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Cancers May 2024Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for... (Review)
Review
Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.
PubMed: 38893092
DOI: 10.3390/cancers16111971 -
International Journal of Molecular... May 2024We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of...
We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a () translocation and a (2) p.S310F mutation, in addition to the known p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the translocation, whereas the and mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.
Topics: Humans; Crizotinib; Female; Afatinib; Aged; Proto-Oncogene Mas; Receptor, ErbB-2; ErbB Receptors; Lung Neoplasms; Proto-Oncogene Proteins; Protein-Tyrosine Kinases; Adenocarcinoma of Lung; Proto-Oncogene Proteins c-met; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38891886
DOI: 10.3390/ijms25115698 -
International Immunopharmacology Jun 2024It is crucial to decipher the modulation of regulatory T cells (Tregs) in tumor microenvironment (TME) induced by chemotherapy, which may contribute to improving the...
It is crucial to decipher the modulation of regulatory T cells (Tregs) in tumor microenvironment (TME) induced by chemotherapy, which may contribute to improving the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC). We retrospectively collected specimens from patients with II-III NSCLC, constituting two cohorts: a neoadjuvant chemotherapy (NAC) cohort (N = 141) with biopsy (N = 58) and postoperative specimens (N = 141), and a surgery-only cohort (N = 122) as the control group. Then, the cell density (Dens), infiltration score (InS), and Treg-cell proximity score (TrPS) were conducted using a panel of multiplex fluorescence staining (Foxp3, CD4, CD8, CK, CD31, ɑSMA). Subsequently, the association of Tregs with cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) was analyzed. Patients with NAC treatment have a higher density of Tregs in both paired (P < 0.001) and unpaired analysis (P = 0.022). Additionally, patients with NAC treatment showed higher infiltration score (paired, P < 0.001; unpaired, P = 0.014) and more CD8T cells around Tregs (paired/unpaired, both P < 0.001). Subgroup analysis indicated that tumors with a diameter of ≤ 5 cm exhibited increase in both Dens and InS, and gemcitabine, pemetrexed and taxel enhanced Dens and TrPS following NAC. Multivariate analysis identified that the Dens, InS and TrPS were significantly associated with better chemotherapy response [OR = 8.54, 95%CI (1.69, 43.14), P = 0.009; OR = 7.14, 95%CI (1.70, 30.08), P = 0.024; OR = 5.50, 95%CI (1.09, 27.75), P = 0.039, respectively] and positive recurrence-free survival [HR = 3.23, 95%CI (1.47, 7.10), P = 0.004; HR = 2.70; 95%CI (1.27, 5.72); P = 0.010; HR = 2.55, 95%CI (1.21, 5.39), P = 0.014, respectively]. Moreover, TrPS and TrPS were negatively correlated with the CMVs and CAFs. These discoveries have deepened our comprehension of the immune-modulating impact of chemotherapy and underscored that the modified spatial landscape of Tregs after chemotherapy should be taken into account for personalized immunotherapy, aiming to ultimately improve clinical outcomes in patients with NSCLC.
PubMed: 38889507
DOI: 10.1016/j.intimp.2024.112434 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal...
OBJECTIVES
First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure.
MATERIALS AND METHODS
Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS).
RESULTS
A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0-652) after progression on osimertinib. Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65). TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis.
CONCLUSIONS
Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.
PubMed: 38889498
DOI: 10.1016/j.lungcan.2024.107856 -
Cell Biochemistry and Biophysics Jun 2024One of the most prevalent types of cancer worldwide today is gastric intestinal (GI) tumors. To guarantee their lives, people with a developed GI require palliative... (Review)
Review
One of the most prevalent types of cancer worldwide today is gastric intestinal (GI) tumors. To guarantee their lives, people with a developed GI require palliative care. This covers the application of targeted medicines in addition to chemotherapy treatments including cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, and pemetrexed. Because of the evidence of drug resistance emerging in poor patient outcomes and prognoses, determining the exact process of medication resistance is motivated. Besides, it is noteworthy that exosomes and noncoding RNAs, like microRNAs and long non-coding RNAs (lncRNAs), produced from tumor cells are implicated in both GI medication resistance and the carcinogenesis and development of GI disease. Biochemical events related to the cell cycle, differentiation of cells, growth, and pluripotency, in addition to gene transcription, splicing, and epigenetics, are all regulated by noncoding RNAs (ncRNAs). Therefore, it should come as a wonder that several ncRNAs have been connected in recent years to drug susceptibility and resistance as well as tumorigenesis. Additionally, through communicating directly with medications, altering the transcriptome of tumor cells, and affecting the immune system, exosomes may govern treatment resistance. Because of this, exosomal lncRNAs often act as a competitive endogenous RNA (ceRNA) of miRNAs to carry out its role in modifying drug resistance. In light of this, we provide an overview of the roles and processes of ncRNA-enriched exosomes in GI medication resistance.
PubMed: 38878101
DOI: 10.1007/s12013-024-01290-0 -
Alternative Therapies in Health and... Jun 2024This study aimed to evaluate the clinical efficacy and safety of siltuximab in combination with pemetrexed and platinum-based chemotherapeutic agents for treating...
OBJECTIVE
This study aimed to evaluate the clinical efficacy and safety of siltuximab in combination with pemetrexed and platinum-based chemotherapeutic agents for treating non-small cell lung cancer (NSCLC) through a randomized trial.
METHODS
Ninety-two NSCLC patients admitted to our hospital between July 2020 and July 2022 were randomly assigned to receive either pemetrexed + platinum drugs (observation group) or sintilimab plus pemetrexed + platinum drugs (experimental group) in a 1:1 ratio. Outcome measures included clinical efficacy, safety, serum tumor marker levels (CA125, CEA, CA199), immune function (CD4+, CD8+, CD4+/CD8+), cell growth factors (VEGF, bFGF, MMP-9), and survival quality indices (KPS, FACT-L scale).
RESULTS
In the observation group, the objective remission rate (ORR) was 36.96%, and the disease control rate (DCR) was 76.09%. In the experimental group, the ORR was 63.04%, and the DCR was 91.30%. Sintilimab enhanced the clinical efficacy of pemetrexed + platinum drugs, as indicated by improved ORR and DCR in the observation group (P < .05). The incidence of toxic side effects was 39.13% in the observation group and 43.48% in the experimental group, showing no significant difference (P > .05). Sintilimab + pemetrexed + platinum drugs demonstrated marked anti-tumor efficacy, reducing serum CA125, CEA, and CA199 concentrations compared to the regimen without sintilimab (P < .05). Patients with sintilimab exhibited enhanced immune function, with significantly higher CD4+ and CD4+/CD8+ levels and lower CD8+ levels (P < .05). Sintilimab + pemetrexed + platinum drugs resulted in lower levels of VEGF, bFGF, and MMP-9 compared to pemetrexed + platinum drugs (P < .05), suggesting better cell growth. Sintilimab + pemetrexed + platinum drugs enriched the survival quality of patients, indicated by higher KPS and FACT-L levels (P < .05). Additionally, the demographic characteristics of patients, including age, gender distribution, and disease stage, were comparable between the two groups.
CONCLUSION
The combination of sintilimab with pemetrexed + platinum-based chemotherapeutic agents shows therapeutic benefits in NSCLC. Improved ORR and DCR in the experimental group underscore clinical relevance. While promising, caution is needed due to the modest sample size and potential biases. A nuanced understanding of limitations is crucial for future research and application. This study prompts further research in NSCLC, advocating for larger cohorts and long-term follow-ups to explore sustained efficacy and potential biomarkers, guiding improvements in patient care.
PubMed: 38870510
DOI: No ID Found -
Journal of Fluorescence Jun 2024Pemetrexed is a chemotherapeutic medicine, under the trade name Alimta. Malignant pleural mesothelioma patients. Its application in lung cancer has been studied. Here...
Utility of Green Chemistry for Sustainable Fluorescence Derivatization Approach for Spectrofluorimetric Quantification of Pemetrexed as Antineoplastic Drug in Pharmaceutical Formulation and Spiked Human Plasma.
Pemetrexed is a chemotherapeutic medicine, under the trade name Alimta. Malignant pleural mesothelioma patients. Its application in lung cancer has been studied. Here in, a second spectrofluorimetric method was advanced for quantifying of Pemetrexed in pharmaceutical formulation and spiked human plasma. That method depends on fluorescence derivatization of Pemetrexed with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) at 75 °C in a (pH 9) of borate buffer to produce a fluorescent derivative which can be detected at 520 nm afterwards excitation at 460 nm. The method has been validated using ICH criteria, and it demonstrated linearity in a range of 2-120 ngmL-1. The proposed method was applied precisely and accurately for quantifying Pemetrexed within pharmaceutical formulation and spiking human plasma without any interferences. Moreover, the method's sustainability was evaluated and compared to the published method using two greenness assessment tools termed analytical eco-scale and Analytical GREENness (AGREE). That findings suggest that the method is more sustainable than the published method.
PubMed: 38865063
DOI: 10.1007/s10895-024-03767-w -
Cureus Jun 2024Sweet syndrome is an uncommon inflammatory disorder characterized by the abrupt appearance of painful, erythematous papules, plaques, or nodules on the skin. Fever and...
