Pancreatic cancer (PC) has a poor prognosis and limited treatment options. The development of resistance to anticancer agents poses a significant challenge in the treatment of PC. Our previous study indicated that basic helix-loop-helix family member e41 (BHLHE41) is associated with the prognosis of lung cancer. Additionally, BHLHE41 affects the prognosis and response to anticancer drugs in several cancers. However, the functional role of BHLHE41 in cancer remains unclear. In PC, its expression has been reported to influence tumor malignancy; however, its impact on chemosensitivity has not yet been elucidated. Therefore, this study aimed to investigate the effects of BHLHE41 on PC chemosensitivity. Genetic modification and MTT assays were performed to evaluate the effect of BHLHE41 on anticancer agents. RNA sequencing (RNA-seq) was conducted to analyze the downstream pathways of BHLHE41. Furthermore, anticancer agent sensitivity tests were performed for the candidate genes identified through RNA-seq. BHLHE41 enhanced the sensitivity of PC cells to gemcitabine (GEM) while suppressing the expression of insulin-like growth factor binding protein 4 (IGFBP4). Additionally, IGFBP4 affected sensitivity to GEM independently of BHLHE41, suggesting that IGFBP4 contributes to resistance to this agent in PC cells. These findings provide novel insights that may help identify potential targets for patients with PC undergoing chemotherapy and open new avenues for research and therapeutic strategies.

Andrographolide, a compound derived from Andrographis paniculata, has exhibited promising antineoplastic effects; however, its effects on pluripotency and cancer stemness remain unclear. Since pluripotency and cancer stemness are key factors in treatment resistance and relapse, it is important to investigate how andrographolide affects these properties. MCF7 cells were treated with andrographolide (7.5-120 μM) for 24 or 48 h. Cell viability was evaluated using the MTT assay. Mitochondrial membrane potential was measured using TMRE. Gene expression of TOMM20, caspase-3, BAX, BCL2 and OCT4 was analyzed using RT-qPCR. Mammosphere and colony formation assays were performed to assess self-renewal and proliferation. MTT assays revealed a dose- and time-dependent reduction in the cell viability following andrographolide treatment. TMRE staining revealed a decrease in the mitochondrial membrane potential of andrographolide-treated MCF7 cells, indicating mitochondrial dysfunction. RT-qPCR analysis showed down-regulation of TOMM20 and caspase-3 expression, although MCF7 cells are typically caspase-3 deficient. Notably, BAX expression was up-regulated following treatment with 60 μM andrographolide, suggesting the induction of apoptosis. A dose-dependent increase in OCT4 expression was observed, with a 13.52-fold rise at 60 μM, indicating a potential shift toward a pluripotent-like state. Gene correlation analysis revealed a negative correlation between TOMM20 and OCT4 expression, suggesting that TOMM20 down-regulation enhances pluripotency. The positive correlation between OCT4 and BAX expression suggests a complex link between apoptosis and stemness. Immunocytochemistry confirmed TOMM20 localization in the cytoplasm. Reduced mammosphere and colony formation indicated decreased self-renewal and proliferation. Andrographolide exerts anti-cancer effects through mitochondrial dysfunction and apoptosis, while paradoxically increases OCT4 expression. These findings may indicate an adaptive cellular survival mechanism, in which OCT4 up-regulation and TOMM20 down-regulation are correlated with cancer-like characteristics.

Partial or radical nephrectomy are the gold standard treatments for localized renal cell carcinoma; however, these treatments can induce kidney disease. This study aimed to investigate the functional outcomes of chronic kidney disease due to medical causes and end-stage renal disease in patients with localized renal cell carcinoma. This retrospective study enrolled 243 patients diagnosed with localized renal cell carcinoma at our Institution. Chronic kidney disease was classified as either surgically induced or attributable to medical causes, and outcomes were compared. Furthermore, a machine-learning model was used to identify important factors related to end-stage renal disease. Of the 243 patients, 5 died of progressive disease, 18 died of other causes, and 8 developed end-stage renal disease. Patients with chronic kidney disease due to medical causes had a higher risk of mortality (p=0.049), and none of the patients with surgically-induced chronic kidney disease developed end-stage renal disease (p<0.0001). Preoperative renal function and proteinuria were key factors related to end-stage renal disease after surgery. Patients with chronic kidney disease due to medical causes exhibited a 0.1% higher risk of end-stage renal disease than those with surgically-induced chronic kidney disease. Patients with proteinuria exhibited a 0.4% higher risk of end-stage renal disease than those without proteinuria. Chronic kidney disease due to medical causes should be considered in surgical decision-making as it is a significant risk factor for mortality and end-stage renal disease. Chronic kidney disease due to medical causes and proteinuria before and after surgery must be treated with care to improve patient survival and avoid the onset of end-stage renal disease.

