Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle.

Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that the circadian clock controls physiological homeostasis of the liver and plays a key role in hepatocarcinogenesis. Despite the progress, cellular and molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing this knowledge gap, we show here that although the human HCC cells Hep3B, HepG2, and Huh7 displayed variations in circadian rhythm profiles, all cells relied on the master circadian clock transcription factors, BMAL1 and CLOCK, for sustained cell growth. Down-regulating Bmal1 or Clock in the HCC cells induced apoptosis and arrested cell cycle at the G2/M phase. Mechanistically, we found that inhibiting Bmal1/Clock induced dysregulation of the cell cycle regulators Wee1 and p21 which cooperatively contribute to tumor cell death. Bmal1/Clock knockdown caused downregulation of Wee1 that led to apoptosis activation and upregulation of p21 which arrested the cell cycle at the G2/M phase. Collectively, our results suggest that the circadian clock regulators BMAL1 and CLOCK promote HCC cell proliferation by controlling Wee1 and p21 levels, thereby preventing apoptosis and cell cycle arrest. Our findings shed light on cellular impact of the clock proteins for maintaining HCC oncogenesis and provide proof-of-principle for developing cancer therapy based on modulation of the circadian clock.

The efficacy and safety of neubotulinumtoxinA for the treatment of forehead horizontal lines in Asians - A clinical, prospective, interventional, split-face study.

BACKGROUND: Botulinum toxin injections are widely sought after in the field of medical aesthetics, offering consumers a variety of brand choices. Two commonly available botulinum toxin products, onabotulinumtoxinA and neubotulinumtoxinA, are featured in numerous clinics, leading many to question whether there are discernible differences in results, given their varying price ranges. OBJECTIVE: To evaluate the efficacy and safety of neubotulinumtoxinA for the treatment of forehead horizontal lines. METHODS: A 12-week prospective, single-centre, interventional split-face study was conducted, including 30 subjects. These enrolled subjects received a single treatment session, with neubotulinumtoxinA applied to the left side of the forehead and onabotulinumtoxinA to the right side. A superficial injection was performed in all individuals, where the product was injected subdermally in the frontalis muscle. Evaluation was conducted at baseline, 7 days, 14, days and 4, 8, and 12 weeks after treatment, both when the eyebrows were at maximum lift and in a resting position. Treatment efficacy was assessed by two physicians and self-assessed by the patients, using the Fitzpatrick Wrinkle Classification system. Adverse events were documented to evaluate safety. RESULTS: The study found no statistically significant difference in the efficacy of neubotulinum and onabotulinum for treating forehead wrinkles, as indicated by p-values above 0.05 for both static and dynamic conditions. No safety and adverse events were observed in both formulations. CONCLUSION: This study has demonstrated that neither formulation is inferior to each other in the treatment of forehead horizontal lines.

Use of platelet rich plasma for skin rejuvenation.

OBJECTIVE: Platelet-rich plasma (PRP) is recognized as a safe and effective therapy for regenerative skin healing and rejuvenation, utilizing autologous blood enriched with various growth factors. This review aims to assess the efficacy of PRP treatments for skin rejuvenation. METHODS: Keywords such as "platelet-rich plasma," "rejuvenation," "skin aging," and "wrinkles" were queried on Ovid, PubMed, and MEDLINE to identify pertinent studies on PRP treatment for skin rejuvenation. RESULTS: Analysis revealed that PRP treatment led to significant enhancements in multiple facial parameters after one to three sessions. Improvements were noted in skin pore size, texture, wrinkle reduction, pigmented spots, collagen density, hyaluronic acid levels, and protection against ultraviolet damage. Combining PRP with hyaluronic acid demonstrated a synergistic effect, particularly enhancing skin elasticity in patients with lower body mass index and firmness in individuals aged 50s and 60s. Incorporating both physical and biometric data for assessment proved superior to relying solely on physical observations for evaluating subtle skin quality and structural changes. CONCLUSION: This study underscores the efficacy of PRP monotherapy for skin rejuvenation and emphasizes the necessity of standardizing PRP preparation protocols in future investigations. Heightened awareness and advancements in technology have contributed to the emergence of higher-quality, less biased studies supporting PRP as a reliable and safe therapeutic option for skin rejuvenation.

Cosmeceuticals in photoaging: A review.

BACKGROUND: Photoaging is a process of the architecture of normal skin damaged by ultraviolet radiation. Topical cosmeceuticals have been used to treat this condition. The authors aimed to understand the mechanism and level of evidence of different commonly used cosmeceuticals used to treat photodamaged skin. OBJECTIVE: A range of commonly used topical cosmeceuticals (botanicals, peptides, and hydroquinone) has been used in cosmetic medicine for many years to treat photodamaged skin. This review article compares their efficacy and level of evidence. MATERIAL AND METHODS: This study was a systematic review to evaluate the efficacy of different topical cosmeceuticals. Keywords including "Photoaging," "Azelaic acid," "Soy," "Green Tea," "Chamomile," "Ginkgo," "Tea Tree Oil," "Resveratrol," "Cucumber," "Ginseng," "Centella asiatica," "Licorice Root," "Aloe Vera," "Peptides," "Argireline," "Hydroquinone," were typed on OVID, PUBMED, MEDLINE for relevant studies published on photoaging treatment. RESULTS: Most of the evidence behind cosmeceuticals is of high-quality ranging from Level I to Level II. In particular, the evidence base behind peptides is the strongest with most studies achieving Level Ib status in the evidence hierarchy. CONCLUSION: Topical cosmeceuticals like botanicals, peptides and hydroquinone can effectively treat photodamaged skin.

Pilot Study of Intensive Trismus Intervention Using Restorabite™ During Unilateral Adjuvant Radiation for Head and Neck Cancer.

Trismus commonly arises after surgery for head and neck cancer (HNC) and its severity is potentiated by postoperative radiotherapy. While the benefit of trismus rehabilitation after surgery and radiotherapy is well established, the evidence during radiotherapy is less clear. This may be due to poor adherence to trismus exercises secondary to acute mucositis. This study assessed the feasibility of using a novel trismus device during adjuvant radiotherapy for HNC in patients with acute postoperative trismus. Prospective single-arm cohort feasibility study. Eligible patients had undergone surgery with curative intent for HNC, planned for adjuvant radiotherapy, and were suitable for trismus rehabilitation. Participants completed a 10-week exercise program using a novel jaw stretching device. Study outcomes were adherence, maximal incisal opening (MIO), and trismus-related function and quality of life scores, assessed at baseline, 10 weeks, and 6 months after commencing exercises. Nine patients diagnosed with trismus after primary surgery were recruited. The mean increase in MIO at 10 weeks was 7.8 mm (range -4 to 15 mm, p = 0.03), and at 6 months was 10.6 mm (range 1-26 mm, p = 0.03). Significant improvements were observed in trismus-related quality of life (Gothenburg Trismus Questionnaire; p = 0.04). Adherence to the exercises was 100% in week 1-2, 67% in weeks 3-6, and 100% at 10 weeks (1 month post radiation). This study demonstrates the feasibility of using a novel jaw stretching device during adjuvant radiotherapy. Further evaluation is warranted to assess the effectiveness of early intervention and prevention of trismus during HNC radiotherapy.Level of Evidence: IV.

Association between Swallowing Outcomes and Dose to Critical Swallow Structures in Patients Undergoing Transoral Robotic Surgery and Post-Operative Radiation Therapy.

