Search Results (523)

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase of the cell cycle. Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2− breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The aim of our study was to evaluate patients’ clinical characteristics, the clinical effectiveness of treatment, measured by progression-free survival (PFS), and the safety profile of combined ribociclib (CDK4/6i) and standard endocrine therapy (aromatase inhibitor) as a first-line treatment for patients with HR+/HER2− advanced or metastatic breast cancer at the Clinic of Oncology, University Clinical Centre Nis, Serbia. Methods: In this study, we present a retrospective prospective analysis of all patients with metastatic HR+/HER2− breast cancer treated with a combination of ribociclib and aromatase inhibitors in the first-line treatment of metastatic HR+/HER2− BC between June 2022 and January 2025, with a follow-up completed in October 2025. A total of 132 patients who met the criteria were included. Results: The median progression-free survival (PFS) in the entire group was 30 months, while the 12-, 24-, and 36-month PFS were 82.15%, 72.24%, and 28.75%, respectively. The overall response rate (ORR) was 41.7%, while the clinical benefit rate (CBR) was 89.3%. There was no statistically significant difference in PFS with respect to tumor grade (p = 0.54), Ki 67 level (<20% vs. >20%, p = 0.83), or the type of adjuvant endocrine therapy used (tamoxifen vs. AI) It is important to emphasize that female patients who had not previously received chemotherapy had a better response to ribociclib compared to those who had (33 m vs. 28 m, p = 0.05). Although a numerical difference in PFS was found in patients with bone-only metastases compared to those with metastases in other organs, the difference was not statistically significant (PFS 33 m vs. 30 m, p = 0.27;), and efficacy was consistent across menopausal status groups. The most common adverse effect was neutropenia, occurring in 89.4% of patients, 47.7% of whom presented with grade 3 or 4. As for hepatotoxicity, transaminase increase occurred in 25 patients (18.8%), 5 of whom (3.8%) were grade 3–4, and QTc interval prolongation occurred in 5.3% of patients. Conclusions: The results in terms of PFS and AEs are consistent with those of pivotal studies and real clinical practice data, but a direct comparison is not possible due to differences in patient populations. Ribociclib once again demonstrated efficacy in all patient subgroups and remains the gold standard, alongside ET, for first-line HR+/HER2-negative mBC. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

Prostate cancer remains one of the most common malignancies in men worldwide, with incidence and mortality steadily increasing across diverse populations. While early detection and radical prostatectomy can achieve durable control in a subset of patients, approximately 40% of men will ultimately experience biochemical recurrence often in the absence of clinically detectable disease. Conventional imaging approaches—CT, MRI, and bone scintigraphy—have limited sensitivity for early relapses, frequently leading to delayed diagnosis and suboptimal treatment planning. The discovery of prostate-specific membrane antigen (PSMA) in 1987 and its subsequent clinical translation into positron emission tomography (PET) imaging with [⁶⁸Ga]Ga-PSMA-11 in 2012, followed by U.S. FDA approval in 2020, has transformed the landscape of prostate cancer imaging. PSMA PET has demonstrated superior accuracy over conventional imaging, as highlighted in the landmark proPSMA trial and now serves as the foundation for theranostic approaches that integrate diagnostic imaging with targeted radioligand therapy. The clinical approval of [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®: (lutetium Lu 177 vipivotide tetraxetan, Advanced Accelerator Applications USA, Inc., a Novartis company) has established targeted radioligand therapy as a viable option for men with metastatic castration-resistant prostate cancer, extending survival in patients with limited alternatives. Emerging strategies, including next-generation ligands with improved tumor uptake and altered clearance pathways, as well as the integration of artificial intelligence for imaging quantification, are poised to further refine patient selection, dosimetry, and treatment outcomes. This review highlights the evolution of PSMA-based imaging and therapy, discusses current clinical applications and limitations, and outlines future directions for optimizing theranostic strategies in prostate cancer care. Full article

Background: Ewing sarcoma (ES) is a rare, aggressive small round cell sarcoma (SRCS) that peaks in adolescence. Given its rarity, atypical age or site presentations increase the risk of misclassification. This study examines age-related clinicopathological patterns in molecularly confirmed canonical ES (FET::ETS-fused). Methods: Between 2016 and 2025, 90 tumors diagnosed as ES or Ewing-like SRCSs underwent targeted RNA sequencing and/or EWSR1 break-apart fluorescence in situ hybridization. Patients were stratified into three age groups: 0–18, 19–39, and ≥40 years. Clinical, anatomical, pathological, molecular, and treatment/outcome variables were compared across strata. Results: Canonical ES accounted for 84% (76/90) of SRCSs, dominated by EWSR1::FLI1 (89%). ES comprised 91% of SRCSs in children but declined to 75% in older adults. Tumors arose mainly in bone (63%), with a significant age association (p = 0.016): children and young adults were primarily skeletal (73% and 62%), whereas older adults were predominantly extraskeletal (78%). Renal ES clustered in adults ≥40 years (p = 0.003). Classic histology predominated; atypical patterns were more common in extraskeletal tumors but lacked age specificity. Ewing-like SRCSs (n = 14), with heterogeneous or absent fusions, displayed a broader age distribution—including infants and older adults—and a marked extraskeletal predominance (86%, p = 0.001). Metastatic presentation strongly predicted inferior survival (p = 0.025). Treatment was multimodal, with neoadjuvant chemotherapy more frequent in children (90%, p = 0.029). Conclusions: Age significantly influences anatomic presentation and certain treatment choices in ES, whereas histology and survival remain broadly similar across groups. Age-linked extraskeletal trends reinforce the importance of routine molecular testing, particularly in underreported Middle Eastern populations. Full article

Background/Objectives: Basal cell carcinoma (BCC) is the most common form of skin cancer, typically exhibiting slow growth and limited metastatic potential. However, in rare, long-standing cases, particularly in high-risk facial regions, deep infiltration into structures such as bone may occur. This study aimed to evaluate whether BCC with bone involvement remains a relevant clinical issue, based on three decades of clinical experience, supplemented by a review of the existing literature. Methods: Medical records of patients treated for facial BCC between 1994 and 2025 at a dermatologic surgery department in Lower Silesia were retrospectively reviewed. Among more than 10,000 cases, eight instances of histologically confirmed bone invasion were identified. Clinical and surgical parameters were analyzed, including patient age, tumor size and location, prior treatment and reconstruction method. Relevant literature was incorporated to provide broader clinical context. Results: Patients with bone-invasive BCC were elderly (mean age: 75.3 years, SD: 10.94 years) and lesions were typically large (mean diameter 38.9 mm), most frequently located on the nose and forehead. Many cases lacked previous treatment. Smaller nasal tumors were managed with local flaps, while larger lesions on the forehead and temple required skin grafts. Findings from the literature confirm that bone invasion is rare and usually associated with long-standing tumors in anatomically high-risk areas. Conclusions: Although rare, BCC with bone infiltration remains a clinically relevant phenomenon, particularly in elderly patients with advanced or recurrent tumors. Early diagnosis, complete excision with histologically clear margins, and individualized surgical planning are essential to prevent deep tissue involvement. Imaging should be reserved for cases in which advanced local invasion is clinically suspected. Full article

The C-X-C motif chemokine ligand 10 (CXCL10) is implicated in the progression of osteosarcoma (OS), the most aggressive pediatric bone malignancy. However, its role often presents a profound clinical paradox: although high circulating levels are strongly linked to poor prognosis, its canonical function is to recruit anti-tumor immune cells. This review unravels these contrasting roles by proposing a novel spatiotemporal model. We argue that in the early stages, immune-evading OS cells initiate the formation of a pre-metastatic niche (PMN) in the lungs, creating a localized inflammatory environment that becomes the primary source of elevated circulating CXCL10. As the disease progresses, elevated systemic levels of CXCL10 overwhelm the localized chemokine gradient at the primary tumor site, creating a potent immune decoy that diverts anti-tumor CXCR3+ T cells away from the tumor. The resulting immune desertification permits unchecked tumor growth and an increased metastatic burden. We also discuss the therapeutic implications of this model, proposing that disrupting the chemokine axis offers a roadmap for developing rational, stage-specific therapies to effectively combat metastatic OS. Full article

Background and Clinical Significance: Metastatic breast cancer is a major global health burden, with common metastatic sites including the bones, lungs, liver, and brain. Cardiac metastasis is rare and often clinically silent, leading to underdiagnosis. Recognizing cardiac involvement, even when asymptomatic, is important for understanding the full extent of disease and ensuring optimal patient care. Case Presentation: We report the case of a woman with advanced breast carcinoma who showed no clinical or imaging evidence of cardiac involvement throughout the course of her illness. Following her death from progressive metastatic disease, an autopsy revealed metastatic carcinoma infiltrating the myocardium and epicardium without gross cardiac abnormalities. Histological and immunohistochemical analysis confirmed the tumor’s origin from breast carcinoma. Conclusions: This case illustrates the potential for clinically occult cardiac metastasis in breast cancer and underscores the importance of pathological examination in detecting hidden metastatic sites. The absence of cardiac symptoms or imaging abnormalities highlights the diagnostic challenge of this rare manifestation and the need for greater awareness in managing advanced malignancies. Full article

Prostate cancer (PCa) exhibits a unique propensity to metastasize to bone, where it predominantly generates osteoblastic lesions. The formation of these lesions is a complex and dynamic process driven by reciprocal interactions between tumor cells and the bone microenvironment. Emerging evidence indicates that extracellular vesicles (EVs) play pivotal roles in the establishment of metastatic colonies and disease progression, as well as in local tumor–bone interactions. Through their diverse cargos, including proteins, lipids, and non-coding RNAs, EVs mediate bidirectional communication that regulates osteoclastogenesis, osteoblast activation, and osteocyte function, ultimately reshaping the bone niche to favor tumor growth. Importantly, EVs exhibit dual and context-dependent functions, acting either as promoters or suppressors of malignancy depending on the cellular source and microenvironmental context. These insights highlight EVs not only as mechanistic drivers of PCa bone metastases but also as promising therapeutic targets. Approaches aimed at modulating EV biogenesis, eliminating deleterious EVs, or harnessing EVs as drug delivery vehicles hold significant potential for advancing treatment strategies against PCa bone metastases. Full article

The chest wall represents a complex musculoskeletal structure that provides protection to intrathoracic organs, mechanical support for respiration, and mobility for the upper limbs. Neoplastic diseases of the chest wall encompass a heterogeneous group of benign and malignant lesions, which may be classified as primary—originating from bone, cartilage, muscle, or soft tissue—or secondary, resulting from direct invasion or metastatic spread, most commonly from breast or lung carcinomas. Approximately half of all chest wall tumors are malignant, and their management remains a significant diagnostic and therapeutic challenge. Surgical resection continues to represent the mainstay of curative treatment, with complete en bloc excision and adequate oncologic margins being critical to minimize local recurrence. Advances in reconstructive techniques, including the use of prosthetic materials, biological meshes, and myocutaneous flaps, have markedly improved postoperative stability, respiratory function, and aesthetic outcomes. Optimal management requires a multidisciplinary approach involving thoracic and plastic surgeons, oncologists, and radiotherapists to ensure individualized and comprehensive care. This review summarizes current evidence on the classification, diagnostic evaluation, surgical strategies, and reconstructive options for chest wall tumors, emphasizing recent innovations that have contributed to improved long-term survival and quality of life in affected patients. Full article

Bone metastases remain a leading cause of morbidity and mortality in patients with advanced breast, prostate, and lung cancers. A striking clinical feature of bone metastasis is the ability of disseminated tumor cells (DTCs) to persist in a dormant state for years or even decades before reawakening to drive overt disease. While the molecular and microenvironmental cues that induce and maintain dormancy have been increasingly studied, the mechanisms governing dormancy escape remain poorly defined yet are critical for preventing relapse. In this review, we synthesize emerging evidence on how the bone microenvironment orchestrates the transition of dormant tumor cells into proliferative lesions. We discuss how osteoclast-mediated bone resorption liberates growth factors such as TGF-β and IGF-1, fueling reactivation; how loss of osteoblast-mediated quiescence signals disrupts the endosteal niche; and how bone marrow adipocytes provide metabolic support through lipid transfer and adipokine secretion. We highlight the role of immune surveillance in maintaining dormancy and how immunosuppressive myeloid populations, regulatory T cells, and inflammatory triggers, such as neutrophil extracellular traps, promote escape. Additional emphasis is placed on extracellular matrix remodeling, mechanotransduction, angiogenic switching, and systemic factors, including aging, hormonal changes, and sympathetic nervous system activation. We also review epigenetic and metabolic reprogramming events within dormant cells that enable reactivation. Finally, we evaluate therapeutic strategies to sustain dormancy or prevent reawakening, including osteoclast-targeted therapies, immune-modulating approaches, and epigenetic or metabolic interventions. By integrating these insights, we identify key knowledge gaps and propose future directions to intercept dormancy escape and delay or prevent metastatic relapse in bone. Full article

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor, mainly affecting adolescents and young adults. While lung metastases are common, visceral metastases in the hepatopancreatobiliary system are extremely rare and usually associated with a poor prognosis. The limited diagnostic and therapeutic options for such metastases make the treatment of affected patients difficult. The possibility of very late metastatic onset in high-grade OS highlights the potential need for extended follow-up (FU) beyond established intervals. Methods: This study combines a retrospective analysis of prospectively collected data from the Vienna Bone and Soft Tissue Tumor Registry with a review of the literature of patients with OS and metastases to the hepatopancreatobiliary system. A descriptive statistical analysis is presented for the entire cohort. In addition, publications from scientific databases (PubMed, Embase) were analyzed to evaluate the frequency, diagnosis, therapy, and prognosis of visceral metastasis from both conventional OS and primary extraskeletal osteosarcoma (ESOS). Results: A total of six male patients with conventional OS and metastases in the liver (5) and pancreas (1), with a mean lesion size of 38 mm (range, 10–120), were included. The median age at the time of visceral metastasis was 29 years (mean, 32 years; range, 20–62 years), and the mean interval since initial diagnosis was five years and ten months (range, 9 months–10 years and 9 months). Visceral metastases are very rare in general and usually occur in advanced stages of disease. We identified 51 cases of visceral metastases from conventional OS and 34 cases of ESOS in the hepatopancreatobiliary system in the literature. The metastasis interval was three years (range, 15 months before diagnosis–17 years) at a median age of 27 years (mean, 32 years; range, 10–69 years). Conclusions: Visceral metastases from OS are rare but represent a significant therapeutic challenge. Early, targeted imaging in combination with improved methods for diagnosis confirmation and interdisciplinary treatment strategies may potentially improve the results. This study underlines the importance of early diagnosis and highlights the need for individualized long-term surveillance strategies exceeding ten years, especially in high-grade OS, aiming at early detection of late-onset metastasis. Full article

Background: Adamantinoma is a very rare primary malignant bone tumor. A histopathological grading is still lacking, and as a result, metastatic risk stratification at diagnosis is challenging. Due to this, imaging could play a role in prognosis prediction and treatment strategy assessment. We aimed to evaluate baseline imaging features and their correlation with the development of metastatic disease. Methods: We retrospectively collected clinical (metastatic disease) and radiological data at baseline (Conventional Radiography, CT, MRI) of all consecutive patients with a histopathological diagnosis of adamantinoma at our sarcoma center between 2006 and 2022. Tumor location, dimensions, main radiological pattern (lytic, sclerotic, mixed), Lodwick–Madewell grading, periosteal reaction, multifocality, soft-tissue extraskeletal component, peritumoral edema, peritumoral enhancement, and vascular invasion were analyzed. Associations between the above-mentioned radiological features and metastatic disease at diagnosis or during follow-up were assessed. Results: Twenty-two patients were included (15 [68.2%] women, median age 27 years old, range 7–58 years old). Six out of twenty-two patients (27.3%) developed distant metastases (only two of them were dedifferentiated adamantinoma): two patients (9%) presented with metastatic disease at diagnosis, while four patients developed metastases during follow-up (18.2%). The following radiological features represent a significant risk for metastatic disease (p = 0.01): (i) presence of an extra-skeletal component (Odds Ratio [OR] = 75.40; 95% CI = 3.15–1802.71), (ii) vascular invasion (OR = 121.00; 95% CI = 4.28–3424.73), (iii) diffuse peritumoral edema (OR = 75.40; 95% CI = 3.15–1802.71), (iv) peritumoral enhancement (OR = 84.33; 95% CI = 2.93–2423.26). All other features analyzed were not significantly associated with the onset of distant metastases. Based on these above-mentioned MRI features, we built two risk models for metastatic disease (excluding peritumoral enhancement, which was not available in five patients, to be applicable on unenhanced MRIs): Model (A) = simultaneous presence of two of those three features (2/3) with a sensitivity of 100% (54.07–100%) and a specificity of 93.75% (69.67–99.84%). Model (B) = simultaneous presence of all three features (3/3) with a sensitivity of 83.33% (35.88–99.58%) and a specificity of 100% (74.1–100%). Conclusions: An accurate evaluation of baseline imaging studies (particularly MRI) in patients affected by adamantinoma may significantly aid in prognosis prediction and the selection of high-metastatic-risk patients. For these patients, strict follow-up controls and more aggressive treatments should be suggested after multidisciplinary discussions in sarcoma centers. Full article

Responses to palliative radiotherapy (RT) for metastatic lesions vary among patients, and molecular determinants of radiosensitivity remain unclear. This study investigated genomic features associated with local progression-free survival (LPFS) in metastatic breast cancer patients treated with palliative RT. Forty-four patients who underwent next-generation sequencing of 523 cancer-related genes were retrospectively analyzed. The biologically effective dose (BED) was calculated using an α/β ratio of 3 Gy, and local progression was defined as recurrence or progression within the irradiated field. A total of 60 metastatic lesions, predominantly in bone (68.3%), were evaluated. Higher BED (≥88 Gy) was significantly associated with longer LPFS (p = 0.011). Among 320 detected mutations mapped to 141 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the PI3K–Akt signaling pathway remained an independent predictor in multivariate analysis (p = 0.03). Subgroup analyses demonstrated that patients with Ras, PI3K–Akt, or FoxO pathway mutations derived greater LPFS benefit from high BED, whereas this advantage was confined to wild-type tumors for the PD-L1/PD-1 checkpoint and choline metabolism pathways. These findings suggest that pathway-specific molecular contexts modulate RT response and may inform individualized radiation dose strategies in metastatic breast cancer. Full article

Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development of more effective and safer therapeutic strategies, our recent studies identified Chondroitin Sulfate Proteoglycan (CSPG)4 as a relevant mediator of the malignant behavior of OSA cells. Targeting CSPG4 DNA-based vaccine demonstrated encouraging antitumor activity against OSA. Nevertheless, since single-agent immunotherapies are often constrained by tumor immune escape, the need for rational combinatorial strategies is of utmost importance. In this perspective, we broaden our analysis to include other potentially complementary targets beyond CSPG4, which may contribute to OSA pathogenesis. Among these, the cystine/glutamate antiporter xCT and Toll-like Receptor 2 (TLR2) emerge as particularly promising due to their established role in tumor progression, therapy resistance, and immune modulation. We discuss the contribution of all these molecules in major hallmarks of OSA—(1) proliferative and survival advantages, (2) metastasis and angiogenesis, and (3) immune evasion—and examine potential strategies for their combined targeting. By leveraging knowledge gained from other cancer models and integrating it with the distinct biological and clinical features of OSA, this perspective seeks to outline rational and innovative combinatorial strategies that may overcome current therapeutic limitations and ultimately improve patient outcomes. Full article

Background: Hypereosinophilia, defined as a peripheral blood eosinophil count greater than 1.5 × 10⁹/L, can arise from allergic, infectious, autoimmune, or malignant conditions. In solid tumors, it is rare and most often linked to mucin-secreting carcinomas, while on extremely rare occasions, it accompanies signet ring cell carcinoma, a highly aggressive form of adenocarcinoma. Case Presentation: A 64-year-old woman presented with dyspnea and hypereosinophilia (2.9 × 10⁹/L). She was admitted with suspected eosinophilic pneumonia, but extensive testing was inconclusive. After bone marrow biopsy, her condition deteriorated; histology revealed metastatic signet ring cell carcinoma. PET/CT showed skeletal metastases without apparent local recurrence, although colonoscopy could not be performed to definitively rule it out. Retrospective review uncovered a 2 mm rectal polyp with signet ring cell carcinoma (SRCC) removed two years earlier. Peripheral eosinophilia progressively increased from 0.16 × 10⁹/L ten months earlier to a peak of 4.29 × 10⁹/L one month prior to admission. She died four weeks after discharge. Conclusions: To the best of our knowledge, this case represents one of the smallest reported primary colorectal SRCC lesions (2 mm) presenting with disseminated disease and paraneoplastic hypereosinophilia as the first diagnostic clue. Monitoring peripheral blood eosinophil counts may provide additional insight into disease activity and prognosis in solid tumors. Full article