SMEK1 promotes clear cell Renal Cell Carcinoma progression via EGFR tyrosine-kinase dependent pathway.

Studying the mechanisms underlying clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, may address an unmet need in ccRCC-targeted drug research. Growing evidences indicate that protein phosphatase 4 (PP4) plays an important role in cancer biology. Here, we characterized the upregulation of PP4 core component SMEK1 in ccRCC using tissue microarrays and revealed that its high expression is closely associated with reduced patient survival. We then conducted cell function experiments and animal experiments to prove the tumor-promoting effect of SMEK1. Next, RNA-seq was performed to explore its underlying mechanism, and the results revealed that SMEK1-regulated genes were extensively involved in cell motility, and the canonical tyrosine kinase receptor EGFR was one of its targets. Moreover, we verified the regulatory effect of SMEK1 on EGFR and its downstream MAPK and AKT pathway through molecular experiments, in which erlotinib, a tyrosine kinase inhibitor, can partially block this regulation, demonstrating that SMEK1 mediates its effects dependent on the tyrosine kinase activity of EGFR. Mechanistically, SMEK1 bond to PRMT5 and facilitated PRMT5-mediated histone methylation to promote the transcription of EGFR. Furthermore, we studied the upstream regulators of SMEK1 and demonstrated that the transcription factor E2F1 could directly bind to the SMEK1 promoter by chromatin immunoprecipitation. Functionally, E2F1 could also induce ccRCC progression by manipulating the expression of SMEK1. Collectively, our findings demonstrate the overexpression of SMEK1 in ccRCC, and reveal a novel E2F1/SMEK1/PRMT5/EGFR-tyrosine-kinase-dependent pathway for ccRCC progression.

The addition of nimotuzumab during concurrent chemoradiotherapy improved survival outcomes in locally advanced nasopharyngeal carcinoma patients with optimal response to induction chemotherapy.

OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.

The efficacy and potential mechanisms of pyrotinib in targeting EGFR and HER2 in advanced oral squamous cell carcinoma.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined. METHODS: 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR. RESULTS: This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (P < 0.014) and poor disease free survival (P < 0.042). In vitro, PYR suppressed the proliferation, colony formation and migration of OSCC cells. It also promoted apoptosis of OSCC cells and induced cell cycle arrest. Furthermore, PYR was able to inhibit the occurrence and development of OSCC effectively in vivo. Western blotting revealed that PYR suppressed OSCC by inhibiting the phosphorylation of HER2, AKT and ERK. CONCLUSIONS: This study exhibited the anti-OSCC effects of PYR in vitro and in vivo, and demonstrated PYR inhibited OSCC cells by inducing apoptosis via the HER2/ AKT and ERK pathway. The result of this study also indicated locally advanced OSCC patients might benefit from HER2 assay and EGFR/HER2 dual inhibit treatment.

The Ineffectiveness of Osimertinib in Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Lung Adenocarcinoma With Bone Metastasis: A Case Report.

This case report examines the effectiveness of osimertinib in a 64-year-old non-smoking female diagnosed with stage IV lung adenocarcinoma and an epidermal growth factor receptor (EGFR) exon 19 mutation, focusing on the treatment's impact on bone metastasis. Despite initial responsiveness to osimertinib, the patient's bone lesions remained largely unresponsive, prompting a comprehensive exploration of alternative treatments and clinical trials. This report highlights the patient's clinical journey, from diagnosis through various treatment phases, culminating in palliative care, and underscores the need for further research into targeted treatments for bone metastasis in lung cancer.

Anti-proliferation evaluation of new derivatives of indole-6-carboxylate ester as receptor tyrosine kinase inhibitors.

Aim: The main goal was to create two new groups of indole derivatives, hydrazine-1-carbothioamide (4a and 4b) and oxadiazole (5, and 6a-e) that target EGFR (4a, 4b, 5) or VEGFR-2 (6a-e). Materials & methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR/VEGFR-2, and the anti-proliferative properties were tested in vitro. Results: Compounds 4a (targeting EGFR) and 6c (targeting VEGFR-2) were the most effective cytotoxic agents, arresting cancer cells in the G2/M phase and inducing the extrinsic apoptosis pathway. Conclusion: The results of this study show that compounds 4a and 6c are promising cytotoxic compounds that inhibit the tyrosine kinase activity of EGFR and VEGFR-2, respectively.

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Synthesis, biological evaluation, and molecular docking studies of novel N-substituted piperazine-tethered thiophene-3-carboxamide selenides as potent antiproliferative agents with EGFR kinase inhibitory activity.

In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

Therapeutic application of extracellular vesicular EGFR isoform D as a co-drug to target squamous cell cancers with tyrosine kinase inhibitors.

Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.

An ultrasensitive DNA-enhanced amplification method for detecting cfDNA drug-resistant mutations in non-small cell lung cancer with selective FEN-assisted degradation of dominant somatic fragments.

OBJECTIVES: Blood cell-free DNA (cfDNA) can be a new reliable tool for detecting epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. However, the currently reported cfDNA assays have a limited role in detecting drug-resistant mutations due to their deficiencies in sensitivity, stability, or mutation detection rate. METHODS: We developed an Archaeoglobus fulgidus-derived flap endonuclease (Afu FEN)-based DNA-enhanced amplification system of mutated cfDNA by designing a pair of hairpin probes to anneal with wild-type cfDNA to form two 5'-flaps, allowing for the specific cleavage of wild-type cfDNA by Afu FEN. When the dominant wild-type somatic cfDNA fragments were cleaved by structure-recognition-specific Afu FEN, the proportion of mutated cfDNA in the reaction system was greatly enriched. As the amount of mutated cfDNA in the system was further increased by PCR amplification, the mutation status could be easily detected through first-generation sequencing. RESULTS: In a mixture of synthetic wild-type and T790M EGFR DNA fragments, our new assay still could detect T790M mutation at the fg level with remarkably high sensitivity. We also tested its performance in detecting low variant allele frequency (VAF) mutations in clinical samples from NSCLC patients. The plasma cfDNA samples with low VAF (0.1 and 0.5 %) could be easily detected by DNA-enhanced amplification. CONCLUSIONS: This system with enhanced amplification of mutated cfDNA is an effective tool used for the early screening and individualized targeted therapy of NSCLC by providing a rapid, sensitive, and economical way for the detection of drug-resistant mutations in tumors.

Oral lichenoid drug eruption due to osimertinib for lung cancer.

INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR) are linked with side effects involving skin and mucosa. Herein, we present a unique case of oral lichenoid drug eruption (LDE) in a patient treated with osimertinib. CASE REPORT: A 75-year-old woman was diagnosed with metastatic EGFR-mutated lung adenocarcinoma, and started on osimertinib 80 mg PO daily. At 24 months of therapy, the patient developed a painful, red, and white striated oral lesion involving the left buccal mucosa and the adjacent buccal aspect of gingivae. Biopsy showed oral LDE. Causality assessment between osimertinib and the oral LDE via Naranjo Adverse Drug Reaction probability scale revealed a score of 5. MANAGEMENT AND OUTCOME: Osimetinib discontinuation was not felt to be in the best interest of the patient. Therefore, diphenhydramine HCL mouthwash every 6 h PRN (before meals) was started. Spicy and hot foods were discontinued. At a four-week follow-up visit, the patient reported moderate improvement in her symptoms. CONCLUSION: Oral LDEs are considered premalignant lesions as they can transform into squamous cell carcinoma; therefore, regular follow-up is needed. Awareness of this potential side effect of osimertinib would also prevent unnecessary (and potentially costly) work-up and lead to its prompt diagnosis and treatment.

Recent Advances in Immunotherapy and Targeted Therapy of Triple Negative Breast Cancer.

The truancy of representation of the estrogen, progesterone, and human epidermal growth factor receptors occurs during TNBC. TNBC is recognized for the upper reappearance and has a poorer diagnosis compared with rest breast cancer (BC) types. Presently, as such, no targeted therapy is approved for TNBC and treatment options are subjected to chemotherapy and surgery, which have high mortality rates. Hence, the current article focuses on the scenario of TNBC vital pathways and discusses the latest advances in TNBC treatment, including immune checkpoint inhibitors (ICIs), PARP suppressors, and cancer vaccines. Immunotherapy and ICIs, like PD 1 and PD L1 suppressors, displayed potential in clinical trials (CTs). These suppressors obstruct the mechanisms which allow tumor cells to evade the system thereby boosting the body's defense against TNBC. Immunotherapy, either alone or combined with chemotherapy has demonstrated patient outcomes such as increased survival rates and reduced treatment-related side effects. Additionally, targeted therapy approaches include BRCA/2 mutation poly ribose polymerase inhibitors, Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors, Epidermal growth factor receptor inhibitors, Fibroblast growth factor inhibitors, Androgen Receptor inhibitors, PIK3/AKT/mTOR pathway inhibitors, Cyclin-dependent kinase (CDK) inhibitors, Notch signaling pathway inhibitors, Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors, Chimeric antigen receptor T (CAR-T) cell therapy, Transforming growth factor (TGF) -ß inhibitors, Epigenetic modifications (EPM), Aurora Kinase inhibitors and antibody-drug conjugates. We also highlight ongoing clinical trials and potential future directions for TNBC therapy. Despite the challenges in treating TNBC, recent developments in understanding the molecular and immune characteristics of TNBC have opened up new opportunities for targeted therapies, which hold promise for improving outcomes in this aggressive disease.

EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report.

Background: Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the tumor protein p53 (TP53). It causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, and central nervous system tumors. There are a few cases reported in the literature of patients with LFS presenting with an epidermal growth factor receptor (EGFR) mutated lung cancer. Still, it has been suggested that there may be an association between the TP53 pathogenic variant and lung cancer with EGFR mutation in somatic cells. Case Description: A 47-year-old non-smoker woman with LFS with a history of multiple tumors, including bilateral breast cancer, pecoma, and sarcoma. In one of her computed tomography, a lesion in the lingula of the lung was detected. It was biopsied, which diagnosed lung adenocarcinoma, and genetic studies detected an EGFR exon 19 deletion. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Conclusions: The association between TP53 and lung cancer with EGFR mutation has been suggested in case reports. Studies in lung cancer cell lines have shown a link between TP53 mutation and EGFR overexpression. Nonetheless, as more cases are reported, further research is needed to comprehend the interrelation between these two pathologies and the risk posed by LFS to the emergence of EGFR-mutated lung cancer.

Synchronous Double Primary Lung Adenocarcinomas With EGFR L858R Point Mutation and MET Exon 14 Skipping Mutation.

Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S1 and another nodule in the left S1+2. Bronchoscopic biopsy diagnosed the right S1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S1 adenocarcinoma detected EGFR L858R mutation. The 18F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S1 and the left S1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT1bN2M0) of adenocarcinoma in the right S1 and suspected another primary lung cancer in the left S1+2. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S1 cancer achieved partial response (PR), while the left S1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S1+2 nodule (cT1bN3M0, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S1+2 cancer achieved and maintained PR by capmatinib, the right S1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.

Clinical Impacts of Allograft Biopsy in Renal Transplant Recipients 10 Years or Longer After Transplantation.

We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.

Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer.

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.

Design and synthesis of novel Thiazolo[5,4-b]pyridine derivatives as potent and selective EGFR-TK inhibitors targeting resistance Mutations in non-small cell lung cancer.

A novel series of substituted thiazolo[5,4-b]pyridine analogues were rationally designed and synthesized via a multi-step synthetic pathway, including Suzuki cross-coupling reaction. The anticancer activity of all forty-five synthesized derivatives was evaluated against HCC827, H1975, and A549 cancer cell lines utilizing the standard MTT assay. A significant number of the thiazolo[5,4-b]pyridine derivatives exhibited potent anticancer activity. Notably, compounds 10b, 10c, 10h, 10i, and 10k emerged as the most promising anticancer agents. The lead compound, N-(3-(6-(2-aminopyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-methylphenyl)-2,5-difluorobenzenesulfonamide (10k), displayed remarkable potency with IC50 values of 0.010 µM, 0.08 µM, and 0.82 µM against the HCC827, NCI-H1975 and A-549 cancer cell lines, respectively, which were comparable to the clinically approved drug Osimertinib. Importantly, the potent derivatives 10b, 10c, 10h, 10i, and 10k exhibited selective cytotoxicity towards cancer cells and showing no toxicity against the normal BEAS-2B cell line at concentrations exceeding 35 µM. Mechanistic studies revealed that the active compound 10k acts as an EGFR-TK autophosphorylation inhibitor in HCC827 cells. Furthermore, apoptosis assays demonstrated that compound 10k induced substantial early apoptosis (31.9 %) and late apoptosis (8.8 %) in cancer cells, in contrast to the control condition exhibiting only 2.0 % early and 1.6 % late apoptosis. Molecular docking simulations of the synthesized compounds revealed that they formed essential hinge interactions and established hydrogen bonding with Cys797, indicating potential target engagement. These findings highlight the potential of the synthesized thiazolo [(Woodburn, 1999; Zigrossi et al., 2022) 5,45,4-b]pyridine derivatives as promising anticancer agents, warranting further investigation for the development of novel targeted therapies against non-small cell lung cancer.

A Randomized, Multi-Center, Open Label Study to Compare the Safety and Efficacy between Afatinib Monotherapy and Combination Therapy with HAD-B1 for the Locally Advanced or Metastatic NSCLC Patients with EGFR Mutations.

BACKGROUND: Lung cancer, especially non-small cell lung cancer (NSCLC), poses a significant health challenge globally due to its high mortality. Afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has shown superior efficacy over traditional chemotherapy in NSCLC treatment. However, issues like secondary resistance and adverse effects call for alternative therapies. HAD-B1, comprising 4 herbal medicines, has shown promise in lung cancer treatment in both preclinical and clinical settings. This study assesses the combination of HAD-B1 and Afatinib in advanced NSCLC patients to potentially improve outcomes by addressing the limitations of current EGFR-TKI therapies. METHOD: A randomized, open-label trial evaluated the efficacy and safety of HAD-B1 with Afatinib in 90 EGFR-mutation-positive NSCLC patients. Participants were divided into treatment and control groups, receiving Afatinib with or without HAD-B1. The study focused on the initial dose maintenance rate and disease control rate (DCR) of Afatinib, alongside secondary outcomes like survival rates and quality of life, under continuous safety monitoring. RESULTS: Among the 90 participants, no significant difference was found in initial dose maintenance (60.98% in the treatment group vs 52.50% in the control, P = .4414) or DCR (80.49% vs 90.00%, P = .2283). Secondary outcomes like PFS, TTP, and OS showed no notable differences. However, physical functioning significantly improved in the treatment group (P = .0475, PPS group). The control group experienced higher rates of adverse events of special interest and adverse drug reactions (P = .01), suggesting HAD-B1 with Afatinib might enhance physical function without increasing adverse effects. CONCLUSION: Combining HAD-B1 with Afatinib potentially improves quality of life and reduces adverse events in advanced NSCLC patients. Further research is necessary to confirm the long-term benefits of this combination therapy, aiming to advance NSCLC treatment outcomes. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) of the Republic of Korea, https://cris.nih.go.kr/ (ID: KCT0005414).

Prospective study of the effect of rituximab on kidney function in membranous nephropathy.

Background: Patients with membranous nephropathy (MN) and poor kidney function or active disease despite previous immunosuppression are underrepresented in clinical trials. It is unknown how effective rituximab is in this population. Methods: This prospective, multi-centre, single-arm, real-world study of patients with active MN [urine protein-creatinine ratio (uPCR) >350 mg/mmol and serum albumin <30 g/L, or a fall in estimated glomerular filtration rate (eGFR) of at least 20% or more over at least 3 months] evaluated rituximab in those with contraindications to calcineurin inhibitors and cytotoxic therapy. The primary outcome was change in rate of eGFR decline before and after rituximab. Complete or partial remission were defined as uPCR <30 mg/mmol or uPCR <350 mg/mmol with a ≥50% fall from baseline, respectively. Results: A total of 180 patients [median age 59 years, interquartile range (IQR) 48-68] received rituximab and were followed up for a median duration of 17 months. Seventy-seven percent had prior immunosuppression. Median eGFR and uPCR at baseline were 49.2 mL/min/1.73 m2 (IQR 34.4-80.6) and 766 mg/mmol (IQR 487-1057), respectively. The annual rate of decline of eGFR fell from 13.9 to 1.7 mL/min/1.73 m2/year following rituximab (Z score = 2.48, P < .0066). At 18 months 12% and 42% of patients were in complete or partial remission, respectively. Rituximab was well tolerated; patient survival was 95.6% at 2 years and in patients in whom eGFR was available, kidney survival was 93% at 2 years. Conclusion: Rituximab significantly reduced the rate of eGFR decline in active MN including those who had received prior immunosuppression or with poor baseline kidney function.

Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Dapagliflozin treatment in patients with chronic kidney disease associated with autosomal dominant polycystic kidney disease.

Introduction: The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. Methods: We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. Results: The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. Conclusion: In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors.