Metastatic Sites Research Articles

Epithelioid trophoblastic tumor in male patients with germ cell tumor: A clinicopathologic analysis of five cases

Epithelioid trophoblastic tumor (ETT) is an extremely rare chorionic-type neoplasm in the testis, with only seven cases reported in the literature. Here, we report five cases of testicular ETT from a single institution, constituting the largest series of this rare tumor to date. The patients had a mean age of 44 years (range, 20–68 years). Four patients had a previous history of testicular germ cell tumor (GCT) treated with chemotherapy, and they developed ETT in metastatic sites in a mean of 11 years (range, 3–15 years) after the initial diagnosis of testicular GCT. Only one patient had ETT in the testis. Three patients had a normal serum beta–human chorionic gonadotropin (β-hCG) level, and two patients had a level that was slightly elevated, but far below that typically seen in patients with choriocarcinoma. ETT was characterized by a proliferation of intermediate trophoblastic cells with abundant eosinophilic cytoplasm, and the tumors frequently had coagulative necrosis with eosinophilic debris, mimicking keratinizing squamous cell carcinoma. The trophoblastic phenotype of ETT was supported by its immunoreactivity for trophoblastic markers, including GATA-3 (3 of 3 cases tested), α-inhibin (3/4), p63 (3/5), and β-hCG (3/4). ETT was also positive for cytokeratin (4/4) and GCT marker SALL4 (3/3). Despite surgery and chemotherapy, two patients died of disease 17 months after ETT diagnosis, and three patients were alive with metastatic disease at a mean of 20 months (range, 15–28 months). Our results demonstrate that ETT may be an aggressive disease associated with distinct pathologic features and poor clinical outcome.

Comparative Analysis of Concurrent Chemoradiotherapy Versus Chemotherapy Alone as First-Line Palliative Treatments for Advanced Esophageal Squamous Cell Carcinoma.

Background: In advanced-stage esophageal squamous cell carcinoma (ESCC), treatment of both the primary tumor and metastatic sites is imperatively required. Consequently, an optimal treatment modality should effectively control both aspects. Therefore, the benefits of concurrent chemoradiotherapy (CCRT) in cases of advanced-stage ESCC should be evaluated. Methods: This retrospective study compared the efficacy and safety of CCRT versus chemotherapy alone for advanced-stage ESCC patients from January 2012 to December 2023 at a university hospital in Southern Thailand. Survival was assessed using the Kaplan-Meier approach, with comparisons being made by the log-rank test. A p-value of <0.05 indicated statistical significance. Results: From a total of 196 patients with stage IV ESCC, 117 (59.7%) received CCRT, while 79 (40.3%) received chemotherapy alone. The median overall survival (OS) time was 9.04 months for CCRT and 5.79 months for chemotherapy (hazard ratio, HR: 0.58 [0.43-0.78]). CCRT significantly improved OS time in stage IVA patients (HR: 0.52 [0.29-0.93]), but not in stage IVB patients (HR: 0.76 [0.51-1.11]). The median progression-free survival (PFS) time was 6.04 months for CCRT and 3.50 months for chemotherapy (HR 0.48 [0.35-0.65]). The objective response rates (ORRs) were 43.6% and 22.8%, respectively (p = 0.003). Hematological toxicities were more common with CCRT, along with mild cases of treatment-associated pneumonitis and dermatitis. Conclusions: Although palliative chemotherapy is the standard treatment for advanced-stage ESCC, CCRT provides significant benefits for patients with stage IVA ESCC, improving OS, PFS, and ORRs, despite there being a higher incidence of adverse events. Thus, CCRT should be considered for patients with stage IVA ESCC with a good performance status.

Hydrogel-Mediated Jamming of Exosome Communications That Counter Tumor Adaption in the Tumor Immune Microenvironment.

Hypoxia, a common occurrence within solid tumors, can stimulate the dissemination of deceptive tumor exosomes, which function as communicative bridges and orchestrate the recruitment of various supportive cell types for enhanced tumor adaptability in a tumor immune microenvironment. Current nanotechnology provides us intelligent strategies to combat the hypoxic tumor microenvironment. However, once exposed to external stimuli, such as chemotherapy, tumor cells simultaneously release malignant signals to develop tumor migration and immunosuppression, posing challenges to clinical practice. Taking advantage of the membrane-targeting therapeutic strategy, the application of a self-assembled short peptide (PepABS-py), affording hydrogels on tumor cell surfaces, can block exosome dissemination with fiber-like nanostructures and effectively limit the systemic adverse effects of traditional therapeutics. Moreover, PepABS-py can attenuate the hypoxic tumor microenvironment in vivo by carrying an inhibitor of the hypoxic tumor-overexpressed CA IX enzyme, where hypoxia is also a crucial regulator to induce tumor exosomes and mediate intercellular communications within the immune system. Herein, its application on jamming exosome communications can target the T cell-related signaling pathway by regulating microRNAs in exosome cargoes and ultimately enhances CD8+ T cell infiltration and alleviates inflammatory monocytes at metastasis sites. Collectively, with the capability of blocking exosome dissemination, PepABS-py can be applied as a promising tumor membrane-targeting therapeutic tool to counter tumor adaption within an immune microenvironment and further advance traditional chemotherapy.

Histology-Proven Gastrointestinal Metastasis from Nongastrointestinal Malignancies: Experience of This Rare Occurrence in a Single Center

Introduction Lymph nodes, lung, liver, bone, and brain are the commonest metastatic sites for malignancies arising in various body sites. Gastrointestinal (GI) tract is a very uncommon metastatic site and the present study describes the single-center experience of GI metastases from non-GI malignancies. Aims and Objectives To study the spectrum of metastatic tumors to GI tract and elucidate their clinicopathological characteristics. Materials and Methods This was a retrospective study done on cases diagnosed from 2015 to 2023 at our institute. All cases of non-GI malignancies metastatic to hollow GI tract were included. Cases with GI primary, hematological malignancies, cases with exclusive serosal deposits, and direct invasion of a GI organ from an adjacent primary tumor were excluded. Apart from hematoxylin &amp; eosin (H&amp;E)-stained slides, immunohistochemistry findings of these were reviewed. Results Thirty-six patients were histologically proven GI metastases from non-GI malignancies diagnosed during the study period. Most cases were seen in 5th to 7th decade with a significant female preponderance (M:F of 1:8). The commonest metastatic GI sites were small bowel (n = 11), sigmoid colon (n = 9), and rectum (n = 7), followed by stomach (n = 3), appendix (n = 3), gall bladder (n = 2), and ampulla (n = 1). Stricture, perforation, and nodular mucosa were the most common endoscopic findings. The most common primary malignancies in females were ovarian serous carcinoma (n =21) followed by squamous cell carcinoma (SCC) of cervix (n = 8). In males, there was no site preference, and the primary sites included prostate, lung, kidney, and oral mucosa. Conclusion The study highlights the rare occurrence of GI metastases from non-GI malignancies. Females are at greater risk of such metastases primarily from ovarian serous carcinoma and cervical SCCs.

Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes.

Breast cancer is the most commonly diagnosed cancer in women, with distant metastasis being the main cause of breast cancer-related deaths. Elucidating the changes in the tumor and immune ecosystems that are associated with metastatic disease is essential to improve understanding and ultimately treatment of metastasis. Here, we developed an in-depth, spatially resolved single-cell atlas of the phenotypic diversity of tumor and immune cells in primary human breast tumors and matched distant metastases, using imaging mass cytometry to analyze a total of 75 unique antibody targets. While the same tumor cell phenotypes were typically present in primary tumors and metastatic sites, suggesting a strong founder effect of the primary tumor, their proportions varied between matched samples. Notably, the metastatic site did not influence tumor phenotype composition, except for the brain. Metastatic sites exhibited a lower number of immune cells overall, but had a higher proportion of myeloid cells as well as exhausted and cytotoxic T cells. Myeloid cells showed distinct tissue-specific compositional signatures and increased presence of potentially matrix remodeling phenotypes in metastatic sites. This analysis of tumor and immune cell phenotypic composition of metastatic breast cancer highlights the heterogeneity of the disease within patients and across distant metastatic sites, indicating myeloid cells as the predominant immune modulators that could potentially be targeted at these sites.

The clinical outcome, pathologic spectrum, and genomic landscape for 454 cases of salivary mucoepidermoid carcinoma

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary tumor. A complete understanding of the high heterogeneity of MEC in histology and genetics would help in accurate diagnosis and treatment. Therefore, We evaluated the clinical features, treatment outcomes, and pathological parameters of 454 MECs and analyzed their genomic features using whole-exome sequencing and whole-transcriptome sequencing. We found that MECs predominantly occurred in females and those in their 4th–5th decades. The parotid gland was the most frequently affected site. All patients underwent complete mass resection with lobectomy; 414 patients were alive without relapse at follow-up, after an average period of 62 months (1–116 months). The disease progressed after initial treatment in 40 patients. The lungs were the most common site of distant metastasis. For classical MECs, histologic gradings of the AFIP, modified Healey, and MSK systems were significantly associated with recurrence and lymph nodal metastasis; these gradings were significantly related to lymph nodal metastasis for the subtypes. Older age, minor salivary gland involvement, clinical symptoms, high TNM stage, high-grade tumor, and improper surgical modality were the main prognostic factors. BAP1 was the most frequently mutated gene in MEC. Mutations in CDKN2A, MET, and TP53 were more frequently found in aggressive tumor phenotypes. MAML2 rearrangement was observed in 42% of patients, and EWSR1 rearrangement in 8%. Specific genetic events (in TP53 and FBXW7) with CRTC1::MAML2 fusion superimposed might be associated with unfavorable prognosis. This study provides new insights into precision therapeutic strategies for MEC.

Treatment indicators and prognostic factors in colorectal neuroendocrine neoplasms and adenocarcinoma with neuroendocrine differentiation: a single center retrospective study.

This study compared survival and metastasis occurrence between colorectal neuroendocrine neoplasms (cNEN) and colorectal adenocarcinoma with neuroendocrine differentiation (cNED) and further explored their prognostic factors and treatment indicators. Patients diagnosed as cNEN and cNED in West China Hospital from January 2009 to December 2020 were enrolled. The diagnosis and metastasis rates were calculated. Univariate and multivariate Cox analyses were conducted for progression-free survival (PFS) in cNEN surgical patients, and generalized linear regression was used for metastatic disease. The study enrolled 435 patients, including 257 neuroendocrine tumors (NET), 52 neuroendocrine carcinomas (NEC), 29 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), and 97 NED patients, of whom 202 received local resection, and 233 received radical resection. Metastasis rates were higher in MiNEN and NEC groups compared to other groups (NED: 28.9%, MiNEN: 58.6%, NEC: 65.4%, NET: 8.6%, p < 0.001). The liver is the main metastatic site in cNEN, whereas cNED metastasized to various sites. For NEC and MiNEN patients, colon location (p = 0.002) and T stage > 2 (p = 0.040) were associated with disease progression separately. Independent risk factors for metastatic NET included tumor grade G2/G3 (p < 0.001), colon location (p = 0.001), size ≥ 1cm (p = 0.005), and CK20 partial positive (p < 0.001). cNEN show high metastatic capacity and are challenging to diagnose. More aggressive treatment and follow-up strategies are necessary for those patients. NET tumor grade higher than G2, size larger than 1cm, or located in the colon should be managed with radical surgery.