Sweet syndrome is an uncommon inflammatory disorder characterized by the abrupt appearance of painful, erythematous papules, plaques, or nodules on the skin. Fever and leukocytosis frequently accompany the cutaneous lesions. In addition, involvement of the eyes, musculoskeletal system, and internal organs may occur. Sweet syndrome has been associated with a broad range of disorders. There are three subtypes: classical Sweet syndrome, malignancy-associated Sweet syndrome, and drug-induced Sweet syndrome. Classical Sweet syndrome is not associated with malignancy or drugs. It is essentially associated with an upper respiratory infection, gastrointestinal infection, inflammatory bowel disease, and pregnancy. Malignancy-associated Sweet syndrome is associated with hematologic malignancy more than solid malignancy, most commonly with acute myeloid leukemia. Drug-induced Sweet syndrome usually develops approximately two weeks after drug exposure, in patients who lack a prior history of exposure to the inciting drug. Here we are discussing our patient, a 68-year-old male who presented eight weeks after starting chemotherapy with pemetrexed, carboplatin, and pembrolizumab for left lung adenocarcinoma with macular rash. On further investigation with biopsy was found to have neutrophilic dermatitis, hence being diagnosed with drug-induced Sweet syndrome. Histopathology revealed a dermis with infiltration of neutrophils with lekocytoclasia.
PubMed: 38859947
DOI: 10.7759/cureus.62027 -
Translational Lung Cancer Research May 2024rearrangements are infrequently observed in non-small cell lung cancer (NSCLC). Advanced genomic detection techniques have unveiled such infrequent genomic variations,...
BACKGROUND
rearrangements are infrequently observed in non-small cell lung cancer (NSCLC). Advanced genomic detection techniques have unveiled such infrequent genomic variations, particularly fusions in approximately 0.5% of NSCLC patients. Tyrosine kinase inhibitors (TKIs) have revolutionized the standard of care in lung cancer and more recently a second generation MET TKI tepotinib received Food and Drug Administration (FDA) approval for MET exon 14 alterations in metastatic NSCLC. Despite this, the therapeutic landscape for -rearranged NSCLC patients remains significantly unexplored. The aim of our report is to detail a unique case of a patient with metastatic lung adenocarcinoma with a novel fusion detected by next-generation sequencing (NGS) following previous treatment resistance.
CASE DESCRIPTION
A 73-year-old female was initially started on carboplatin, pemetrexed and pembrolizumab with maintenance, but eventually had progression in the left upper lobe (LUL). Upon progression she was enrolled in a clinical trial of a monoclonal antibody with or without a PD-1 inhibitor, but brain metastasis progression was eventually detected by magnetic resonance imaging (MRI) requiring stereotactic radiosurgery (SRS) and a craniotomy. The trial drug was eventually discontinued due to progression and toxicity and NGS on bronchoscopy tissue revealed fusion. The patient was initiated on tepotinib and continues with clinical and radiological stable disease for over 12 months. The patient's response to a MET inhibitor, tepotinib, underscores the potential efficacy of selective MET inhibitors for individuals with previously unexplored fusions.
CONCLUSIONS
The positive response to tepotinib of a patient with NSCLC harboring a novel -Fusion underscores the importance of the use of comprehensive next-generational sequencing-based panels and highlights the necessity for additional research and clinical exploration of selective MET inhibitors for managing NSCLC with rearrangements.
PubMed: 38854944
DOI: 10.21037/tlcr-24-34 -
The Lancet. Oncology Jul 2024Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic... (Randomized Controlled Trial)
Randomized Controlled Trial
Dendritic cells loaded with allogeneic tumour cell lysate plus best supportive care versus best supportive care alone in patients with pleural mesothelioma as maintenance therapy after chemotherapy (DENIM): a multicentre, open-label, randomised, phase 2/3 study.
BACKGROUND
Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma.
METHODS
In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0-1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m plus platinum [cisplatin 75 mg/m or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid vs other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 10 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with ClinicalTrials.gov, NCT03610360, and is closed for accrual.
FINDINGS
Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5-22·4), median overall survival was 16·8 months (95% CI 12·4-20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3-21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77-1·57]; log-rank p=0·62). The most common grade 3-4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1-2 in severity. No deaths were determined to be treatment related.
INTERPRETATION
MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities.
FUNDING
Amphera BV and EU HORIZON.
Topics: Humans; Female; Male; Dendritic Cells; Aged; Middle Aged; Pleural Neoplasms; Mesothelioma; Antineoplastic Combined Chemotherapy Protocols; Mesothelioma, Malignant; Maintenance Chemotherapy; Cisplatin; Carboplatin; Pemetrexed
PubMed: 38848742
DOI: 10.1016/S1470-2045(24)00191-8