoma: Multi-Layered Strategy and Core Role of MDM2 Amplification/Co-Amplification and MDM2 Immunostaining.

Primary cardiac tumours are relatively uncommon (75% are benign). Across the other 25%, representing malignant neoplasia, sarcomas account for 75-95%, and primary cardiac intimal sarcoma (PCIS) is one of the rarest findings. We aimed to present a comprehensive review and practical considerations from a multidisciplinary perspective with regard to the most recent published data in the specific domain of PCIS. We covered the issues of awareness amid daily practice clinical presentation to ultra-qualified management in order to achieve an adequate diagnosis and prompt intervention, also emphasizing the core role of MDM2 immunostaining and MDM2 genetic analysis. An additional base for practical points was provided by a novel on-point clinical vignette with MDM2-positive status. According to our methods (PubMed database search of full-length, English publications from January 2021 to March 2023), we identified three studies and 23 single case reports represented by 22 adults (male-to-female ratio of 1.2; male population with an average age of 53.75 years, range: 35-81; woman mean age of 55.5 years, range: 34-70) and a 4-year-old child. The tumour-related clinical picture was recognized in a matter of one day to ten months on first admission. These non-specific data (with a very low index of suspicion) included heart failure at least NYHA class II, mitral regurgitation and pulmonary hypertension, acute myocardial infarction, ischemic stroke, obstructive shock, and paroxysmal atrial fibrillation. Awareness might come from other complaints such as (most common) dyspnoea, palpitation, chest pressure, cough, asthenia, sudden fatigue, weakness, malaise, anorexia, weight loss, headache, hyperhidrosis, night sweats, and epigastric pain. Two individuals were initially misdiagnosed as having endocarditis. A history of prior treated non-cardiac malignancy was registered in 3/23 subjects. Distant metastasis as the first step of detection (n = 2/23; specifically, brain and intestinal) or during follow-up (n = 6/23; namely, intestinal, brain and bone, in two cases for each, and adrenal) required additional imagery tools (26% of the patients had distant metastasis). Transoesophageal echocardiography, computed tomography (CT), magnetic resonance imagery, and even 18F-FDG positronic emission tomography-CT (which shows hypermetabolic lesions in PCIS) represent the basis of multimodal tools of investigation. Tumour size varied from 3 cm to ≥9 cm (average largest diameter of 5.5 cm). The most frequent sites were the left atrium followed by the right ventricle and the right atrium. Post-operatory histological confirmation was provided in 20/23 cases and, upon tumour biopsy, in 3/23 of them. The post-surgery maximum free-disease interval was 8 years, the fatal outcome was at the earliest two weeks since initial admission. MDM2 analysis was provided in 7/23 subjects in terms of MDM2-positive status (two out of three subjects) at immunohistochemistry and MDM2 amplification (four out of five subjects) at genetic analysis. Additionally, another three studies addressed PCISs, and two of them offered specific MDM2/MDM2 assays (n = 35 patients with PCISs); among the provided data, we mention that one cohort (n = 20) identified a rate of 55% with regard to MDM2 amplification in intimal sarcomas, and this correlated with a myxoid pattern; another cohort (n = 15) showed that MDM2-positive had a better prognostic than MDM2-negative immunostaining. To summarize, MDM2 amplification and co-amplification, for example, with MDM4, CDK4, HMGA3, CCND3, PDGFRA, TERT, KIT, CCND3, and HDAC9, might improve the diagnosis of PCIS in addition to MDM2 immunostaining since 10-20% of these tumours are MDM2-negative. Further studies are necessary to highlight MDM2 applicability as a prognostic factor and as an element to be taken into account amid multi-layered management in an otherwise very aggressive malignancy.

CD3 and CD20 Expressions and Infiltrating Patterns in Salivary Gland Tumors.

Tumor-infiltrating lymphocytes (TILs) represent a subset of immunological constituents within the tumor microenvironment that can influence cancer growth. We retrospectively evaluate the density and pattern of CD3 and CD20 expression in salivary gland tumors and their relation to clinical pathologic parameters. A total of 44 formalin-fixed paraffin-embedded blocks of salivary gland tumors were included. These tumors were stained immunohistochemically with CD3 and CD20. The chi-square test was used to relate immune scoring, intensity, and clinical pathological parameters to different salivary tumors. p-value < 0.05 was considered statistically significant. The intra-tumoral CD3 infiltrating count was high and diffused in (71.4%) of pleomorphic adenomas (PAs) followed by mucoepidermoid carcinomas (MECs) (66.7%). At the same time, adenoid cystic carcinomas (AdCCs) exhibited significantly low infiltration (71.4%) (p = 0.046). The three types of tumors exhibited high tumor-infiltrating counts diffused in peripheral areas with significant differences between malignant tumors (p = 0.047). The intra-tumoral CD20 infiltrating count significantly differed among the tumors (p = 0.002); it was low in all PAs and AdCCs, while MECs showed an equal percentage of expression. However, in the peripheral area, PAs and MECs exhibited significantly (p = 0.007) high infiltrating counts (69.2% and 84.6), and the lowest infiltrating count was predominantly found for AdCCs. The two markers had a significant positive correlation between the mean of CD3 in the intra-tumoral and peripheral regions and CD20 in the peripheral zone across the total samples. In conclusion, the density of CD3 expression is notably higher than CD20 across tumor types. PAs and MECs showed high-density scores, while AdCCs were characterized by low scores. TIL expression was found to be significantly associated with patients' outcomes in the intra-tumoral area.

Wild-Type Anaplastic Lymphoma Kinase Expression in Solitary Pulmonary Nodules: A Potential Marker for Primary Lung Squamous Cell Carcinoma in Patients With Previous Neck Squamous Cell Carcinoma.

In patients with a history of head and neck squamous cell carcinoma (HNSCC), distinguishing between primary lung squamous cell carcinoma (LSCC) and pulmonary metastasis of HNSCC is critical when a solitary pulmonary nodule is observed. However, differentiation in clinical practice remains challenging because no golden-standard immunohistochemical (IHC) marker has been established to identify the primary organ of squamous cell carcinoma (SCC). The anaplastic lymphoma kinase (ALK) gene harbors rearrangements in approximately 4-6% of non-small cell lung cancer (NSCLC) cases. The detection of ALK rearrangements is well-established through anti-ALK IHC. While anti-ALK IHC is primarily positive in adenocarcinoma within NSCLC, wild-type ALK without rearrangements is occasionally detected in other histological types, such as SCC. We report two surgical cases with a history of laryngeal cancer that exhibited solitary pulmonary SCC, in which only the lung lesions demonstrated positivity for wild-type ALK through IHC and fluorescence in-situ hybridization method, allowing for the diagnosis of primary LSCC and following postoperative strategy.

CSChighE-cadherinlow immunohistochemistry panel predicts poor prognosis in oral squamous cell carcinoma.

Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1+/CD44+/BMI-1- tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSChighE-cadherinlow (ALDH1highp75NTRhighE-cadherinlow) and CSCintermediateE-cadherinlow (ALDH1 or p75NTRhighE-cadherinlow) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSChighE-cadherinlow at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC.

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer.

Objective: Effective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer. Methods: Ovarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure ("pre-PARPi") and/or after progression on PARPi ("post-PARPi") were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value. Results: In total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0-90) overall, 10 (0-190) in pre-PARPi samples (n = 34), and 25 (1-170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients. Conclusion: RAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.

Decay-Accelerating Factor Differentially Associates With Complement-Mediated Damage in Synovium After Meniscus Tear as Compared to Anterior Cruciate Ligament Injury.

We have reported that anterior cruciate ligament (ACL) injury leads to the differential dysregulation of the complement system in the synovium as compared to meniscus tear (MT) and proposed this as a mechanism for a greater post-injury prevalence of post traumatic osteoarthritis (PTOA). To explore additional roles of complement proteins and regulators, we determined the presence of decay-accelerating factor (DAF), C5b, and membrane attack complexes (MACs, C5b-9) in discarded surgical synovial tissue (DSST) collected during arthroscopic ACL reconstructive surgery, MT-related meniscectomy, osteoarthritis (OA)-related knee replacement surgery and normal controls. Multiplexed immunohistochemistry was used to detect and quantify complement proteins. To explore the involvement of body mass index (BMI), after these 2 injuries, we examined correlations among DAF, C5b, MAC and BMI. Using these approaches, we found that synovial cells after ACL injury expressed a significantly lower level of DAF as compared to MT (p<0.049). In contrast, C5b staining synovial cells were significantly higher after ACL injury (p<0.0009) and in OA DSST (p<0.039) compared to MT. Interestingly, there were significantly positive correlations between DAF & C5b (r=0.75, p<0.018) and DAF & C5b (r=0.64 p<0.022) after ACL injury and MT, respectively. The data support that DAF, which should normally dampen C5b deposition due to its regulatory activities on C3/C5 convertases, does not appear to exhibit that function in inflamed synovia following either ACL injury or MT. Ineffective DAF regulation may be an additional mechanism by which relatively uncontrolled complement activation damages tissue in these injury states.

Cumin (Cuminum cyminum L.) seeds accelerates wound healing in rats: Possible molecular mechanisms.

Wound healing is a complex, intricate, and dynamic process that requires effective therapeutic management. The current study evaluates the wound healing potentials of methanolic extract of Cuminum cyminum L. seeds (CCS) in rats. Sprague Dawley (24) rats were distributed into four cages, wounds produced on the back of the neck, and received two daily topical treatments for 14 days: A, rats received normal saline; B, wounded rats treated with intrasite gel; C and D, rats received 0.2 mL of 250 and 500 mg/kg of CCS, respectively. After that, wound area and closure percentage were evaluated, and wound tissues were dissected for histopathological, immunohistochemical, and biochemical examinations. Acute toxicity trials of methanolic extract of CCS showed the absence of any physiological changes or mortality in rats. CCS application caused a significant reduction in wound size and a statistically elevated percentage of wound contraction than those of vehicle rats. CCS treatment caused significant up-regulation of collagen fiber, fibroblasts, and fewer inflammatory cells (inflammation) in granulation tissues. TGF-ß1 (angiogenetic factor) was significantly more expressed in CCS-treated rats in comparison to normal saline-treated rats; therefore, more fibroblasts transformed into myofibroblasts (angiogenesis). CCS-treated rats showed remarkable antioxidant potentials (higher SOD and CAT enzymes) and decreased MDA (lipid peroxidation) levels in their wound tissue homogenates. Hydroxyproline amino acid (collagen) was significantly up-regulated by CCS treatment, which is commonly related to faster wound closure area. The outcomes suggest CCS as a viable new source of pharmaceuticals for wound treatment.

Comprehensive Analysis of the Immunosuppressive Function of Regulatory T Cells in Human Hepatocellular Carcinoma Tissues.

BACKGROUND: Immune-based therapies are commonly employed to combat hepatocellular carcinoma (HCC). However, the presence of immune-regulating elements, especially regulatory T cells (Tregs), can dramatically impact the treatment efficacy. A deeper examination of the immune-regulation mechanisms linked to these inhibitory factors and their impact on HCC patient outcomes is warranted. METHODS: We employed multicolor fluorescence immunohistochemistry (mIHC) to stain Foxp3, cytokeratin, and nuclei on an HCC tissue microarray (TMA). Leveraging liver cancer transcriptome data from TCGA, we built a prognostic model focused on Treg-associated gene sets and represented it with a nomogram. We then sourced liver cancer single-cell RNA sequencing data (GSE140228) from the GEO database, selectively focusing on Treg subsets, and conducted further analyses, including cell-to-cell communication and pseudo-time trajectory examination. RESULTS: Our mIHC results revealed a more substantial presence of Foxp3+Tregs in HCC samples than in adjacent normal tissue samples (P < .001). An increased presence of Foxp3+Tregs in HCC samples correlated with unfavorable patient outcomes (HR = 1.722, 95% CI:1.023-2.899, P = .041). The multi-factorial prognosis model we built from TCGA liver cancer data highlighted Tregs as a standalone risk determinant for predicting outcomes (HR = 3.84, 95% CI:2.52-5.83, P < .001). Re-analyzing the scRNA-seq dataset (GSE140228) showcased distinctive gene expression patterns in Tregs from varying tissues. Interactions between Tregs and other CD4+T cell types were predominantly governed by the CXCL13/CXCR3 signaling pathway. Communication pathways between Tregs and macrophages primarily involved MIF-CD74/CXCR4, LGALS9/CD45, and PTPRC/MRC1. Additionally, macrophages could influence Tregs via HLA-class II and CD4 interactions. CONCLUSION: An elevated presence of Tregs in HCC samples correlated with negative patient outcomes. Elucidating the interplay between Tregs and other immune cells in HCC could provide insights into the modulatory role of Tregs within HCC tissues.

Histone H3 trimethylation on lysine 27 immunostaining pattern in DICER1-associated tumors.

Background: DICER1-associated tumors are heterogeneous and affect several organs. DICER1-associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry. Methods: We explored the H3K27me3 immunostaining pattern in other DICER1-associated tumors. Twelve tumors from eleven patients with confirmed DICER1 mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody. Results: The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of DICER1-associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One DICER1-associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining. Conclusions: H3K27me3 expression is not universally lost in DICER1-associated tumors and thus is not predictive of DICER1 mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to DICER1-associated intracranial sarcoma.

Initial insights into the interaction of antibodies radiolabeled with Lutetium-177 and Actinium-225 with tumor microenvironment in experimental human and canine osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 (225Ac) or beta-emitting Lutetium-177 (177Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS. BASIC PROCEDURES: SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with 177Lu- or 225Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays. MAIN FINDINGS: IHC revealed a reduction in IGF2R-positive OS cells and OS stem cell populations post therapy with 225Ac- and 177Lu-labeled IF3 antibody. Notably, radiolabeled IF3 antibody effectively diminished pro-tumorigenic M2 macrophages, highlighting its therapeutic promise. The study also unveiled varied responses of natural killer (NK) cells and M1 macrophages, shedding light on the intricate TME interplay. Time-dependent increase in γ-H2AX staining in canine Gracie and human OS-33 tumors treated with [177Lu]Lu-IF3 and [225Ac]Ac-IF3 was observed at 24 and 72 h post-RIT. PRINCIPAL CONCLUSIONS: These findings suggest that radiolabeled antibodies offer a hopeful avenue for personalized OS treatment, emphasizing the importance of understanding their impact on the TME and potential synergies with immunotherapy.

Laminin receptor 1 expression in premalignant and malignant squamous lesions of the cervix.

Laminin receptor 1 (LAMR) may have a role in the progression of premalignant squamous epithelial lesions to cervical cancer. Therefore, we aimed to investigate the expression of laminin receptor 1 (LAMR) in normal, premalignant, and malignant tissues of the uterine cervix. Paraffin blocks of 129 specimens with the diagnoses of normal cervical tissue (n = 33), cervical intraepithelial neoplasia (CIN) 1 (n = 30), CIN 2 (n = 14), CIN 3 (n = 28), and squamous cell carcinoma (n = 24) were immunohistochemically stained with LAMR antibody and its expression percentage, pattern, and intensity in these tissues were assessed. Compared to the other groups, the nonstaining with LAMR was highest in low grade squamous intraepithelial lesion (LSIL) (p < 0.0001). LAMR expression, which was positive in less than 50% of cells with weak staining, increased significantly between normal cervical epithelium and high-grade squamous intraepithelial lesion (HSIL) or invasive carcinoma, as well as between LSIL and HSIL (p < 0.0001). Between LSIL and invasive carcinoma, a significant increment was also observed for weak staining in less than 50% of cells (p < 0.001). LAMR expression, which was positive in more than 50% of cells with strong staining, was significantly higher in normal cervical tissue compared to the other groups (p < 0.0001). Disease progression related gradual increment of LAMR expression from normal cervical epithelium or LSIL towards HSIL or cervical cancer reveals that LAMR may play an important role in the transition from premalignant to malignant state in cervical lesions.

Expression of p16 protein in breast cancer.

Breast cancer is the most common cancer and a leading cause of death in women in Saudi Arabia. P16 is a tumour suppressor gene that plays a crucial role in regulating cell cycle. Several studies have investigated the significance of p16 expression in various cancer types. However, the significance of p16 in breast cancer remains controversial and insufficiently studied. The present study aims to examine the association between p16 expression and clinicopathological factors in breast cancer using immunohistochemistry staining. The study utilised 475 prospectively collected tissue samples from 475 women with breast cancer in Saudi Arabia. Nuclear and cytoplasmic immunohistochemical staining of p16 was observed in 338 (71%) of the cases and showed significant direct associations with adverse tumour features, including high tumour grade (p < 0.0001), negative oestrogen receptor/progesterone receptor status (p < 0.001), and lymph node metastasis (p = 0.02). Our study revealed a significant association between p16 protein expression and the established negative prognostic parameters in breast carcinoma including tumour grade, lymph node metastasis, and oestrogen receptor and progesterone receptor status.