Gestational Trophoblastic Tumours: Experience of the Oncology Department of the Moulay Ismail Military Hospital in Meknes (10 Cases)

Gestational trophoblastic tumors (GTTs) are the malignant forms of gestational trophoblastic diseases. They always follow a pregnancy, most often molar. The diagnosis of GTT is based on an abnormal course of HCG (chorionic gonadotropin hormone) and/or signs of ultrasound invasion and/or histological confirmation. We report a retrospective series of 10 cases of GTT collected at the Medical Oncology Department of the Moulay Ismail Military Hospital in Meknes over an 8-year period from January 2012 to January 2020. The analysis of our series led to the conclusion that: The average age of onsetis 42 years. 90% of our patients were pauciparic. The causal pregnancy was in 90% of the cases a molar pregnancy. The extension assessment was mainly based on the TAP CT identifying the lung as the main metastatic site in 40% of cases. 5 patients (50% of cases) underwent hysterectomy with post operative chemotherapy. 60% of our patients were classified as low risk according to the FIGO score and received methotrexate mono-chemotherapy. 4 patients were classified as high-risk and were treated with poly chemotherapy, the main protocol of which was EMA-CO. All our patients benefited from clinical and biological monitoring, before each chemotherapy session; then weekly and monthly after negativation, up to 12 months in case of good prognosis GTT, and up to 18 months in case of bad prognosis GTT. One case of MTX relapse (the case of IPTT) was reported and for which a 2nd line CMT with a favourable evolution was indicated. This study allowed us to analyze the cure rate, which was 100% for patients who were treated and had completed their monitoring.

Metastatic tumours to the parotid: A 20-year single institutional experience with an emphasis on 14 unusual presentations

The parotid gland is a rare site for distant metastasis. We aim to provide an overview of metastatic tumours to the parotid over the past 20 years, focusing on clinicopathological analysis of 14 rare diagnoses. To the best of our knowledge, we are the first group to present the most up-to-date and largest case series on unusual metastases to the parotid. A total of 93 metastatic cases were identified from 2004 to 2023, on the pathology information system at North West London Pathology, with squamous cell carcinoma (n = 45, 48.4 %) as the most common primary, followed by malignant melanoma (n = 29, 31.2 %) and Merkel cell carcinoma (n = 4, 4.3 %). We came across 14 rare tumours that had metastasised to the parotid, including metastatic adenocarcinoma from kidney (n = 3, 3.2 %), lung (n = 3, 3.2 %) and breast (n = 1, 1.1 %), olfactory neuroblastoma (n = 3, 3.2 %), soft tissue sarcoma (n = 2, 2.2 %), small cell carcinoma (n = 1, 1,1 %) and hidradenocarcinoma (n = 1, 1.1 %). Half of all secondary neoplastic lesions (50.5 %) were found in intra-parotid nodes, while the other half (49.5 %) were found in parotid parenchyma. Our study offers valuable insights into the various tumour types that can metastasise to the parotid across a wide age range. It underscores the necessity of maintaining a broad differential diagnosis. Keeping an open mind regarding the potential primary sources of the tumour is imperative for accurate diagnosis and effective treatment planning.

Exploring the Frequency and Risk Factors of Hyperprogressive Disease in Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

Hyperprogressive disease (HPD) is described as the unexpected rapid growth of a tumour accompanied by a decline in performance status. While immune checkpoint inhibitors (ICIs) have improved outcomes in advanced melanoma, HPD remains a significant challenge in a subset of patients. Although HPD has been extensively studied in various solid tumours, research specifically focusing on advanced melanoma remains limited. We analysed 158 advanced melanoma patients, with 66.5% (n = 105) receiving anti-PD-1 and 33.5% (n = 53) receiving nivolumab plus ipilimumab. The median overall survival was 4.9 months for patients with HPD compared to 8.9 months for those with progressive disease without HPD (p = 0.014). Factors associated with HPD included liver metastasis (p = 0.002), three or more metastatic sites (p < 0.001), elevated lactate dehydrogenase levels (p = 0.004), and Eastern cooperative oncology group performance status ≥2 (p = 0.023). Multivariate analysis identified the Royal Marsden Hospital score (HR 3.675, 95% CI: 1.166-11.580, p = 0.026) as an independent risk factor for HPD, with the MDA-ICI score also trending towards significance (HR 4.466, 95% CI: 0.947-21.061, p = 0.059). This study provides valuable insights into the frequency and factors associated with HPD in advanced melanoma patients treated with ICIs, highlighting the relevance of clinical markers and scoring systems in predicting HPD risk.

