New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.

In the article that accompanies this editorial, Dr. Solomon and colleagues present a post-hoc analysis of investigator-assessed efficacy outcomes, safety, and biomarker analyses encompassing approximately 5 years’ worth of data from the CROWN trial (NCT03052608) of lorlatinib compared with crizotinib in patients with treatment naïve advanced / metastatic ALK+ NSCLC demonstrating a PFS benefit for lorlatinib which exceeds 5 years and a 96% probability of preventing brain metastases within this time frame. These updated data are unprecedented for the treatment of ALK+ NSCLC, and for NSCLC treated with targeted therapies in general, making a compelling argument for lorlatinib as the preferred first line ALK TKI.

Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS) and UC (PRS) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients.

Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer.

Purpose: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response.

Experimental Design: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL).

Mixed exposure to phthalates and organic UV filters affects Children's pubertal development in a gender-specific manner.

Background: Previous studies showed phthalates and UV filters are endocrine-disruptive and associated with puberty. However, few studies have examined effects of mixed exposure.

Methods: Six phthalate metabolites and 12 organic UV filters were detected among 223 school-age children.

Serum lactate is associated with increased illness severity in immunocompromised pediatric hematology oncology patients presenting to the emergency department with fever.

Introduction: Determining which febrile pediatric hematology/oncology (PHO) patients will decompensate from severe infection is a significant challenge. Serum lactate is a well-established marker of illness severity in general adult and pediatric populations, however its utility in PHO patients is unclear given that chemotherapy, organ dysfunction, and cancer itself can alter lactate metabolism. In this retrospective analysis, we studied the association of initial serum lactate in febrile immunosuppressed PHO patients with illness severity, defined by the incidence of clinical deterioration events (CDE) and invasive bacterial infection (IBI) within 48 hours.

Antibody-Drug Conjugates for Melanoma and Other Skin Malignancies.

While most skin malignancies are successfully treated with surgical excision, advanced and metastatic skin malignancies still often have poor long-term outcomes despite therapeutic advances. Antibody-drug conjugates (ADCs) serve as a potentially promising novel therapeutic approach to treat advanced skin cancers as they combine antibody-associated antigen specificity with cytotoxic anti-tumor effects, thereby maximizing efficacy and minimizing systemic toxicity. While no ADCs have gained regulatory approval for advanced skin cancers, several promising agents are undergoing preclinical and clinical investigation.

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

Background: Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined.

Methods: We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients.

A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

Purpose: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer.

Methods: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis.

Prenatal fine particulate matter exposure associated with placental small extracellular vesicle derived microRNA and child neurodevelopmental delays.

Background And Aims: Prenatal fine particulate matter (PM) exposure has been linked to adverse neurodevelopment. However, epidemiological evidence remains inconclusive and little information about the effects of various PM components on child neurodevelopment is currently known. The underlying mechanism was also not elucidated.

Management of Acral and Mucosal Melanoma: Medical Oncology Perspective.

Acral and mucosal melanomas (MM) are rare subtypes of melanoma that are biologically and clinically distinct from cutaneous melanoma. Despite the progress in the treatment of cutaneous melanomas with the development of targeted and immune therapies, the therapeutic options for these less common subtypes remain limited. Difficulties in early diagnosis, the aggressive nature of the disease, and the frequently occult sites of origin have also contributed to the poor prognosis associated with acral and MM, with substantially worse long-term prognosis.

Lipid peroxidation biomarkers associated with height and obesity measures in the opposite direction in women.

Objective: This study aimed to investigate whether and how lipid peroxidation markers are associated with height and obesity measures.

Methods: In two independent samples of women (Study 1: n = 1,005; Study 2: n = 1,158), systemic levels of lipid peroxidation were assessed by urinary markers F -isoprostanes (F -IsoPs) and its major metabolite (F -IsoP-M), with gas chromatography/negative ion chemical ionization mass spectrometry assays. Anthropometric parameters were directly measured and genetically estimated, and they were used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models.

Many Medicare Beneficiaries Do Not Fill High-Price Specialty Drug Prescriptions.

For high-price drugs, Medicare Part D beneficiaries who do not receive a low-income subsidy must pay a percentage of the drug's price for each medication fill. Without that subsidy, which lowers out-of-pocket spending, beneficiaries typically pay hundreds or thousands of dollars for a single fill. We estimated the proportion of Part D beneficiaries in fee-for-service Medicare, with and without a subsidy, who do not initiate treatment (that is, do not fill a new prescription) with high-price Part D drugs newly prescribed for four conditions.

A Tale of Two Histologies: Dissecting the Biology of Lineage Transformation in Lung Cancer.

Lineage plasticity is an important, and likely underappreciated, mechanism of treatment resistance in lung cancer. Here, Quintanal-Villalonga and colleagues integrate results from multiomic analyses to provide key new insights into the biology of lineage plasticity. See related article by Quintanal-Villalonga et al.

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma.

Quality of dietary carbohydrate is more important than its quantity in lipid peroxidation.

Background: High glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation.

Objectives: We aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females.

Immune-checkpoint inhibitors: long-term implications of toxicity.

The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued.

Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy.

The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs.

Facebook Recruitment for Children with Advanced Cancer and Their Parents: Lessons from a Web-based Pediatric Palliative Intervention Study.

Participant recruitment for pediatric palliative intervention studies is a chronic challenge for researchers. Digital recruitment strategies, or digital technology-assisted recruitment methods used to remotely reach and enroll research subjects, can help address these recruitment challenges for pediatric palliative care clinical trials. This study (a) describes Facebook recruitment procedures targeting children with cancer and their parents for a pediatric palliative intervention randomized clinical trial, (b) reports recruitment results, and (c) discusses successful strategies to recruit pediatric populations via Facebook advertisements.