THEMIS2, a protein that plays a role in immune regulation, has recently been identified as a key factor in breast cancer progression. This study aimed to identify novel oncogenic regulators in circulating tumor cells (CTCs) that contribute to breast cancer metastasis and chemoresistance, elucidating the regulatory axis involving THEMIS2, VEGFR2 and microRNAs (miRNAs), specifically miR-125b-5p. Using RNA-sequencing of breast cancer CTCs, THEMIS2 was identified as a significantly upregulated gene. miRNA target predictions and expression profiling in primary tumors and normal breast specimens were conducted to evaluate candidate regulators. Functional assays including sphere formation, migration, luciferase reporter activity, VEGFR phosphorylation analysis and in vivo tumor models were employed to investigate the roles of THEMIS2 and miR-125b-5p in metastasis and drug sensitivity. THEMIS2 was found upregulated in CTCs and breast cancer cell lines with metastatic potential. miR-125b-5p, but not miR-125a-5p, was significantly down-regulated in metastatic models and identified as a direct post-transcriptional suppressor of THEMIS2. THEMIS2 enhanced VEGFR2 phosphorylation and promoted metastatic traits and resistance to docetaxel and bevacizumab. miR-125b-5p suppressed metastasis and restored chemosensitivity by targeting 3'UTR of THEMIS2, an effect reversible with anti-miR-125b or ectopic THEMIS2 expression. We unraveled a novel miR-125b-5p-THEMIS2-VEGFR2 signaling axis as a key modulator of breast cancer metastasis and chemoresistance. These findings provide mechanistic insight and suggest that miR-125b-5p or THEMIS2 may serve as therapeutic targets or prognostic biomarkers in aggressive breast cancers.

This study aimed to report clinical outcomes of spine stereotactic body radiation therapy (SBRT) using biaxially rotational dynamic radiation therapy (BROAD-RT), which is a novel non-coplanar volumetric-modulated arc therapy (VMAT) technique that does not require couch rotation or patient repositioning. We retrospectively analyzed 13 patients who received spine SBRT using BROAD-RT in a prospective feasibility study conducted between August 2020 and April 2022. The prescribed dose was 27 Gy in 3 fractions. Patient-specific dosimetric quality assurance (QA) using ArcCHECK was conducted. The median age of patients was 73 years old. Primary cancers involved the prostate (23.0%, N=3), lung (15.4%, N=2), breast (15.4%, N=2), liver (15.4%, N=2), thyroid (15.4%, N=2), malignant meningioma (7.7%, N=1), and synovial sarcoma (7.7%, N=1). Overall, 84.6% of patients (N=11) had oligo-metastatic disease at the time of SBRT. QA showed average (±standard deviation) passing rates of 96.4 ± 2.5%. The median follow-up period was 36.2 months. Local control (LC) and overall survival (OS) rates were 84.6 and 100% at one year, and 59.8 and 68.4% at three years, respectively. The cumulative incidence of grade ≥2 vertebral compression fracture (VCF) was 7.7 and 23.1% at one and three years, respectively. Other than VCF, no grade ≥3 toxicities or radiation-induced myelopathies were observed. BROAD-RT enabled the easy application of non-coplanar VMAT in spine SBRT with marked accuracy. Treatment with 27 Gy in three fractions resulted in acceptable toxicity, although LC was relatively low. These findings highlight both the feasibility of BROAD-RT and the need for further investigation of dose and fractionation strategies.

Combined prompt cancer diagnosis and treatment is a key pursuit of the scientific community. Since the 20th century, a variety of early cancer detection methods (screening tests) have been developed. Histopathological examination of cancerous tissues is the "gold standard" in establishing the final diagnosis, as well as documenting the adequacy of the therapeutic intervention, although unable to detect neoplastic/malignant cells in real-time. In the current experimental research, we present a novel, innovative medical diagnostic device and demonstrate its potential utilization as a screening test for the early detection of neoplastic/malignant lesions in real-time. A group of 215 patients were enrolled in the study. The innovative medical diagnostic device was used to collect a sufficient number of measurements from head and neck neoplastic -including skin - lesions. Using special software algorithms, the cell membrane was simulated with an equivalent electric circuit. The excitation response of the biological tissues was calculated by applying a dielectric spectroscopy method. The presence of neoplastic cells was detected as a significantly increased contribution of the capacitive reactance to the total impedance of the tissues under examination (θ angle). The θ angle extracted measurements were compared to the respective histopathologic reports. θ angle values were found to be statistically different between normal, non-neoplastic, and malignant tissues (p<0.001). In terms of physics, the unknown complex impedance of the tissue under assessment as well as the capacitive reactance can be experimentally measured and therefore cancerous cells can be distinguished from healthy cells by the changes in the measured capacity reactance contribution (θ angle differences). The described innovative medical device leads reliable results for the early detection of neoplastic/malignant cells in real-time.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide due to its high incidence and poor prognosis. Although targeted therapies and immunotherapies have advanced, survival outcomes remain unsatisfactory for lung-cancer patients. Recombinant methioninase (rMETase), which targets methionine addiction, a fundamental and general hallmark of cancer, has demonstrated synergistic efficacy with chemotherapeutic agents in numerous cancer types. We have previously shown synergy of rMETase and ivermectin against pancreatic-, colon-, and breast-cancer cells. The present study aimed to investigate the synergistic efficacy of rMETase in combination with cisplatinum and ivermectin on lung-cancer cells compared to normal fibroblasts. The human lung-adenocarcinoma cell line A549 and normal human-fibroblast cell strain Hs27 were seeded in 96-well plates (1,000 cells/well) containing Dulbecco's Modified Eagle's medium and incubated for 24 h. The cells were then treated for 72 h with rMETase (0.0625-8 U/ml), cisplatinum (0.25-32 μM), or ivermectin (1-128 μM). Cell viability was assessed using the WST-8 assay, and the 30% inhibitory concentration (IC30) for each drug was calculated for both cell types. To evaluate synergy, both cell types were treated with each drug alone or in two-drug and three-drug combinations based on their respective IC30 values, and cell viability was measured. To assess the time-dependent effects of the triple-combination treatment, A549 lung-cancer cells and Hs27 fibroblasts were cultured under the same conditions and treated with the triple combination. Cell viability was then measured at 24, 48, 72, and 96 h after treatment initiation. The IC30 value of rMETase was 0.46 U/ml; cisplatinum was 0.33 μM; and ivermectin was 2.08 μM for A549 lung-cancer cells. For normal Hs27 fibroblasts the IC30 value for rMETase was 0.5 units/ml; for cisplatinum was 0.35 μM and for ivermectin was 6.4 μM. When these 3 agents were combined at their respective A549 IC30 concentrations, A549 cell viability was significantly reduced compared to monotherapy or dual combinations (p<0.05), indicating synergy. In contrast, triple-combination-treatment using the A549 IC30 values or the Hs27 IC30 values, had minimal effect and no synergy on Hs27 normal fibroblasts, demonstrating selectivity for cancer cells. Furthermore, for A549 cells, the triple-combination therapy significantly decreased cell viability as early as 24 h after treatment initiation (p<0.05), and essentially eradicated the lung-cancer cells with minimal effect on the normal fibroblasts during this time period. The present study demonstrated that the combination of rMETase, cisplatinum, and ivermectin exerts selective synergy on lung-cancer cells, which was not observed on normal fibroblasts. Moreover, the present combination therapy has a strong synergistic efficacy at early time points on the lung-cancer cells. Further studies are warranted to elucidate the underlying mechanisms of synergy of the present combination treatment selectively on cancer cells and to evaluate the in vivo efficacy and safety of the present treatment strategy.

We aimed to assess the results of neoadjuvant radiochemotherapy (N-RCT) in a cohort of 54 patients with middle and lower third locally advanced rectal cancer (LARC) treated in real-world practice at a German certified oncologic rectal center for the treatment of rectal cancer. From September 2016 to December 2023, 54 patients (median age of 66.5 years, range=33-82 years) with middle and lower third rectal cancer received N-RCT. Mean tumor distance from anal verge was 5.34 cm (±2.93). The distribution into UICC stages was as follows: stage II, n=6; stage III, n=45; stage IV, n=3. All patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) using the volumetric intensity modulated arc therapy (VMAT) technique and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-42). Total mesorectal excision (TME) was performed six to eight weeks after the N-RCT. Adjuvant chemotherapy was performed in 34/54 patients after surgery in accordance with the German S3 guideline. With a median follow-up of 38 months (range=4-79), local recurrence occurred in 4 out of 54 patients (7%), and distant metastasis in 11 out of 54 patients (20%). During the follow-up period, 8 out of 54 patients (15%) died. The 3-year overall survival and disease-free survival rates were 91% and 76%, respectively. Pathological downstaging (ypT < cT) was achieved in 28 of 54 patients (52%) (p=0.001), and ypN ≤ cN in 35 out of 54 patients (65%) (p=0.001). Among the 54 patients who underwent surgery, 53 had an R0 resection, while 1 patient had an R1 resection. Sphincter-preserving surgery was performed in 26 patients (48%). A pathological complete response (pCR) was observed in 7 patients (13%). No grade 3 or 4 radiogenic side effects were observed. This study demonstrates that N-RCT followed by TME yields favorable oncological outcomes with manageable toxicity in patients with locally advanced rectal cancer. Our results align with previously published findings. Further research is required to optimize patient selection and to assess the long-term benefits of evolving neoadjuvant strategies in routine clinical practice.

Immune checkpoint inhibitors (ICIs) have emerged as a first-line treatment for advanced non-small cell lung cancer (NSCLC), offering the potential for long-term survival. However, predictors of sustained clinical benefit in patients without driver gene mutations remain poorly defined. This study aimed to identify clinical and therapeutic factors associated with long-term survival in NSCLC patients treated with ICIs. We retrospectively analyzed 97 NSCLC patients treated with ICIs. Patients who survived for >3 years were classified as the long-term survival group, and those who did not were categorized as the non-long-term survival group. Clinical characteristics and treatment-related factors were compared between these two groups. Of the 97 patients, 22 (22.7%) were classified into the long-term survival group. This group included a higher proportion of younger patients, patients who responded to initial ICI therapy, and patients who discontinued treatment due to immune-related adverse events (irAEs). Multivariate analysis identified younger age and low neutrophil-to-lymphocyte ratio (NLR) as independent predictors of long-term survival. Adenocarcinoma histology and switching administration of ICIs (i.e., changing from a PD-1 to a PD-L1 inhibitor or vice versa) showed clinically suggestive, though marginally significant, associations with prolonged survival. Younger age and low NLR were associated with long-term survival in NSCLC patients treated with ICIs. Adenocarcinoma and switching administration may have potential clinical relevance. These findings highlight the importance of patient selection and strategic management of ICI therapy. Nevertheless, confirmation in larger prospective cohorts is warranted.

Pulmonary emphysema has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, the relationship between emphysema severity and the clinicopathological and molecular features of NSCLC remains poorly understood. This study aimed to evaluate whether the extent of emphysematous change, measured as the low attenuation area percentage (LAA%) on computed tomography (CT), is associated with clinicopathological and molecular features in resected NSCLC. We retrospectively analyzed 218 patients with NSCLC who underwent curative surgical resection and molecular profiling, including assessment of driver gene alterations and programmed death-ligand 1 (PD-L1) expression. Emphysema severity was quantified using preoperative CT with three-dimensional image analysis software and expressed as the LAA% within the resected lobe. Patients were stratified into high (≥1.0%) and low (<1.0%) LAA% groups. Associations between LAA% and clinicopathological and molecular features were examined. Among the 218 patients, 83 (38.1%) were classified into the high LAA% group. High LAA% was significantly associated with male sex, higher smoking index, reduced forced expiratory volume (FEV) 1.0%, and pleural and vascular invasion in NSCLC. In adenocarcinoma, high LAA% was also associated with higher histological grade and increased spread through air spaces. Moreover, high LAA% was significantly associated with a higher prevalence of KRAS mutations, a lower prevalence of EGFR mutations, and elevated PD-L1 expression (≥50%) in NSCLC. Emphysema severity, as assessed using LAA% on preoperative CT, is associated with aggressive clinicopathological and molecular features in NSCLC. These findings may contribute to optimizing individualized postoperative treatment strategies.