Histone deacetylase upregulation of neuropilin-1 in osteosarcoma is essential for pulmonary metastasis

The lungs represent the most common site of metastasis for osteosarcoma (OS). Despite our advances in developing targeted therapies for treating solid malignancies, broad acting chemotherapies remain the first line treatment for OS. In assaying the efficacy of approved therapeutics for non-OS malignancies, we previously identified the histone deacetylase 1 and 2 (HDAC1 and 2) inhibitor, romidepsin, as effective for the treatment of established lung metastatic OS. Yet, romidepsin has noted toxicities in humans and so here we aimed to define the primary mechanisms through which HDAC1/2 mediate OS progression to identify more selective druggable targets/pathways. Microarray and proteomics analyses of romidepsin treated OS cells revealed a significant suppression of neuropilin-1 (NRP1), a known regulator of cancer cell migration and invasion. Silencing of NRP1 significantly reduced OS proliferation, migration, invasion and adhesion in vitro. More strikingly, in vivo, reduced NRP1 expression significantly mitigated the lung metastatic potential of OS in two independent models (K7M2 and SAOS-LM7). Mechanistically, our data point to NRP1 mediating this effect via the down regulation of migration machinery, namely SRC, FAK and ROCK1 expression/activity, that is in part, related to NRP1 interaction with integrin beta 1 (ITGB1). In summary, our data indicate that romidepsin down regulation of NRP1 significantly mitigates the ability of OS cells to seed the lung and establish metastases, and that targeting NRP1 or its effectors with selective inhibitors may be a viable means with which to prevent this deadly aspect of the disease.

N-linked fucosylated glycans are biomarkers for prostate cancer with a neuroendocrine and metastatic phenotype.

Prostate cancer (PCa) is a heterogeneous disease with a spectrum of pathology and outcomes ranging from indolent to lethal. Although there have been recent advancements in prognostic tissue biomarkers, limitations still exist. We leveraged Matrix Assisted Laser Desorption Ionization (MALDI) imaging of formalin-fixed, paraffin embedded (FFPE) prostate cancer specimens to determine if N-linked glycans expressed in the extracellular matrix of lethal neuroendocrine prostate cancer were also expressed in conventional prostate adenocarcinomas that were associated with poor outcomes. We found that N-glycan fucosylation was abundant in neuroendocrine prostate cancer as well as adenocarcinomas at time of prostatectomy that eventually developed recurrent metastatic disease. Analysis of patient derived xenografts revealed that this fucosylation signature was enriched differently across metastatic disease organ sites, with the highest abundance in liver metastases. These data suggest that N-linked fucosylated glycans could be an early tissue biomarker for poor PCa outcomes. Implications: These studies identify that hyper-fucosylated N-linked glycans are enriched in neuroendocrine prostate cancer and conventional prostate adenocarcinomas that progress to metastatic disease, thus advancing biomarker discovery and providing insights into mechanisms underlying metastatic disease.

Discordance of human epidermal growth factor receptor 2-low status between breast primary and distant metastases with clinical-pathological correlation.

Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in-situ hybridisation (ISH) (HER2-low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical-pathological correlation, with specific interest in HER2-low. Biomarker studies and clinical-pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed. One hundred and forty-seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty-six (86%) were initially classified as 'HER2-negative'; of these, 67 (46%) were reclassified as HER2-low. Patients with HER2-positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2-low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty-nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as 'HER2-negative', and 62 (37%) were reclassified as HER2-low. Like HER2-low primaries, HER2-low metastases were frequently ER-positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2-positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2-low to HER2 0 (33 of 169, 20%), HER2 0 to HER2-low (17 of 169, 10%) and HER2-low to positive (10 of 169, 6%). All HER2-low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2-low to HER2 0 (16 of 47, 34%). A significant proportion of previous 'HER2-negative' primaries and DM cases were reclassified as HER2-low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis.

Renal Oncocytoma: A Systematic Review of Its Metastatic Features.

Oncocytomas are referred to as benign kidney neoplasms. They primarily affect adults, with patients over 70 years old being the most affected. Renal oncocytomas (ROs) are frequently detected by excision, biopsy, or scan. Hematuria, flank pain, and a palpable mass are the traditional trio of symptoms. Oncocytomas appear as well-circumscribed, tanor mahogany-coloured masses with a central scar that is stellate. Histological features include well-circumscribed lesions, bland cytology, eosinophilic cytoplasm, regular nuclei with prominent central nucleoli, and nested architecture. ROs are rarely linked to an aggressive clinical course and have an excellent prognosis. There is proof that the disease can spread to the liver and bones.Some literature has also reported oncocytoma metastases to the lung and liver. This systematic review of the literature examines and evaluates the malignant potential of oncocytoma. The purpose of the study was to determine whether ROs can be diagnosed as a benign condition or if malignancy needs to be considered and investigated. Seventeen studies were analysed which had a total of 412 ROs. Four patients (one percent) died as a result of their illness. There was evidence of disease progression in every patient who passed away from their illness. Six patients (1.5%) experienced disease progression in total. Three hundred and seventeen patients (80%) underwent radical nephrectomy, while 81 patients (20%) underwent partial nephrectomy. Liver, bone, lung, lymphadenopathy, and local recurrence were among the metastasis sites. Perinephric fat invasion, renal sinus fat invasion, renal capsular invasion, and vascular invasion are characteristics of metastatic behavior that have been found. Despite this, the small number of patients who experienced disease progression and/or death as a result of ROs implies that aggressive malignant behavior is not always correlated with the presence of metastatic features or disease. Oncocytomas should be viewed as having a low potential for malignancy rather than as benign. Individuals who exhibit aggressive characteristics, such as vascular invasion and/or perinephric fat invasion, have an atypically good prognosis. Despite advancements in imaging and immunochemical techniques, it is indisputable that ROs, which were first classified as renal tumours in 1976, continue to pose a diagnostic challenge for multidisciplinary teams.There is considerable variation in practice across the globe due to difficulties in confirming ROs, especially when it comes to metastatic disease. There is even more variation in the management of follow-up care that follows. This will remain the MDT's current state until randomised controlled trials, long-term results, and a better comprehension of the behavior of this tumour are obtained.

The Immune Landscape in Brain Metastasis.

The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted and immunotherapy. Thus, there is a high medical need for new therapeutic options. Recent advances employing high-throughput and spatially resolved single-cell analyses have provided unprecedented insights into the composition and phenotypes of the diverse immune cells in the metastatic brain, revealing a unique immune landscape starkly different from that of primary brain tumours or other metastatic sites. This review summarises the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, along with their dynamic interactions with metastatic tumour cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumour-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment. We also review pre-clinical and clinical trials evaluating the therapeutic potential of targeting the immune microenvironment in brain metastasis. Given the substantial evidence highlighting a significant role of the immune microenvironmental niche in brain metastasis pathogenesis, a comprehensive understanding of the key molecular and cellular factors within this niche holds great promise for developing novel therapeutic approaches as well as innovative combinatory treatment strategies for brain metastasis.

Immuno-PET Imaging of EGFR with 64Cu-NOTA Panitumumab in Subcutaneous and Metastatic Nonsmall Cell Lung Cancer Xenografts.

