Parotid Metastasis of Early-Stage Upper Eyelid Sebaceous Carcinoma: A Case Presentation and a Literature Review.

Metastasis from early-stage sebaceous carcinoma of the eyelid to the salivary glands is considered very rare, occurring in less than 3% of early-stage patients. We report the case of a 72-year-old Caucasian man with a parotid tumor. Fine needle aspiration was consistent with a salivary duct carcinoma. A subtotal parotidectomy with ipsilateral neck dissection was performed. The pathology report revealed a sebaceous carcinoma with one parotid and two cervical lymph nodes infiltrated. The patient had a history of an early-stage sebaceous carcinoma of the upper eyelid two years before, which was revealed after the histological examination. An early-stage eyelid sebaceous carcinoma can metastasize to lymph nodes of the parotid glands. A close follow-up should not be neglected.

One-step rapid tracking and isolation of senescent cells in cellular systems, tissues, or animal models via GLF16.

Identification and isolation of senescent cells is challenging, rendering their detailed analysis an unmet need. We describe a precise one-step protocol to fluorescently label senescent cells, for flow cytometry and fluorescence microscopy, implementing a fluorophore-conjugated Sudan Black-B analog, GLF16. Also, a micelle-based approach allows identification of senescent cells in vivo and in vitro, enabling live-cell sorting for downstream analyses and live in vivo tracking. Our protocols are applicable to cellular systems, tissues, or animal models where senescence is present. For complete details on the use and execution of this protocol, please refer to Magkouta et al.1.

Horizontal pharyngeal closure during total laryngectomy reduces rates of pharyngocutaneous fistula.

PURPOSE: Pharyngocutaneous fistula (PCF) is a possible complication following total laryngectomy (TL), with a mean incidence of 17%. We intended to investigate the effect of pharyngeal closure type during TL on the prevention of PCF. METHODS: We retrospectively reviewed patients that underwent TL with a horizontal pharyngeal closure over a 10-year period. The frequency of PCF clinically, dysphagia, total oral diet, postoperative dilatation of the neopharynx and voice problems were tabulated. RESULTS: Seventy-seven subjects underwent TL due to laryngeal tumor without pharyngeal extension. Of them, 45 underwent a salvage TL. PCF occurred in 1/77 subjects. The rest of the subjects (76/77) did not develop a PCF, neither in the early nor in the late postoperative phase. All subjects (15/77) that underwent implantation of a voice prosthesis were satisfied with their voice. No subject complained about dysphagia. Every subject achieved total oral diet. CONCLUSION: The horizontal pharyngeal closure is a safe pharyngeal closure technique during TL, reduces PCF rates (< 2%), results in excellent voice rehabilitation and swallowing function, and can also be used during salvage TL instead of a major pectoral flap. This type of closure should be used only in selected patients with laryngeal disease without pharyngeal extension.

Pulsed Electromagnetic Fields (PEMFs) Trigger Cell Death and Senescence in Cancer Cells.

The currently available anti-cancer therapies, such as gamma-radiation and chemotherapeutic agents, induce cell death and cellular senescence not only in cancer cells but also in the adjacent normal tissue. New anti-tumor approaches focus on limiting the side effects on normal cells. In this frame, the potential anti-tumor properties of Pulsed Electromagnetic Fields (PEMFs) through the irradiation of breast cancer epithelial cells (MCF-7 and MDA-MB-231) and normal fibroblasts (FF95) were investigated. PEMFs had a frequency of 8 Hz, full-square wave type and magnetic flux density of 0.011 T and were applied twice daily for 5 days. The data collected showcase that PEMF application decreases the proliferation rate and viability of breast cancer cells while having the opposite effect on normal fibroblasts. Moreover, PEMF irradiation induces cell death and cellular senescence only in breast cancer cells without any effect in the non-cancerous cells. These findings suggest PEMF irradiation as a novel, non-invasive anti-cancer strategy that, when combined with senolytic drugs, may eliminate both cancer and the remaining senescent cells, while simultaneously avoiding the side effects of the current treatments.

Matrix-based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a head and neck cancer (HNC) with a high mortality rate. OSCC is developed in the oral cavity and it is triggered by many etiologic factors and can metastasize both regionally and distantly. Recent research advances in OSCC improved our understanding on the molecular mechanisms involved in and the initiation of OSCC metastasis. The key roles of the extracellular matrix (ECM) in OSCC are an emerging area of intensive research as the ECM macromolecular network is actively involved in events that regulate cellular morphological and functional properties, transcription and cell signaling mechanisms in invasion and metastasis. The provisional matrix that is formed by cancer cells is profoundly different in composition and functions as compared with the matrix of normal tissue. Fibroblasts are mainly responsible for matrix production and remodeling, but in cancer, the tumor matrix in the tumor microenvironment (TME) also originates from cancer cells. Even though extensive research has been conducted on the role of ECM in regulating cancer pathogenesis, its role in modulating OSCC is less elucidated since there are several issues yet to be fully understood. This critical review is focused on recent research as to present and discuss on the involvement of ECM macromolecular effectors (i.e., proteoglycans, integrins, matrix metalloproteinases) in OSCC development and progression.

PTEN Deregulation Mechanisms in Salivary Gland Carcinomas.

Among the tumour suppressor genes that affect critically cell functions and homeostasis, phosphatase and tensin homolog deleted in chromosome 10 (PTEN- gene locus: 10q21) regulates the PI3K/Akt/mTOR signalling pathway. PTEN is deleted, mutated or epigenetically hyper-methylated in a variety of human solid malignancies. Salivary gland carcinomas (SGCs) belong to the head and neck carcinomas (HNCs) super category of solid malignancies. Histo-pathologically, they demonstrate a significant diversity due to a variety of distinct and mixed subtypes. Genetically, they are characterized by a broad spectrum of gene and chromosomal imbalances. Referring specifically to suppressor genes, PTEN deregulation plays a critical role in signaling transduction in the corresponding SGC pre- and malignant epithelia modifying the response rates to potential targeted therapeutic strategies. In the current review, we explored the role of PTEN deregulation mechanisms that are involved in the onset and progression of SGCs.

The Value of the Endoscope-Holding Arm in Transoral Pharyngeal Surgery.

BACKGROUND: Transoral pharyngeal surgery is mainly feasible with the use of a microscope or robotic systems. Data about alternative methods, with lower costs and easier availability, are sparse. We intended to examine to what extent the endoscope-holding arm is a suitable alternative to the microscope or robotic systems. MATERIAL AND METHODS: We retrospectively reviewed subjects who underwent pharyngeal tumor resection with the endoscope-holding arm in our university department. RESULTS: We identified 13 subjects who underwent transoral pharyngeal surgery between November 2020 and November 2023. Most subjects presented with an oropharyngeal tumor (6/11 in the lateral wall or tonsil; 4/11 in the tongue base). The oropharyngeal lateral wall or tonsillar tumors were exposed with a standard mouth gag. The tongue-base tumors or hypopharyngeal tumors were exposed with an operating laryngoscope. Advantages over the microscope included an angled view. Advantages over robotic systems included haptic feedback and a faster setup. Advantages over both the microscope and robotic systems included lower costs and easier availability. Visualization with the endoscope was sufficient and similar to that of the microscope. Bimanual action was possible with surgical forceps and a monopolar electrode. CONCLUSIONS: Transoral pharyngeal surgery was feasible with the endoscope-holding arm. The endoscope-holding arm could be a cost-efficient alternative to the microscope or robotic systems.

The interplay between tumor and nodal microenvironments for the formation of nodal premetastatic niche in head and neck cancer.

Head and neck cancer (HNC) encompasses a number of malignancies originating in the head and neck area. In patients with HNC, cervical lymph nodes constitute metastatic sites for cancer cells that escape primary tumors. The premetastatic niche (PMN) is a crucial concept in understanding metastatic disease. PMN refers to the microenvironment resulting mainly from primary tumor cells to foster metastatic tumor cell growth at a distant organ. Tumor microenvironment (TME) plays an important part in the pathogenesis of PMN. A significant prognostic factor is the close association between metastases of lymph nodes and organ dissemination in many different malignancies. The nodal premetastatic niche (NPMN) is a particular type of PMN located within the lymph nodes. NPMN formation is specifically important in HNC as regional lymph node metastasis commonly occurs. The formation happens when tumor cells create a supportive microenvironment within lymph nodes, facilitating their survival, growth, spread, and invasion. This complex mechanism involves multiple steps and cellular interactions between the primary tumor and tumor microenvironment. Several extracellular matrix (ECM) macromolecules, cytokines, and growth factors are implicated in this process. The aim of this article is to present the most recent data on the regulation of the lymph node PMN at molecular and cellular levels in HNC, as well as insights with respect to the relationship between primary tumor cells and the microenvironment of lymph nodes, and the formation of NPMN. We also critically discuss on potential targets for preventing or disrupting nodal metastases and identify potential biomarkers for predicting HNC outcomes.

Impact of Amplified Oncogenes on Salivary Gland Carcinomas.

In normal epithelia, proto-oncogenes regulate critical intra- or intercellular functions, including cell growth and proliferation, apoptosis, and signaling transduction from the cell periphery (extracellular space) to the nucleus mediated by different pathways. Oncogenes are the mutated or amplified forms of the corresponding proto-oncogenes that are crucially involved in cell neoplastic and malignant transformation during carcinogenesis. Salivary gland carcinomas (SGCs) demonstrate a variety of histogenetic types. They are characterized by a broad spectrum of chromosomal and gene alterations. In particular, amplifications in specific genes [human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Mouse double minute 2 homolog (MDM2), androgen receptor (AR), programmed death (ligand 1 (PD-L1), neurogenic differentiation factor 2 (NEUROD2), phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 protein (PREX1), cyclin-dependent kinase4/6 (CDK4/6), proline-rich acidic protein 1 (PRAP1), kell antigen system (KEL), glutamate receptor subunit epsilon 2 (GRIN2D), Ewing sarcoma RNA-binding protein 1 (EWSR1), MYC proto-oncogene (MYC)] combined or not with chromosomal numerical imbalances (aneuploidy/ polysomy/monosomy) form different genetic signatures affecting the response to monoclonal antibody-based, oncologicaly targeted regimens. Different SGC histotypes demonstrate specific combinations of mutated/amplified genes that modify their clinicohistological features. In the current molecular review, we present the most important amplified oncogenes and their impact on the biological behavior of SGCS.

Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer.

Purpose: We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC). Experimental Design: Forty-one patients with HNSCC were randomized to cisplatin plus olaparib (arm A), olaparib alone (arm B), no treatment (arm C) or durvalumab plus olaparib (arm D). The primary endpoint was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67. Secondary endpoints included objective response rate (ORR), safety, and pathologic complete response (pCR) rate. Paired baseline and resection tumor biopsies and blood samples were evaluated for prespecified biomarkers. Results: A decrease in Ki67 of at least 25% was observed in 44.8% of treated patients, as measured by quantitative immunofluorescence. The ORR among treated patients was 12.1%. pCR was observed in 2 patients. Two serious adverse events occurred in 2 patients.Programmed death ligand 1 (PD-L1) levels [combined positive score (CPS)] were significantly higher after treatment in arms A and D. Expression of CD163 and colony-stimulating factor 1 receptor (CSF1R) genes, markers of M2 macrophages, increased significantly posttreatment whereas the expression of CD80, a marker of M1 macrophages, decreased. Conclusion: Preoperative olaparib with cisplatin or alone or with durvalumab was safe in the preoperative setting and led to decrease in Ki67 of at least 25% in 44.8% of treated patients. Olaparib-based treatment modulates the tumor microenvironment leading to upregulation of PD-L1 and induction of protumor features of macrophages. Significance: HNSCC is characterized by defective DNA repair pathways and immunosuppressive tumor microenvironment. PARP inhibitors, which promote DNA damage and "reset" the inflammatory tumor microenvironment, can establish an effective antitumor response. This phase II WOO trial in HNSCC demonstrated the immunomodulatory effects of PARP inhibitor-induced DNA damage. In this chemo-naïve population, PARP inhibitor-based treatment, reduced tumor cell proliferation and modulated tumor microenvironment. After olaparib upregulation of PD-L1 and macrophages, suggests that combinatorial treatment might be beneficial. Synopsis: Our WOO study demonstrates that preoperative olaparib results in a reduction in Ki67, upregulation of PD-L1 CPS, and induction of protumor features of macrophages in HNSCC.

Mutational Signatures in Salivary Gland Carcinomas.

Salivary gland carcinomas belong to the head and neck carcinoma super category of malignancies. They are characterized by histopathological diversity and comprise a variety of entities and subtypes. Mucoepidermoid, adenoid cystic and salivary duct carcinomas represent the most prominent malignancies. Concerning their corresponding genetic background, a broad spectrum of gene and chromosomal imbalances has been detected. Point mutations and deletions, amplifications and translocations, combined or not with chromosomal aneuploidy/polysomy/monosomy, create a landscape of specific genetic signatures that affect the biological behavior of these tumors and modify response rates to potential targeted therapeutic strategies. In the current molecular review, we focused on the categorization and description of the most important mutational signatures in salivary gland carcinomas.

The Role of Exosomes in Epithelial-to-Mesenchymal Transition and Cell Functional Properties in Head and Neck Cancer.

Exosomes are nanosized vesicles that are produced in normal and cancer cells, promoting intracellular communication. In head and neck cancer (HNC), exosomes are involved in many undesirable events of cancer development and progression, including angiogenesis, tumor microenvironment (TME) remodeling, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, extracellular matrix (ECM) degradation, and drug resistance. Exosomes are involved in altering the signaling pathways in recipient cells by the cargoes they carry. Proteins, lipids, and nucleic acids such as DNA fragments and RNAs (i.e., mRNAs, miRNAs, and long non-coding RNAs) are carried in the exosomes to promote cell communication. EMT is a critical cellular process in which epithelial cells are forced to become mesenchymal cells by the actions of SNAIL/SLUG, TWIST, and ZEB family transcription factors carried in exosomes that facilitate metastasis. In this critical review, we focused on exosome biogenesis, their cargoes, and their involvement in EMT induction and metastasis during HNC. Insights into exosome isolation and characterization, as well as their key role in ECM remodeling and degradation, are also presented and critically discussed. More importantly, this article addresses the role of exosomes in HNC and drug resistance induced in drug-sensitive cancer cells. In addition, exosomes have a great potential to be used as diagnostic and therapeutic tools. A better understanding on exosome biogenesis, composition, and functions in HNC will aid in developing novel therapeutic strategies to treat HNC, overcome therapy resistance, and avoid metastasis, which is a significant cause of cancer death.

Machine learning approaches to predict drug efficacy and toxicity in oncology.

In recent years, there has been a surge of interest in using machine learning algorithms (MLAs) in oncology, particularly for biomedical applications such as drug discovery, drug repurposing, diagnostics, clinical trial design, and pharmaceutical production. MLAs have the potential to provide valuable insights and predictions in these areas by representing both the disease state and the therapeutic agents used to treat it. To fully utilize the capabilities of MLAs in oncology, it is important to understand the fundamental concepts underlying these algorithms and how they can be applied to assess the efficacy and toxicity of therapeutics. In this perspective, we lay out approaches to represent both the disease state and the therapeutic agents used by MLAs to derive novel insights and make relevant predictions.

Anti-EGFR/BRAF-Tyrosine Kinase Inhibitors in Thyroid Carcinoma.

Alterations in significant genes located on chromosome 7 - including epidermal growth factor receptor (EGFR) and also v-Raf murine sarcoma viral oncogene homolog B (BRAF) as a mitogen-activated protein kinase (MAPK)  - combined or not with numerical imbalances of the whole chromosome (aneuploidy-polysomy) are crucial genetic events involved in the development and progression of malignancies. Identification of EGFR/BRAF-dependent specific somatic mutations and other mechanisms of deregulation (i.e., amplification) is critical for applying targeted therapeutic approaches [tyrosine kinase inhibitors (TKIs] or monoclonal antibodies (mAbs). Thyroid carcinoma is a specific pathological entity characterized by a variety of histological sub-types. Follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) represent its main sub-types. In the current review, we explore the role of EGFR/BRAF alterations in thyroid carcinoma in conjunction with the corresponding anti-EGFR/BRAF TKI-based novel therapeutic strategies for patients with specific genetic signatures.

Pediatric Laryngopharyngeal Reflux in the Last Decade: What Is New and Where to Next?

BACKGROUND: Laryngopharyngeal reflux may affect people of any age; still, most of the accumulated knowledge concerns adults, and evidence regarding pediatric populations remains relatively restricted. This study aims to review the most recent and emerging aspects of pediatric laryngopharyngeal reflux from the last ten years. It also attempts to identify gaps in knowledge and highlight discrepancies that future research should urgently address. METHODS: An electronic search of the MEDLINE database was conducted, limited to January 2012 through December 2021. Non-English language articles, case reports, and studies that concerned a purely or predominantly adult population were excluded. The information from the articles with the most relevant contribution was initially categorized by theme and subsequently synthesized into a narrative form. RESULTS: 86 articles were included, of which 27 were review articles, eight were surveys, and 51 were original articles. Our review systematically maps the research done in the last decade and provides an updated overview and the current state-of-the-art in this subject. CONCLUSIONS: Despite discrepancies and heterogeneity in accumulating research, evidence gathered so far endorses a need for refining an escalating multiparameter diagnostic approach. A step-wise therapeutic plan appears to be the most reasonable management approach, starting with behavioral changes for mild to moderate, uncomplicated cases and escalating to personalized pharmacotherapy options for severe or nonresponsive cases. Surgical options could be considered in the most severe cases when potentially life-threatening symptoms persist despite maximal medical therapy. Over the past decade, the amount of available evidence has been gradually increasing; however, its strength remains low. Several aspects remain markedly under-addressed, and further adequately powered, multicenter, controlled studies with uniformity in diagnostic procedures and criteria are urgently needed.

APOBEC3B Is Co-Expressed with PKCα/NF-κB in Oral and Oropharyngeal Squamous Cell Carcinomas.

The enzymatic activity of APOBEC3B (A3B) has been implicated as a prime source of mutagenesis in head and neck squamous cell carcinoma (HNSCC). The expression of Protein Kinase C α (PKCα) and Nuclear Factor-κΒ p65 (NF-κΒ p65) has been linked to the activation of the classical and the non-canonical NF-κB signaling pathways, respectively, both of which have been shown to lead to the upregulation of A3B. Accordingly, the aim of the present study was to evaluate the expression of PKCα, NF-κΒ p65 and A3B in non-HPV related oral and oropharyngeal squamous cell carcinomas (SCC), by means of immunohistochemistry and in silico methods. PKCα was expressed in 29/36 (80%) cases of oral and oropharyngeal SCCs, with 25 (69%) cases showing a PKCα+/A3B+ phenotype and only 6/36 (17%) cases showing a PKCα-/A3B+ phenotype. Εxpression of NF-κB p65 was seen in 33/35 (94%) cases of oral and oropharyngeal SCCs, with 30/35 (86%) cases showing an NF-κB p65+/A3B+ phenotype and only 2/35 (6%) cases showing an NF-κB p65-/A3B+ phenotype. In addition, mRNA expression analysis, using the UALCAN database, revealed strong expression of all three genes. These findings indicate that the expression of A3B is associated with PKCα/NF-κB p65 expression and suggest a potential role for the PKC/NF-κB signaling pathway in the development of oral and oropharyngeal cancer.

