Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors.

Importance: Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined. Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs. Design, Setting, and Participants: This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line. Exposure: Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs). Main Outcomes and Measures: The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS. Results: Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001). Conclusions and Relevance: In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

Improving Reporting on Qualitative Methods Used in the Development and Validation of Patient-Reported Outcome Measures for Mental Health Concerns.

Qualitative methodologies are recommended in the development and evaluation of psychological instruments. However, reporting on qualitative methods in instrument development studies remains variable and often insufficient to support claims surrounding content validity. In the current article, we present a commentary discussing the critical role qualitative inquiry plays in the development of patient-reported outcome measures. We outline the current state of reporting in qualitative instrument development and evaluation studies with a focus on mental health literature and highlight the clinical relevance of this topic for health care professionals. Despite challenges, we express confidence in the potential value of substantively engaging with qualitative methods and comprehensive reporting and summarize recommendations to this effect based on the current literature. [Journal of Psychosocial Nursing and Mental Health Services, 61(3), 40-44.].

Late effects in survivors treated for lymphoma as adolescents and young adults: a population-based analysis.

PURPOSE: The study objective is to describe and quantify the incidence of treatment-induced late effects in AYA lymphoma patients. METHODS: Consecutive patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) at 15-24 years of age were identified. All patients in British Columbia who received radiation therapy (RT) from 1974 to 2014 with ≥ 5-year survival post-RT were included. Late effects' analyses included only survivors who received RT to the relevant anatomical site(s) and/or relevant chemotherapy, and were reported as cumulative incidence (CI) ± standard error. RESULTS: Three hundred and five patients were identified (74% HL). Median age of diagnosis was 21 years. Median follow-up was 19.1 years for secondary malignancy and 7.2 years for other endpoints. Hypothyroidism was the most prevalent late effect, with a CI of 22.4 ± 2.8% and 35.1 ± 4% at 5 and 10 years, respectively. CI of in-field secondary malignancy was 0.4 ± 0.4% at 10 years and 2.8 ± 1.2% at 20 years. CI of symptomatic pulmonary toxicity was 4.6 ± 1.5% and 6.8 ± 2.0% at 5 and 10 years, respectively, and was higher in patients receiving multiple RT courses (p = 0.009). Esophageal complications occurred at a CI of 1.4 ± 0.8% at 5 years and 2.2 ± 1.1% at 10 years. CI of xerostomia/dental decay was 2.6 ± 1.3% at 5 years and 4.9 ± 2.1% at 10 years. CI of cardiac disease was at 2.3 ± 0.9% at 5 years and 4.4 ± 1.5% at 10 years. CI of infertility was 6.5 ± 1.6% at 5 years and 9.4 ± 2.1% at 10 years. CONCLUSION: Survivors of AYA lymphoma have a high incidence and diverse presentation of late effects. IMPLICATIONS FOR CANCER SURVIVORS: AYA lymphoma survivors should be educated about their risks of late effects and offered screening and follow-up when appropriate.

Evaluation of the discussion of late effects and screening recommendations in survivors of adolescent and young adult (AYA) lymphoma.

PURPOSE: The study objective was to assess the discussion of late effects (LEs) and screening recommendations (SRs) for adolescent and young adults (AYAs) treated for lymphoma. METHODS: A retrospective study was conducted on AYA lymphoma survivors aged 15-24 years at diagnosis who received radiation therapy (RT) ± chemotherapy between 1984 and 2010 at any of the six British Columbia (BC) Cancer treatment centers across the province. Charts were reviewed to evaluate discussion of LEs and SRs. Susceptibility to specific LEs was determined by reviewing treatment details. RESULTS: Of 305 patients, 212 (70%) had documented discussion of at least one specific LE, 39 (13%) had non-specific documentation only, and 54 (18%) had no documented discussion of LEs. Accounting only for patients susceptible to each LEs, the most frequently discussed LEs was radiation-induced (RI) neoplasm (42%), and the least frequently discussed LEs was carotid artery stenosis (0.4%). The most common SRs discussed in susceptible patients was for RI breast cancer (43%). Of patients discharged between 1985 and 1999 vs 2000 and 2014, LEs were discussed in 63 vs 93% (P < 0.0005), and SRs were discussed in 30 vs 65%, respectively (P < 0.0005). Older age at discharge, presence of a discharge note, and occurrence of a discharge appointment were associated with increased discussion of SRs. CONCLUSIONS: Most survivors of AYA lymphoma received some discussion of LEs and SRs, but each relevant LEs and SRs was discussed in only a minority of susceptible patients. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of AYA lymphoma and their primary care professionals may not be appropriately informed of health risks and how to screen for them.

A Triple Combination of Metformin, Acetylsalicylic Acid, and Oseltamivir Phosphate Impacts Tumour Spheroid Viability and Upends Chemoresistance in Triple-Negative Breast Cancer.