Objective: About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG2 monoclonal antibody panitumumab. The main goal of the present study was to investigate 64Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. Methods: Bifunctional chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of 64Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for in vitro and in vivo experiments. Cell uptake of [64Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [18F]FLT PET. Immuno-PET with [64Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed ex vivo biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. Results: MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [64Cu]CuCl2 was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [64Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein (n = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein (n = 3). PET imaging revealed high uptake of [64Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV)mean reached 4.70 ± 0.42 and 5.37 ± 0.40 (n = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 (n = 4; p < 0.001). In the metastatic model, the following SUVmean were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both n = 16 lesions from 4 mice; p < 0.001) after injection of 1 mg panitumumab. Detailed ex vivo biodistribution confirmed immuno-PET analysis in both models. Panitumumab reduced radioactivity uptake into subcutaneous tumors from 11.01 ± 0.72 (n = 4) to 3.67 ± 0.33% ID/g (n = 5; p < 0.001), and in metastatic liver lesions from 29.44 ± 8.14 (n = 4) to 8.35 ± 1.30% ID/g (n = 5; p < 0.001), respectively. Conclusions: [64Cu]Cu-NOTA-panitumumab was successfully used for immuno-PET imaging of EGFR-expressing subcutaneous and metastatic NSCLC tumors. This result represents the basis for developing radiotheranostics for targeting EGFR in cancers and for selecting the right patients for the right treatment at the right time.

Real-World Clinical Outcomes of Treatment With Olaparib for BRCA1/2 Mutation-Positive Metastatic Breast Cancer in Japanese Patients.

Background Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations. However, real-world data are scarce. Methodology A total of 10 cases from our institute and 17 cases from the relevant Japanese literature were reviewed. All 27 patients had MBC with confirmed deleterious germline BRCA mutations. Tumor reduction, response duration, disease-free interval (DFI), overall survival (OS), and safety were assessed. Additionally, exploratory research was conducted on the characteristics of a subgroup of patients who had a long-term response to olaparib. Results In the 10 cases from two Juntendo hospitals who received olaparib from July 2018 to December 2021, the median age was 48 years (range = 37-63 years). The same numbers of BRCA1 and BRCA2 mutations and the same ratios of luminal and triple negative (TN) breast cancer cases were observed. The metastatic sites, mainly visceral, included the lungs (n = 4), liver (n = 5), and bone (n = 6). The median duration of drug use was four months (range = 1-36 months). The median number of treatment regimens from metastasis to olaparib administration was 2.0 (range = 1-9 regimens). The median DFI was 21 months (range = 0-106 months). The median OS was not reached (range = 16-191 months). In the subgroup analysis of six cases in which olaparib was effective for four months or more, there was a case where DFI was longer than 100 months. Treatment-related toxicities (TRTs) included neutropenia (n = 5; 50%), anemia (n = 4; 40%), thrombocytopenia (n = 2; 20%), nausea (n = 1; 10%), and fatigue (n = 1; 10%). CTCAE (version 5.0) grade ≥3 TRTs included anemia (n = 1; 10%) and neutropenia (n = 5; 50%). On the other hand, neutropenia was previously said to be as low as 27.3%, lower than anemia (40.0%), in a population including various races. We additionally examined another 17 cases from the Japanese literature. Conclusions To our knowledge, this study reports the first real-world data of Japanese patients with MBC and confirmed deleterious germline BRCA mutations. Our data showed that olaparib is effective in the real world. The incidence of neutropenia seemed higher in Japanese patients.

Detection of cardiac neuroendocrine tumour metastases by somatostatin receptor PET/CT: a systematic review and meta-analysis.

Cardiac neuroendocrine tumour metastases (CNTM) are rare, but advancements in molecular imaging including somatostatin receptor PET/CT (SSTR-PET/CT) could lead to a more frequent identification. The aim of this article is to perform a systematic review and meta-analysis on the detection of CNTM by SSTR-PET/CT. A comprehensive literature search of studies on CNTM detected by SSTR-PET/CT was carried out. Three different bibliographic databases were screened (Cochrane library, PubMed/MEDLINE, EMBASE) until 20 August 2024. Two review authors independently selected the eligible original articles and performed the quality assessment and the data extraction. Main findings of eligible studies were summarized and a proportion meta-analysis on the prevalence of patients with CNTM among those with neuroendocrine neoplasm (NEN) performing SSTR-PET/CT was carried out using a random-effects model. Ten articles reporting data on 163 patients with CNTM were included in the systematic review. SSTR was able to detect CNTM earlier compared to other radiological imaging techniques. Most patients with CNTM had other metastatic sites and CNTM were often asymptomatic. The meta-analysis of seven articles demonstrated a pooled prevalence of 1.5% (95% confidence interval: 1.0-1.9%) of patients with CNTM (n = 119) among those performing SSTR-PET/CT for NEN (n = 9,300). Moderate statistical heterogeneity was found (I 2 test: 62%). Evidence-based data demonstrate that SSTR-PET/CT enables early and better detection of CNTM compared to other radiological imaging methods. CNTM are encountered with a pooled prevalence of 1.5% of NEN patients performing SSTR-PET/CT. Prospective and multicentric studies are warranted to better clarify the impact of CNTM detection by SSTR-PET/CT on overall survival and clinical decision-making in NEN patients.

Identification Of Risk Factors Of Bone Metastasis Among Iraqi Breast Cancer Women

Background: The most common site of metastases in people with breast cancer is bone metastasis. Patients with advanced phases of cancer are associated with an increased prevalence of several types of metastases, one of which is bone metastasis. Object: Assessment of the risk factors for bone metastases in patients with breast cancer. Patients and Methods: This is a retrospective study of 316 patients with breast cancer who either had bone metastases at the time of diagnosis or developed it later on. The study was carried out between January 2013 and April 2018. Three hundred and sixteen patients were assigned into two groups. In the case group, 100 patients with breast cancer had been diagnosed with bone metastasis by CT, MRI, bone scan, and PET scan; in the control group, there were 216 cases in are control group with breast cancer metastasis to sites other than bone. The questionnaire was created to record all factors (with the exception of demographic information), such as age, histopathological reading for invasive lobular carcinoma, invasive ductal carcinoma, or another type of cancer, ER status, PR status, Her2neu status, lymph node status and stage, and menopausal status. Results: The majority were 45 years of age or younger, and 96.5% of them had invasive ductal carcinoma in terms of hormonal status. Positive ER and PR status is found in 67.7% and 67.1% of the cases, respectively; 40.5% of the cases had amplified Her2neu receptors, 78.5% of the cases had positive lymph nodes, and 41.9% of the cases had (N1) stage. The highest proportion of bone metastasis was associated with negative ER and PR receptors (46.2% and 49%, respectively), while no significant statistical association (P= 0.65). Conclusion: negative ER, PR status, and Her2neu receptors not amplified, lymph node involvement, age 45 and less, infiltrating lobular carcinoma (ILC) histological type, and menopausal state are significant risk factors for bone metastasis in breast cancer.

Unraveling the metastasis-preventing effect of miR-200c in vitro and in vivo.

Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR-200c) can hamper certain steps of the invasion-metastasis cascade. However, it is still unclear whether miR-200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR-200c expression in MDA-MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR-200c-expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR-200c on collective- and single-cell migration in vitro, utilizing MDA-MB 231 and MCF7 cell systems with genetically modified miR-200c expression. Analysis of collective-cell migration revealed confluence-dependent motility of cells with altered miR-200c expression. Additionally, scratch assays showed an enhanced predisposition of miR-200c-negative cells to leave cell clusters. The in-between stage of collective- and single-cell migration was validated using transwell assays, which showed reduced migration of miR-200c-positive cells. Finally, to measure migration at the single-cell level, a novel assay on dumbbell-shaped micropatterns was performed, which revealed that miR-200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR-200c impedes metastasis formation in vivo and migration in vitro and highlights miR-200c as a metastasis suppressor in breast cancer.