BACKGROUND: The radiation dose to dysphagia and aspiration-related structures (DARS) for patients undergoing transoral robotic surgery (TORS) and post-operative radiation therapy (PORT) for primary oropharyngeal carcinoma is unknown. METHODS: This prospective study measured swallowing using the MD Anderson Dysphagia Inventory at baseline and then 12-months after PORT. Dosimetric parameters were collected. RESULTS: 19 patients were recruited between 2017 and 2019. Worse swallow function at 12-months after PORT was associated with dose-parameters to the oesophageal inlet muscle, superior pharyngeal constrictor muscle and cervical oesophagus. Mean dose, V50Gy, and V60Gy to the base of tongue and pharyngeal constrictors was significantly lower in those receiving PORT to the neck alone. CONCLUSION: Dose to DARS was lower in patients who received PORT to the neck alone. In patients treated with TORS and PORT, poorer swallowing outcomes at 12 months post-treatment were associated with increased dose to oesophageal inlet muscle, superior constrictor muscle, and cervical oesophagus.

Injection Guidelines for Treating Midface Volume Deficiency With Hyaluronic Acid Fillers: The ATP Approach (Anatomy, Techniques, Products).

Midface rejuvenation is among the most valuable indications of hyaluronic acid dermal fillers, because malar projection and full upper cheeks significantly contribute to a youthful appearance. Hyaluronic acid fillers have evolved over the past 2 decades to meet specific clinical needs such as strong projection capacity and adaptability to facial dynamism. As a result, they now represent the treatment of choice for midface rejuvenation throughout age ranges by offering the potential for noninvasive treatment, immediate results, and minimal downtime. Because the 5-layered structure of the midface plays a central role in the human face, injecting the midface area may also indirectly improve other aesthetic concerns such as infraorbital hollowing and nasolabial folds. Nonetheless, midface rejuvenation requires a tailored treatment approach and a thorough knowledge of anatomy to minimize procedural risks and achieve natural-looking results. This article provides an extensive anatomical description of the midface and of the usual course and depth of vascular structures circulating nearby to delineate a treatment area and minimize procedural risks. Furthermore, considering the differential mobility and mechanical constraints of each layer of the midface, a multilayer treatment algorithm is proposed for adapting the treatment strategy to patient specificities (including age, gender, skin type, and morphology). Emphasis is also placed on desirable filler properties to create deep structural support on the one hand and accompany facial movement on the other hand.

A Toxicity Prediction Tool for Potential Agonist/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures.

Because the health effects of many compounds are unknown, regulatory toxicology must often rely on the development of quantitative structure-activity relationship (QSAR) models to efficiently discover molecular initiating events (MIEs) in the adverse-outcome pathway (AOP) framework. However, the QSAR models used in numerous toxicity prediction studies are publicly unavailable, and thus, they are challenging to use in practical applications. Approaches that simultaneously identify the various toxic responses induced by a compound are also scarce. The present study develops Toxicity Predictor, a web application tool that comprehensively identifies potential MIEs. Using various chemicals in the Toxicology in the 21st Century (Tox21) 10K library, we identified potential endocrine-disrupting chemicals (EDCs) using a machine-learning approach. Based on the optimized three-dimensional (3D) molecular structures and XGBoost algorithm, we established molecular descriptors for QSAR models. Their predictive performances and applicability domain were evaluated and applied to Toxicity Predictor. The prediction performance of the constructed models matched that of the top model in the Tox21 Data Challenge 2014. These advanced prediction results for MIEs are freely available on the Internet.

Baicalein Targets GTPase-Mediated Autophagy to Eliminate Liver Tumor-Initiating Stem Cell-Like Cells Resistant to mTORC1 Inhibition.

Drug resistance is a major problem in the treatment of liver cancer. Mammalian Target of Rapamycin 1 (mTORC1) inhibitors have been tested for the treatment of liver cancer based on hyperactive mTOR in this malignancy. However, their clinical trials showed poor outcome, most likely due to their ability to upregulate CD133 and promote chemoresistance. The CD133+ tumor-initiating stem cell-like cells (TICs) isolated from mouse and human liver tumors are chemoresistant, and identification of an approach to abrogate this resistance is desired. In search of a compound that rescinds resistance of TICs to mTORC1 inhibition and improves chemotherapy, we identified baicalein (BC), which selectively chemosensitizes TICs and the human hepatocellular carcinoma (HCC) cell line Huh7 cells but not mouse and human primary hepatocytes. Nanobead pull-down and mass-spectrometric analysis, biochemical binding assay, and three-dimensional computational modeling studies reveal BC's ability to competitively inhibit guanosine triphosphate binding of SAR1B guanosine triphosphatase, which is essential for autophagy. Indeed, BC suppresses autophagy induced by an mTORC1 inhibitor and synergizes cell death caused by mTORC1 inhibition in TIC and Huh7 spheroid formation and in the patient-derived xenograft model of HCC. The BC-induced chemosensitization is rescued by SAR1B expression and phenocopied by SAR1B knockdown in cancer cells treated with a mTORC1 inhibitor. Conclusion: These results identify SAR1B as a target in liver TICs and HCC cells resistant to mTORC1 inhibition.

Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients.

Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this transition from chronic alcoholic steatohepatitis (ASH) to AH is largely unknown. To address this question, unbiased RNA sequencing and proteomic analyses were performed on livers of the recently developed AH mouse model, which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared to gene expression profiling data from AH patients. This cross-analysis has identified Casp11 (CASP4 in humans) as a commonly up-regulated gene known to be involved in the noncanonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice and patients, but not in chronic ASH mice and healthy human livers. Gasdermin-D (GSDMD), which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers in mice and patients. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and severity of AH in the mouse model. Conversely, the deficiency of interleukin-18, the key antimicrobial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Furthermore, hepatocyte-specific expression of constitutively active GSDMD worsens hepatocellular lytic death and polymorphonuclear leukocyte inflammation. CONCLUSION: These results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737-1753).

Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6.

BACKGROUND & AIMS: Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with the development of metabolic syndrome, tumorigenesis, and stem cell characteristics. We investigated whether and how SCD promotes liver fibrosis and tumor development in mice. METHODS: Rodent primary hepatic stellate cells (HSCs), mouse liver tumor-initiating stem cell-like cells (TICs), and human hepatocellular carcinoma (HCC) cell lines were exposed to Wnt signaling inhibitors and changes in gene expression patterns were analyzed. We assessed the functions of SCD by pharmacologic and conditional genetic manipulation in mice with hepatotoxic or cholestatic induction of liver fibrosis, orthotopic transplants of TICs, or liver tumors induced by administration of diethyl nitrosamine. We performed bioinformatic analyses of SCD expression in HCC vs nontumor liver samples collected from patients, and correlated levels with HCC stage and patient mortality. We performed nano-bead pull-down assays, liquid chromatography-mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation analyses to identify MUFA-interacting proteins. We examined the effects of SCD inhibition on Wnt signaling, including the expression and stability of low-density lipoprotein-receptor-related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative polymerase chain reaction analyses. RESULTS: SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD messenger RNA (mRNA) correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector ß-catenin increased sterol regulatory element binding protein 1-dependent transcription of Scd, and ß-catenin in return was stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of Ras-related nuclear protein 1 (Ran1) to transportin 1 and reduced nuclear import of elav-like protein 1 (HuR), increasing cytosolic levels of HuR and HuR-mediated stabilization of mRNAs encoding LRP5 and LRP6. Genetic disruption of Scd and pharmacologic inhibitors of SCD reduced HSC activation and TIC self-renewal and attenuated liver fibrosis and tumorigenesis in mice. Conditional disruption of Scd2 in activated HSCs prevented growth of tumors from TICs and reduced the formation of diethyl nitrosamine-induced liver tumors in mice. CONCLUSIONS: In rodent HSCs and TICs, we found SCD expression to be regulated by Wnt-ß-catenin signaling, and MUFAs produced by SCD provided a forward loop to amplify Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, contributing to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development in mice. Components of the identified loop linking HSCs and TICs might be therapeutic targets for liver fibrosis and tumors.

Nonlinear frequency up-conversion via double topological edge modes.

We study the nonlinear frequency up-conversion in a plasmonic thin film sandwiched between one-dimensional photonic crystals (PCs) of different Zak phases by rigorous numerical time-domain nonlinear hydrodynamic calculations. We show that the proposed hetero-structure can support robust fundamental and high-order topological edge modes that simultaneously enhance the third-harmonic generation. Numerical simulations also show that femtosecond pulses can excite double topological edge modes through optical tunneling in band gaps, leading to a large nonlinear response. The obtained third harmonic generation (THG) conversion efficiency of the hetero-structure is three orders of magnitude larger than that of a single plasmonic film. The results presented here may open new avenues for designing high-efficiency nonlinear photonic devices.

Electrical tunability due to coalescence of exceptional points in parity-time symmetric waveguides.

We demonstrate theoretically the electric tunability due to the coalescence of exceptional points in PT-symmetric waveguides bounded by imperfect conductive layers. Owing to the competition effect of multimode interaction, multiple exceptional points and PT phase transitions could be attained in such a simple system, and their occurrences are strongly dependent on the boundary conductive layers. When the conductive layers become very thin, it is found that the oblique transmittance and reflectance of the same system can be tuned between zero and one by a small change in the carrier density. The results may provide an effective method for fast tuning and modulation of optical signals through electrical gating.

The present and future of genome editing in cancer research.

The widespread use of high-throughput genome sequencing methods is profoundly changing the way we understand, classify, and treat human cancers. To make sense of the deluge of sequencing data generated in the clinic, more effective and rapid assessments of the functional relevance of newly discovered cancer-associated mutations are urgently needed. In this review, we discuss how genome editing technologies are responding to this major challenge. Largely focusing on CRISPR-based methods, we will highlight their potential to accelerate discovery, discuss their current limitations, and speculate about future applications.

Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice.

UNLABELLED: Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (polymorphonuclear; PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat and the rest from intragastric feeding of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericellular fibrosis to AH in 57% (15 of 26) of mice, accompanied by inductions of chemokines (Spp1, Cxcl1, and interleukin [Il]-17a), progenitor genes (Cd133, Cd24, Nanog, and epithelial cell adhesion molecule), PMN infiltration, and clinical features of AH, such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce AH incidence and inductions of progenitor and fibrogenic genes, but rather enhances the Il-17a induction and PMN infiltration in some mice. Furthermore, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. CONCLUSION: These results suggest that SPP1 has a protective, rather than causal, role for experimental AH reproduced in our model.

Alcohol directly stimulates epigenetic modifications in hepatic stellate cells.

BACKGROUND & AIMS: Alcohol is a primary cause of liver disease and an important co-morbidity factor in other causes of liver disease. A common feature of progressive liver disease is fibrosis, which results from the net deposition of fibril-forming extracellular matrix (ECM). The hepatic stellate cell (HSC) is widely considered to be the major cellular source of fibrotic ECM. We determined if HSCs are responsive to direct stimulation by alcohol. METHODS: HSCs undergoing transdifferentiation were incubated with ethanol and expression of fibrogenic genes and epigenetic regulators was measured. Mechanisms responsible for recorded changes were investigated using ChIP-Seq and bioinformatics analysis. Ethanol induced changes were confirmed using HSCs isolated from a mouse alcohol model and from ALD patient's liver and through precision cut liver slices. RESULTS: HSCs responded to ethanol exposure by increasing profibrogenic and ECM gene expression including elastin. Ethanol induced an altered expression of multiple epigenetic regulators, indicative of a potential to modulate chromatin structure during HSC transdifferentiation. MLL1, a histone 3 lysine 4 (H3K4) methyltransferase, was induced by ethanol and recruited to the elastin gene promoter where it was associated with enriched H3K4me3, a mark of active chromatin. Chromatin immunoprecipitation sequencing (ChIPseq) revealed that ethanol has broad effects on the HSC epigenome and identified 41 gene loci at which both MML1 and its H3K4me3 mark were enriched in response to ethanol. CONCLUSIONS: Ethanol directly influences HSC transdifferentiation by stimulating global changes in chromatin structure, resulting in the increased expression of ECM proteins. The ability of alcohol to remodel the epigenome during HSC transdifferentiation provides mechanisms for it to act as a co-morbidity factor in liver disease.