INTRODUCTION: Targeted multimodal approaches need to be strategically developed to control tumour growth and prevent metastatic burden successfully. Breast cancer presents a unique clinical problem because of the variety of cellular subtypes that arise. The tumour stage and cellular subtypes often dictate the appropriate clinical treatment regimen. Also, the development of chemoresistance is a common clinical challenge with breast cancer. Higher doses and additional drug agents can produce additional adverse effects leading to a more aggressive malignancy. Acetylsalicylic acid (ASA), metformin (Met), and oseltamivir phosphate (OP) were investigated for their efficacy to sensitize MDA-MB-231 triple-negative breast cancer and its tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR) together in combination with Tmx treatment. METHODS: Microscopic imaging, the formation of 3D multicellular tumour spheroids, immunocytochemistry, flow cytometry, Annexin V Assay, Caspase 3/7 Apoptosis Assay, tube formation assay and analysis, and WST-1 cell viability assay evaluated the formation of MCTS, morphologic changes, cell viability, apoptosis activity and the expression levels of ALDH1A1, CD44 and CD24 on the cell surface, MDA-MB231 triple-negative breast cancer, tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR). RESULTS: The results using a triple combination of ASA, Met and OP on MDA-MB-231 and MDA-MB-231-TmxR cells and their matrix-free 3D multicellular tumour spheroids (MCTS) formed by using the cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP)) peptide method demonstrate a consistent and significant decrease in cell and tumour spheroid viability and volume with increased apoptotic activity, and increased sensitivity to Tmx therapy. Tmx treatment of MDA-MB-231 cells in combination with ASA, Met and OP markedly reduced the CD44/CD24 ratio by 6.5-fold compared to the untreated control group. Tmx treatment of MDA-MB-231-TmxR cells in combination with ASA, Met and OP markedly reduced the ALDH1A1 by 134-fold compared to the same treatment for the parental cell line. Also, the triple combination treatment of ASA, Met, and OP inhibited vasculogenic endothelial cell tube formation and induced endothelial cell apoptosis. CONCLUSION: For the first time, the findings demonstrate that repurposing ASA, Met, and OP provides a novel and promising targeted multimodal approach in the treatment of triple-negative breast cancer and its chemoresistant variant.

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide.

BACKGROUND: Prostaspheres-based three dimensional (3D) culture models have provided insight into prostate cancer (PCa) biology, highlighting the importance of cell-cell interactions and the extracellular matrix (EMC) in the tumor microenvironment. Although these 3D classical spheroid platforms provide a significant advance over 2D models mimicking in vivo tumors, the limitations involve no control of assembly and structure with only limited spatial or glandular organization. Here, matrix-free prostaspheres from human metastatic prostate carcinoma PC3 and DU145 cell lines and their respective gemcitabine resistant (GemR) variants were generated by using cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP)). MATERIALS AND METHODS: Microscopic imaging, immunocytochemistry (ICC), flow cytometry, sialidase, and WST-1 cell viability assays were used to evaluate the formation of multicellular tumor spheroid (MCTS), cell survival, morphologic changes, and expression levels of α2,6 and α2,3 sialic acid (SA) and E- and N-cadherin in DU145, PC3, and their GemR variants. RESULTS: By using the cyclo-RGDfK(TPP) peptide platform in a dose- and time-dependent manner, both DU145 and DU145GemR cells formed small MCTS. In contrast, PC3 and PC3GemR cells formed irregular multicellular aggregates at all concentrations of cyclo-RGDfK(TPP) peptide, even after 6 days of incubation. ICC and flow cytometry results revealed that DU145 cells expressed higher amounts of E-cadherin but lower N-cadherin compared with PC3 cells. By using Maackia amurensis (α2,3-SA-specific MAL-II) and Sambucus nigra (α2,6-SA specific SNA) lectin-based cytochemistry staining and flow cytometry, it was found that DU145 and DU145GemR cells expressed 5 times more α2,6-SA than α2,3-SA on the cell surface. PC3 cells expressed 4 times more α2,3-SA than α2,6-SA, and the PC3GemR cells showed 1.4 times higher α2,6-SA than α2,3-SA. MCTS volume was dose-dependently reduced following pretreatment with α2,6-SA-specific neuraminidase (Vibrio cholerae). Oseltamivir phosphate enhanced cell aggregation and compaction of 3D MCTS formed with PC3 cells. CONCLUSION: The relative levels of specific sialoglycan structures on the cell surface correlate with the ability of PCa cells to form avascular multicellular prostaspheres.

Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity.

One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation.

Sialylation transmogrifies human breast and pancreatic cancer cells into 3D multicellular tumor spheroids using cyclic RGD-peptide induced self-assembly.

Multicellular tumor spheroids (MTS) have been at the forefront of cancer research, designed to mimic tumor-like developmental patterns in vitro. Tumor growth in vivo is highly influenced by aberrant cell surface-specific sialoglycan structures on glycoproteins. Aberrant sialoglycan patterns that facilitate MTS formation are not well defined. Matrix-free spheroids from breast MCF-7 and pancreatic PANC1 cancer cell lines and their respective tamoxifen (TMX) and gemcitabine (Gem) resistant variants were generated using the RGD platform of cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK (TPP)). MCF-7 and MCF-7 TMX cells formed tight spheroids both in the classical agarose-and RGD-based platforms while all PANC1 cells formed loose aggregates. Using lectin histochemistry staining, sialidase assay, neuraminidase (Vibrio cholerae) and oseltamivir phosphate (OP) neuraminidase inhibitor treatments, MCF-7 and PANC1 cells and their drug-resistant variants expressed different sialic acid (SA) content on their cell surfaces. α-2,3- and α-2,6-sialic acid surface residues facilitated spheroid formation under cyclo-RGDfK(TPP)-induced self-assembly. Pretreatment with α-2,3- SA specific Maackia amurensis (MAL-II) lectin, α-2,6-SA specific Sambucus nigra (SNA) lectin, and exogenous α-2,6-SA specific neuraminidase (Vibrio cholerae) dose-dependently reduced spheroid volume. OP enhanced cell aggregation and compaction forming spheroids. PANC1 and MDA-MB231 xenograft tumors from untreated and OP-treated RAGxCγ double mutant mice expressed significantly higher levels of α-2,3- SA over α-2,6-SA. MCF-7 spheroids also expressed a high α-2,3-SA to α-2,6-SA ratio. These results suggest that the relative levels of specific sialoglycan structures on the cell surface correlate with the ability of cancer cells to form avascular multicellular tumor spheroids and in vivo xenograft tumors.