JAK Inhibitor Upadacitinib Induces Remission in Refractory Immune-Related Colitis Triggered by CTLA-4 and PD-1 Inhibitor Combination Therapy in Malignant Pleural Mesothelioma: A Case Report.

BACKGROUND: Immune checkpoint inhibitors have demonstrated efficacy against various cancers; however, there is a rising incidence of immune-related colitis. Some cases of immune-related colitis prove resistant to treatment, even with the administration of glucocorticoids or infliximab, and there is currently no established standard treatment for such cases. CASE: The patient, a 73-year-old male, had undergone combination therapy for malignant pleural mesothelioma for 2 years, utilizing both ipilimumab (a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor). Unfortunately, the treatment led to side effects, specifically immune-related adverse event (irAE) enterocolitis. Steroid and infliximab treatment failed to improve the patient's condition. Treatment with tacrolimus was attempted, but the patient remained unresponsive. Subsequently, 45 mg of upadacitinib, a Janus kinase (JAK) inhibitor, was administered. Symptoms improved rapidly following upadacitinib administration, and endoscopy also revealed positive results. With the increasing incidence of immune-related colitis, some patients have become resistant to treatment with glucocorticoids and infliximab. In this case, the irAE enterocolitis was improved by upadacitinib administration. CONCLUSION: In cases where immune-related colitis proves resistant to treatment with glucocorticoids, infliximab, or tacrolimus, upadacitinib represents a potential option as a JAK inhibitor.

Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.

Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.

Immunotherapy for Treatment of Pleural Mesothelioma: Current and Emerging Therapeutic Strategies.

Pleural mesothelioma is a rare malignancy associated with asbestos exposure and very poor prognosis, with a 5-year overall survival of 12%. Outcomes may vary according to stage at time of diagnosis and histologic subtype. Most recently, clinical trials utilizing dual checkpoint inhibitor regimens and chemotherapy in combination with immune oncologic agents have demonstrated impactful changes in outcomes. In this article, we review studies that have led to the successful implementation of immunotherapy in clinical practice for the treatment of this disease and highlight ongoing clinical trials exploring the use of different immunotherapy strategies for the treatment of pleural mesothelioma. We also discuss the challenges of immunotherapy-based approaches in the context of mesothelioma and future strategies currently being investigated to overcome them.

Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial.

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).

Antigen targeting and anti-tumor activity of a novel anti-CD146 212Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma.

Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target. This study characterized CD146 expression and binding/internalization kinetics of the CD146-targeting antibody OI-3 coupled with 212Pb (212Pb-TCMC-OI-3) in human mesothelioma cells. Flow cytometry showed that both chimeric (chOI-3) and murine (mOI-3) antibodies rapidly bound and internalized within 1-6 h in MSTO-211H cells. 212Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212Pb and 212Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212Pb-TCMC-mIgG1. The ability of 212Pb-TCMC-mOI-3 to target and inhibit the growth of intraperitoneal mesothelioma xenografts supports targeted radionuclide therapy's efficacy for metastatic peritoneal mesothelioma. This study highlights the potential of localized CD146-targeted radioimmunotherapy for malignant mesothelioma, offering a new avenue for improving patient outcomes.

Effect of postoperative normothermic intraperitoneal chemotherapy on the prognosis of MPM patients receiving CRS+HIPEC: A single-center case-control study.

BACKGROUND: The comprehensive treatment strategy, mainly cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), combined with systemic and intraperitoneal chemotherapy, is the standard treatment for malignant peritoneal mesothelioma (MPM), which can significantly prolong the survival of patients. The aim of this study is to investigate the clinical significance of postoperative normothermic intraperitoneal chemotherapy (NIPEC) in MPM patients. METHODS: Data of 152 MPM patients who underwent CRS + HIPEC and postoperative intravenous chemotherapy were retrospectively analyzed. Patients were divided into the Non-NIPEC group and the NIPEC group according to whether they received NIPEC after surgery. The baseline characteristics of the two groups were compared, and the survival outcome was analyzed in subgroups according to completeness of cytoreduction (CC) score. Multivariate survival analysis was used to determine the independent prognostic factors. RESULTS: In CC 0-1 and CC 2-3 subgroups, there was no significant difference in baseline characteristics between Non-NIPEC and NIPEC groups. Survival analysis showed that for CC 0-1 patients, there was no significant difference in overall survival (OS) between Non-NIPEC and NIPEC groups (P = 0.503). However, for CC 2-3 patients, the median OS of the NIPEC group was significantly longer than that of the Non-NIPEC group (24.5 vs. 10.3 months, P = 0.005). Pathological type, preoperative thrombosis and postoperative NIPEC (HR = 0.423, 95%CI: 0.228-0.786, P = 0.006) were independent prognostic factors for CC 2-3 patients. CONCLUSIONS: For MPM patients receiving CRS + HIPEC, postoperative intraperitoneal combined with intravenous chemotherapy may improve the survival of CC 2-3 patients, but CC 0-1 patients do not seem to derive the same benefit.

GFPT2: A novel biomarker in mesothelioma for diagnosis and prognosis and its molecular mechanism in malignant progression.

BACKGROUND: Mesothelioma (MESO) is an insidious malignancy with a complex diagnosis and a poor prognosis. Our study unveils Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) as a valuable diagnostic and prognostic marker for MESO, exploring its role in MESO pathogenesis. METHODS: We utilised tissue samples and clinicopathologic data to evaluate the diagnostic and prognostic significance of GFPT2 as a biomarker for MESO. The role of GFPT2 in the malignant progression of MESO was investigated through in vitro and in vivo experiments. The activation of NF-κB-p65 through O-GlcNAcylation at Ser75 was elucidated using experiments like HPLC-QTRAP-MS/MS and mass spectrometry analysis. RESULTS: The study demonstrates that GFPT2 exhibits a sensitivity of 92.60% in diagnosing MESO. Overexpression of it has been linked to an unfavourable prognosis. Through rigorous verification, we have confirmed that elevated GFPT2 levels drive malignant proliferation, invasiveness, and metastasis in MESO. At the molecular level, GFPT2 augments p65 O-GlcNAcylation, orchestrating its nuclear translocation and activating the NF-κB signalling pathway. CONCLUSIONS: Our insights suggest GFPT2's potential as a distinctive biomarker for MESO diagnosis and prognosis, and as an innovative therapeutic target, offering a new horizon for identification and treatment strategies in MESO management.

Diagnosis of Pleural Mesothelioma: Is Everything Solved at the Present Time?

Ranked high in worldwide growing health issues, pleural diseases affect approximately one million people globally per year and are often correlated with a poor prognosis. Among these pleural diseases, malignant pleural mesothelioma (PM), a neoplastic disease mainly due to asbestos exposure, still remains a diagnostic challenge. Timely diagnosis is imperative to define the most suitable therapeutic approach for the patient, but the choice of diagnostic modalities depends on operator experience and local facilities while bearing in mind the yield of each diagnostic procedure. Since the analysis of pleural fluid cytology is not sufficient in differentiating historical features in PM, histopathological and morphological features obtained via tissue biopsies are fundamental. The quality of biopsy samples is crucial and often requires highly qualified expertise. Since adequate tissue biopsy is essential, medical or video-assisted thoracoscopy (MT or VATS) is proposed as the most suitable approach, with the former being a physician-led procedure. Indeed, MT is the diagnostic gold standard for malignant pleural pathologies. Moreover, this medical or surgical approach can allow diagnostic and therapeutic procedures: it provides the possibility of video-assisted biopsies, the drainage of high volumes of pleural fluid and the administration of sterile calibrated talcum powder under visual control in order to achieve pleurodesis, placement of indwelling pleural catheters if required and in a near future potential intrapleural therapy. In this context, dedicated diagnostic pathways remain a crucial need, especially to quickly and properly diagnose PM. Lastly, the interdisciplinary approach and multidisciplinary collaboration should always be implemented in order to direct the patient to the best customised diagnostic and therapeutic pathway. At the present time, the diagnosis of PM remains an unsolved problem despite MDT (multidisciplinary team) meetings, mainly because of the lack of standardised diagnostic work-up. This review aims to provide an overview of diagnostic procedures in order to propose a clear strategy.

Peritoneal Dissemination in Patients with Recurrence After Post-pleurectomy/decortication for Pleural Mesothelioma.

BACKGROUND: In clinical practice, peritoneal dissemination after curative-intent surgery for pleural mesothelioma occasionally recurs. This study investigated the risk factors and prognosis associated with post-pleurectomy/decortication peritoneal dissemination in pleural mesothelioma, which are rarely reported. METHODS: This retrospective review included 160 patients who experienced recurrence after pleurectomy/decortication for pleural mesothelioma between January 2011 and December 2021. Patients with recurrence were classified according to the initial recurrence pattern. The P group experienced recurrence with peritoneal dissemination, and the non-P group experienced recurrence without peritoneal dissemination. The analysis determined the risk factors for peritoneal dissemination using multivariable logistic regression analysis. Survival was analyzed using the Kaplan-Meier method and the log-rank test. RESULTS: Of the 160 patients, 20 (12.5%) exhibited peritoneal dissemination and were assigned to the P group, whereas 140 (87.5%) had recurrence without peritoneal dissemination and were assigned to the non-P group. Multivariable logistic regression analysis showed that diaphragm reconstruction (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.0-8.0; p = 0.048) and female sex (OR, 3.7; 95% CI 1.26-10.8; p = 0.017) were associated with the P group. Post-recurrence survival was worse in the P group than in the non-P group (1-year post-recurrence survival: 22.2% vs. 65.3%; median: 6.7 months vs. 19.4 months; p = 0.0013). CONCLUSIONS: Peritoneal dissemination occurred in approximately one of every eight patients with recurrence after pleurectomy/decortication for pleural mesothelioma, and the incidence was significantly higher among females and patients undergoing diaphragm reconstruction. Moreover, postoperative recurrence of peritoneal dissemination was associated with a poor prognosis.

Primary Intrahepatic Mesothelioma: Case Series and Systematic Review of Literature.

BACKGROUND: Primary intrahepatic mesothelioma (PIHMM) has been rarely reported. Its typical clinical presentation, radiological features and pathology have not been defined. Here, we aimed to summarize its diagnosis and treatment. METHODS: We conducted a retrospective analysis of three cases of PIHMM in the First Affiliated Hospital of Zhejiang University School of Medicine and reviewed the current literature to investigate the clinical and pathological characteristics and prognosis of PIHMM. RESULTS: Based on our case series and the literature, the mean age of PIHMM was 59.7 (41-83) years. Most patients present with nonspecific symptoms such as abdominal pain, fever, weight loss and weakness. On imaging, PIHMM usually presented as a solid, heterogeneous soft tissue mass with irregular margins and significant enhancement of the margins in the arterial phase. Immunohistochemical markers such as calretinin, cytokeratin (CK)5/6, D2-40, WT-1, mesothelin CK and vimentin may be useful for diagnosis. The 3-year relapse-free survival rate (RFS) was 51.85%, the 3-year overall survival (OS) rate was 83.33% and the 3-year postoperative overall survival rate was 100%. CONCLUSION: PIHMM can only be diagnosed by careful postoperative pathology, because of its nonspecific clinical presentations, serological indicators or imaging features. Immunohistochemical staining is very useful to distinguish this tumor from other liver tumors. Surgery is the mainstay of treatment.

Volatile organic compound analysis of malignant pleural mesothelioma chorioallantoic membrane xenografts.

Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure. MPM is often diagnosed late, at a point where limited treatment options are available, but early intervention could improve the chances of successful treatment for MPM patients. Biomarkers to detect MPM in at-risk individuals are needed to implement early diagnosis technologies. Volatile organic compounds (VOCs) have previously shown diagnostic potential as biomarkers when analysed in MPM patient breath. In this study, chorioallantoic membrane (CAM) xenografts of MPM cell lines were used as models of MPM tumour development for VOC biomarker discovery with the aim of generating targets for investigation in breath, biopsies or other complex matrices. VOC headspace analysis of biphasic or epithelioid MPM CAM xenografts was performed using solid-phase microextraction and gas chromatography-mass spectrometry. We successfully demonstrated the capture, analysis and separation of VOC signatures from CAM xenografts and controls. A panel of VOCs was identified that showed discrimination between MPM xenografts generated from biphasic and epithelioid cells and CAM controls. This is the first application of the CAM xenograft model for the discovery of VOC biomarkers associated with MPM histological subtypes. These findings support the potential utility of non-invasive VOC profiling from breath or headspace analysis of tissues for detection and monitoring of MPM.

Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment.

The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.

[Erionite, an exposure factor linked to pleural mesothelioma]. / L'érionite, un facteur expositionnel lié au mésothéliome pleural.

Mesotheliomas are neoplasia developed from the mesothelium, a layer covering the viscera (visceral layer) and the cavity where the organs are (parietal layer). The best known, and the most frequently encountered is the pleural mesothelioma. This disease has a close link with exposure to asbestos, a mineral fibre now banned in several countries. However, other exposure factors have also been incriminated, including another one recognised as a certain carcinogenic agent for several years now : erionite. We present the case of a patient with pleural mesothelioma whose exposure to erionite could be demonstrated. The presentation of this clinical case will be complemented by a literature review on this less known and mostly environmental exposure, contrary to asbestos which is mostly professional.

Les mésothéliomes sont des néoplasies se développant à partir du mésothélium, feuillet recouvrant, d'une part, les viscères (feuillet viscéral) et, d'autre part, la cavité où se trouvent les organes (feuillet pariétal). Le plus connu, et le plus fréquemment rencontré, est le mésothéliome pleural. Cette maladie a un lien étroit avec l'exposition à l'amiante, fibre minérale maintenant interdite dans plusieurs pays. Cependant, d'autres facteurs expositionnels ont également été incriminés, dont un autre reconnu comme cancérogène certain depuis plusieurs années : l'érionite. Nous présentons le cas d'un patient atteint d'un mésothéliome pleural pour lequel une exposition à l'érionite a pu être étayée. La présentation du cas clinique sera complétée d'une revue de la littérature sur cette exposition particulière moins connue et majoritairement environnementale, contrairement à l'amiante dont l'exposition est majoritairement professionnelle.