The Dual Role of Oxidative-Stress-Induced Autophagy in Cellular Senescence: Comprehension and Therapeutic Approaches.

The contemporary lifestyle of the last decade has undeniably caused a tremendous increase in oxidative-stress-inducing environmental sources. This phenomenon is not only connected with the rise of ROS levels in multiple tissues but is also associated with the induction of senescence in different cell types. Several signaling pathways that are associated with the reduction in ROS levels and the regulation of the cell cycle are being activated, so that the organism can battle deleterious effects. Within this context, autophagy plays a significant role. Through autophagy, cells can maintain their homeostasis, as if it were a self-degradation process, which removes the "wounded" molecules from the cells and uses their materials as a substrate for the creation of new useful cell particles. However, the role of autophagy in senescence has both a "dark" and a "bright" side. This review is an attempt to reveal the mechanistic aspects of this dual role. Nanomedicine can play a significant role, providing materials that are able to act by either preventing ROS generation or controllably inducing it, thus functioning as potential therapeutic agents regulating the activation or inhibition of autophagy.

The Landscape of Single Nucleotide Polymorphisms in Papillary Thyroid Carcinoma.

Thyroid carcinoma represents a leading malignancy among those derived from human endocrine systems. It comprises a variety of different histological subtypes, including mainly papillary carcinoma, follicular carcinoma, anaplastic carcinoma, and medullar carcinoma. A broad spectrum of genetic imbalances, comprising gross chromosomal (polysomy/aneuploidy) and specific gene (mutations, amplifications, deletions) alterations, has been reported. Interestingly, the role of isolated, specific gene polymorphisms, especially of the single nucleotide polymorphism (SNP) type, in thyroid carcinoma is under investigation. SNPs are the most common genetic variations in the genome. The current molecular review focuses on the impact of specific SNPs on the biological behavior of papillary thyroid carcinoma in their carriers.

A Clinical Case of Delayed Posttraumatic Frontal Sinus Cerebrospinal Fluid Leakage Management Via External Surgical Approach.

ABSTRACT: Cerebrospinal fluid rhinorrhea is frequently encountered after a fracture of the skull base. Individual fractures of the posterior wall of the frontal sinus after brain injury are uncommon. The authors present a case of a 33-year-old man with a distant history of skull base injury after a traffic accident, 12 years ago. He presented with intermittent rhinorrhea and reported 2 episodes of bacterial meningitis the last 7 years since the injury. Cerebrospinal fluid leakage was confirmed with ß2-transferrin testing. Computed tomography and magnetic resonance imaging revealed a small defect of the posterior and superior wall of the left frontal sinus and an ipsilateral meningoencephalocele.Finally, there was a communication between intracranial space and frontal sinus that caused meningitis.A coronal incision and frontal craniotomy with preservation of anterior pericranium was performed (frontal sinus cranialization using osteoplastic flap). In order to determine the precise margins of the frontal sinus and allow an accurate anterior table bone osteotomy and complete exposure of the sinus, the authors used a coronal view of skull X-ray. Scissors are then used to cut along the margins of the sinus. An "R" is scratched into the right side of template to record orientation. The template was sterilized and brought onto the surgical field and then placed over the left sinusAn external surgical approach (anterior table bone osteotomy) with the modern technique of osteoplastic flap access was performed. An elevator was used to separate the dura from the posterior table along the entire margin of the defect. Meningoplasty (cauterization of the meningoencephalocele) and closure of the osseous defect was followed. The authors repaired the defect of the posterior wall of the left frontal sinus using a combination of underlay and overlay technique. Femoral fascia from right thigh and fibrin glue were placed in order to cover the leak of the posterior wall of the left frontal sinus, respectively.Patients who present with a short or/ and distant history of traumatic brain injury should be evaluated for complication of a cerebrospinal fluid leak.

Interplay of Developmental Hippo-Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer.

Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related 'hubs' such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR-Hippo-Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.