Impulse and reason? Justifications in problem gambling.

People often use justifications to make desirable choices, but little is known about these justificatory thoughts in gambling. We conducted an exploratory Study 1 (n = 101) and a confirmatory Study 2 (n = 154) using online surveys, recruiting gamblers with prior and current experience of trying to reduce their gambling. Using justifications recognized in the domains of eating and consumer behavior (e.g., prior use of effort, feelings of achievement), we examined whether justifications were associated with problem gambling severity, and whether they explained additional variance above trait impulsivity and cognitive distortions. In both studies, justifications were positively associated with problem gambling severity, after accounting for trait impulsivity and cognitive distortions. Additionally, justifications were positively correlated with trait urgency and cognitive distortions, indicating that such thinking may not be antithetical to impulsivity. These data provide proof-of-principle evidence that justificatory thinking occurs in the context of gambling, is related to problem gambling severity, and may therefore represent a neglected aspect of gambling-related cognitions.

Using dermal filler to camouflage forehead osteoma: A case report.

OBJECTIVE: To review the technique and outcomes of using dermal filler to camouflage forehead osteoma, providing a minimally invasive alternative to surgical excision. BACKGROUND: Forehead osteoma, commonly known as a forehead bump or bone spur, can be a cosmetic concern. Surgical excision, while effective, carries risks of scarring and postoperative complications. An innovative approach using dermal filler offers a potential solution. METHODS: A hyaluronic acid-based filler is injected into the deep subcutaneous plane over the bony prominence using a cannula. The fanning technique ensures even distribution of the filler. The procedure's safety, patient selection, and communication between the injector and patient are emphasized to achieve optimal results. RESULTS: The technique provides immediate aesthetic improvement with results that can last up to 12 months, depending on the filler used. While generally safe, potential complications include infections, swelling, asymmetry, and lumpiness. Proper technique, patient selection, and good communication between the injector and patient are critical to achieving optimal outcomes. CONCLUSION: Using dermal filler to camouflage forehead osteoma is a minimally invasive alternative to surgical excision, offering immediate and long-lasting results with minimal downtime and fewer risks. Further studies are needed to refine the technique and optimize outcomes.

A qualitative exploration of the pathway to diagnosis and treatment of cutaneous squamous cell carcinoma of the head and neck with perineural spread.

BACKGROUND: Perineural spread (PNS) is associated with a poor prognosis in cutaneous squamous cell carcinoma of the head and neck (cSCCHN). Hence, investigating facilitators and barriers of early diagnosis and treatment of PNS in cSCCHN may improve outcomes. METHODS: Patients were recruited from an institutional database. Semi-structured interviews were conducted according to the Model of Pathways to Treatment. Thematic analysis was based on the four main intervals in the framework using a data-driven analytical method. RESULTS: Seventeen participants were interviewed. Facilitators included patients' past experiences, symptom progression, trust in healthcare professionals (HCPs), and capacity to leverage relationships. Barriers included difficult diagnoses, limited access to cancer services, lack of care coordination, and lack of awareness of PNS among primary health care providers. CONCLUSION: These findings emphasise the complexity early diagnosis and treatment of PNS. Interventions like clinical practice guidelines, education for HCPs, and telehealth could facilitate timely detection and management.