[Malignant mesothelioma of the vaginal testis: diagnostic and therapeutic considerations]. / Le mésothéliome malin de la vaginale testiculaire : aspects diagnostiques et thérapeutiques.

Mesothelioma of the testicular vagina is a rare malignant tumour, most often discovered by chance. The rarity of this type of tumour has not led to the development of specific guidelines. Median survival is estimated at 30 months. The lack of data and official recommendations makes surgical and medical management and follow-up difficult. Men who have not undergone radical orchiectomy die very rapidly after diagnosis. The remission rate at 1 year post-orchidectomy is 47 %, the recurrence rate at 1 year is 53 % and 92 % of relapses occur within 5 years post-operatively. The treatment option of hemiscrotectomy in the first instance has rarely been used; a second-look resection with negative margins may be proposed. The usefulness of adjuvant chemotherapy and/or radiotherapy has not been clearly demonstrated. Local recurrence is accompanied by metastasis in 85 % of cases. In the case of metastatic cancer (15 %), the retro-peritoneal, inguinal and iliac lymph nodes may be invaded. Follow-up by injected thoraco-abdomino-pelvic CT scan is recommended every 3 months for 2 years, then once a year for 3 years, for a total of 5 years of close follow-up. The long-term recurrence rate is 3 %.

Le mésothéliome de la vaginale testiculaire est une tumeur maligne rare et souvent de découverte fortuite. Sa rareté d'apparition n'a pas permis de développer des recommandations spécifiques. La survie médiane est estimée à 30 mois. Le manque de recommandations officielles rend sa prise en charge chirurgicale, médicale et son suivi difficiles. Les hommes n'ayant pas bénéficié d'orchidectomie radicale décèdent très rapidement après le diagnostic. Le taux de rémission à 1 an post-orchidectomie est de 47 %, le taux de récurrence à 1 an est de 53 % et 92 % des rechutes se font endéans les 5 ans post-opératoires. L'option thérapeutique par hémi-scrotectomie en première intention a rarement été pratiquée, une résection de «second look¼ en marges saines peut être proposée. L'utilité d'une chimiothérapie et/ou d'une radiothérapie adjuvante n'a pas été clairement démontrée. Une rechute locale est accompagnée de métastases dans 85 % des cas. En cas de cancer d'emblée métastatique (15 %), les relais ganglionnaires rétro-péritonéaux, inguinaux et iliaques peuvent être envahis. Un suivi par scanner thoraco-abdomino-pelvien injecté est recommandé tous les 3 mois pendant 2 ans, puis 1 fois par an pendant 3 ans pour un total de 5 ans. Le taux de récidive au long cours est de 3 %.

Patient characteristics, treatment patterns, and survival outcomes for patients with malignant pleural mesothelioma in Denmark between 2011 and 2018: a nationwide population-based cohort study.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with poor prognosis and limited treatment options. Immunotherapy shows potential for improved outcomes; however, real-world evidence on its use will take time to accumulate. This study examined patient characteristics, treatment patterns, overall survival (OS), and predictors of mortality among patients diagnosed with MPM in Denmark prior to the introduction of newer treatments. METHODS: This historical cohort study based on routinely collected Danish National Registry data included adults newly diagnosed with MPM between 01 January 2011 and 31 May 2018. Summary statistics were used to describe patient characteristics and initial treatment. OS was estimated using Kaplan-Meier methods; Cox regression was used to compare patient mortality against the (age/sex-matched) general population and to investigate mortality predictors. RESULTS: Overall, 880 patients were included; 44% had advanced MPM, 37% had non-advanced MPM, and 19% had unknown MPM stage. Median age at diagnosis was 71.9 years, and 82% of the patients were male. Within 180 days of diagnosis, no treatment was recorded for 215 patients (54%) with advanced MPM and 150 (46%) with non-advanced MPM. Median time-to-initial treatment (interquartile range) was 47 days (31-111) overall, 40 days (28-77) in patients with advanced MPM, and 53 days (35-121) with non-advanced MPM. Median OS was 13.7 months overall (non-advanced MPM: 18.0 months vs. advanced MPM: 10.0 months). Predictors of higher mortality were older age at diagnosis, histology, and advanced MPM stage. INTERPRETATION: These findings provide a baseline upon which to evaluate MPM epidemiology as newer treatments are adopted in routine practice.

Unleashing precision: A review of targeted approaches in pleural mesothelioma.

This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM.