Case report: A case of Savolitinib in the treatment of MET amplification mutation advanced lung adenocarcinoma with rare bilateral breast metastasis.

Background: The distant metastasis of lung cancer primarily occurs in the bones, liver, brain, and lungs, while the breast is an extremely rare site of metastasis. There is very limited literature on the occurrence of breast metastasis from lung cancer, and metastatic lesions in the breast are prone to being misdiagnosed as primary breast cancer, requiring careful attention and differentiation in the clinical diagnostic and treatment process. Case summary: The patient, a 63-year-old female, initially presented with an EGFR exon 21 L858R mutated left lung adenocarcinoma in 2017, treated successfully with surgical resection and subsequent monitoring. The relapse of disease occurred in January 2020. Despite maintaining a prolonged progression-free survival (PFS) with first-generation EGFR-TKI Afatinib, disease progression occurred in 2022 without detectable resistance mutations. Transition to second-generation TKI Furmonertinib resulted in poor control, with rapid progression including unusual bilateral breast metastases that exhibited inflammatory breast cancer-like peau d'orange changes. Standard chemotherapy achieved only short-term stability. Upon detecting a MET amplification mutation, treatment with Savolitinib was initiated. Remarkably, this led to significant clinical and radiographic improvement, notably resolving the peau d'orange appearance and reducing multiple lesions across the body. Conclusion: This case underscores the importance of continuous genetic profiling and tailored treatment approaches in managing advanced lung adenocarcinoma, particularly when presenting with rare metastatic sites and complex genetic landscapes. The successful application of Savolitinib following the identification of a MET amplification mutation highlights its potential in overcoming resistance mechanisms in NSCLC, providing a significant therapeutic option for similarly challenging cases.

[Retracted] MicroRNA­19b promotes the migration and invasion of ovarian cancer cells by inhibiting the PTEN/AKT signaling pathway.

[This retracts the article DOI: 10.3892/ol.2018.8695.].

Myosteatosis is associated with coronary artery calcification in patients with type 2 diabetes.

BACKGROUND: Myosteatosis, rather than low muscle mass, is the primary etiologic factor of sarcopenia in patients with type 2 diabetes mellitus (T2DM). Myosteatosis may lead to a series of metabolic dysfunctions, such as insulin resistance, systematic inflammation, and oxidative stress, and all these dysfunctions are closely associated with the acceleration of T2DM and atherosclerosis. AIM: To investigate the association between myosteatosis and coronary artery calcification (CAC) in patients with T2DM. METHODS: Patients with T2DM, who had not experienced major cardiovascular events and had undergone both abdominal and thoracic computed tomography (CT) scans, were included. The mean skeletal muscle attenuation was assessed using abdominal CT images at the L3 level. The CAC score was determined from thoracic CT images using the Agatston scoring method. Myosteatosis was diagnosed according to Martin's criteria. Severe CAC (SCAC) was defined when the CAC score exceeded 300. Logistic regression and decision tree analyses were performed. RESULTS: A total of 652 patients with T2DM were enrolled. Among them, 167 (25.6%) patients had SCAC. Logistic regression analysis demonstrated that myosteatosis, age, duration of diabetes, cigarette smoking, and alcohol consumption were independent risk factors of SCAC. Myosteatosis was significantly associated with an increased risk of SCAC (OR = 2.381, P = 0.003). The association between myosteatosis and SCAC was significant in the younger patients (OR = 2.672, 95%CI: 1.477-4.834, P = 0.002), but not the older patients (OR = 1.456, 95%CI: 0.863-2.455, P = 0.188), and was more prominent in the population with lower risks of atherosclerosis. The decision tree analyses prioritized older age as the primary variable for SCAC. In older patients, cigarette smoking was the main contributing factor for SCAC, while in younger patients, it was myosteatosis. CONCLUSION: Myosteatosis is a novel risk factor for atherosclerosis in patients with T2DM, especially in the population with younger ages and fewer traditional risk factors.

[Research Progress of Iron Metabolism in Disease Progression and Drug Resistance of Multiple Myeloma--Review].

Iron metabolism is involved in the development and drug resistance of many malignancies, including multiple myeloma (MM). Based on recent studies on iron metabolism and MM, this paper reviews the relationship between iron metabolism and disease process of MM in terms of iron overload leading to ferroptosis in MM cells, the role of iron deficiency in oxidative respiration and proliferation of MM cells, and the interaction between ferroptosis and autophagy in the disease process. The mechanisms by which iron metabolism-related substances lead to MM cells' resistance to proteasome inhibitors (PI) through inducing redox imbalance and M2 macrophage polarization are also briefly described, aiming to provide a theoretical basis for the application of iron metabolism-related drugs to the clinical treatment of MM patients.

Matrix metalloproteinases and tissue inhibitors in multiple myeloma: promote or inhibit?

Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) play a vital role in the pathogenesis of multiple myeloma (MM), especially for tumor invasion and osteolytic osteopathy. By breaking down extracellular matrix (ECM) components and releasing the proteins composing the ECM and growth factors, as well as their receptors, MMPs affect tissue integrity and promote cancer cell invasion and metastasis. A vital pathophysiological characteristic of MM is the progress of osteolytic lesions, which are brought on by interactions between myeloma cells and the bone marrow microenvironment. MMPs, certainly, are one of the fundamental causes of myeloma bone disease due to their ability to degrade various types of collagens. TIMPs, as important regulators of MMP hydrolysis or activation, also participate in the occurrence and evolution of MM and the formation of bone disease. This review focuses on the role of MMP-1, MMP-2, MMP-7, MMP-9, MMP-13, MMP-14, and MMP-15 and the four types of TIMPs in the invasion of myeloma cells, angiogenesis, osteolytic osteopathy, to offer some novel perspectives on the clinical diagnostics and therapeutics of MM.

[Clinical Role of M Protein in Multiple Myeloma and Lymphoma --Review].

M protein is often expressed in multiple myeloma and also can be detected in several lymphoma such as Waldenstrm macroglobulinaemia. M protein level can reflect the malignant degree and even genetic abnormality of multiple myeloma and lymphoma to some extent to predict the progress of the diseases, and the therapeutic response and prognosis of the disease can be evaluated by monitoring the M protein level and its change degree. This article reviews the role of M protein in the progression and prognosis of multiple myeloma and lymphoma, and discusses the differences in M protein expression between multiple myeloma and lymphoma, in order to provide new insights for clinical diagnosis, monitoring and evaluation of therapeutic effect.

Upregulation of LINC01503 promotes cervical cancer progression by targeting the miR-615-3p/CCND1 axis.

Mounting evidence indicates that long non-coding RNAs influence the progression of cervical cancer, but the precise function of LINC01503 in the pathogenesis of the disease remains unknown. Here, we found higher levels of LINC01503 in cervical cancer tissues. High LINC01503 expression was associated with enhanced progression of cervical cancer as indicated by advanced FIGO stage, increased metastasis of tumor cells to lymph nodes, and invasion into deeper cervical tissues. LINC01503 inhibition markedly suppressed the invasion and proliferative ability of tumor cells. Mechanistically, LINC01503 was demonstrated to negatively modulate the expression of miR-615-3p in cervical cancer. CCND1 was found to be a target of miR-615-3p. Rescue experiments indicated that LINC01503 inhibition suppressed the invasion and proliferative ability of the tumor cells, a phenomenon that was reversed following miR-615-3p inhibition or CCND1 overexpression. Collectively, these data indicate that LINC01503 enhances the progression of cervical cancer cells via interaction with miR-615-3p/CCND1 axis.

The primary pulmonary NUT carcinomas and some uncommon somatic mutations identified by next-generation sequencing: a case report.

Nuclear protein in testis (NUT) carcinoma (NUT-C) is an exceedingly rare and aggressive squamous tumor characterized by an acquired rearrangement of the NUT gene involving the NUTM1 (Nut midline carcinoma, family member 1, NUT) gene encoding the nuclear protein of the testis on 15q14. As a rare tumor, there is little information available on the clinicopathologic and molecular cytogenetic findings of NMC. We herein reported a case of a 69-year-old man diagnosed with lung NMC involving the rearrangement of chromosomal region 15q14 harboring the NUTM1 gene. It was exceptionally rare for the patient's involving of the lung but having the chance to be totally resected. After radical surgery, the patient accepted further four cycles of chemotherapy and remains disease-free after 10 months. The immunohistochemical staining of PDL1 was negative and next-generation sequencing technology identified genomic alterations in discoidin domain receptor tyrosine kinase 2 (DDR2), cyclin D1 (CCND1), B-cell leukemia/lymphoma 1 (BCL1), colony-stimulating factor 1 receptor (CSF1R), runt related transcription factor 1 (RUNX1) and death domain-associated protein 6 (DAXX6) from the paraffin-embedded tissue. This case will contribute to not only a better understanding of the molecular mechanism of the primary pulmonary NUT carcinomas but also the potential therapeutic option for the patient.

Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer.

OBJECTIVE: To evaluate the influence of a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) treatment on the clinical features of leptomeningeal metastasis (LM) progression and outcome in advanced non-small cell lung cancer (NSCLC) patients. METHODS: We retrospectively evaluated advanced NSCLC patients receiving effective first-generation EGFR TKI treatment (e.g., treatment > 6 months) at our institution between January 2008 and February 2014. Incidence, time to progression, and treatment outcome of LM were examined. RESULTS: In our cohort, 29/420 patients (6.9%) developed LM. Among the patients harboring L858R or deletion of exon 19 in EGFR, the incidence of LM was 10.7% (21/197) and 3.4% (7/203), respectively (P = 0.006). The median time to LM progression was 16.5 months (95% confidence interval (CI), 11.9-20.8). The median overall survival (OS) after LM diagnosis was 5.2 months (95% CI, 3.2-7.2). In a subgroup analysis, OS was improved in patients with performance status (PS) ≤ 2 vs. PS > 2 (14.2 months vs. 2.3 months, respectively; P < 0.001). OS was also improved among patients who received, rather than did not receive, anti-tumor treatment (6.0 months vs. 1.9 months, respectively; P < 0.001) or whole brain radiotherapy (WBRT) (6.0 months vs. 3.9 months, respectively; P = 0.038). Multivariate analysis indicated that WBRT is a good prognostic factor (P = 0.048), whereas best support care (P = 0.033) and PS > 2 (P = 0.034) were poor prognostic factors. CONCLUSION: A greater incidence of LM was observed in NSCLC patients harboring EGFR mutations after effective EGFR TKI treatment. In particular, the primary mutation, L858R, potentially predicts a higher risk of LM compared with deletion of exon 19. These results highlight the importance of determining mutation status when evaluating the biological behavior of LM in NSCLC patients who positively respond to EGFR TKI treatment.

MicroRNA-19b promotes the migration and invasion of ovarian cancer cells by inhibiting the PTEN/AKT signaling pathway.

Local and systemic metastasis is the main reason for the poor survival rate of patients with ovarian cancer (OC). MicroRNAs (miRNAs/miRs) are short non-coding RNAs that serve critical roles in the initiation and progression of OC. The present study demonstrated that expression of miR-19b was significantly increased in OC tissues and cell lines. Analysis of clinicopathological features revealed that the increased expression of miR-19b was associated with advanced International Federation of Gynecology and Obstetrics stage and lymphatic metastasis of OC patients. Loss-of-function experiments demonstrated that the silencing of miR-19b reduced the migration and invasion of OVCAR-3 cells; contrarily, the overexpression of miR-19b facilitated the migration and invasion of CAOV-3 cells. Furthermore, miR-19b regulated the expression of phosphatase and tensin homolog (PTEN) and the activity of the PTEN/RAC serine/threonine-protein kinase pathway in vitro. Notably, the results of dual-luciferase reporter assays indicated that PTEN was a direct downstream target of miR-19b in OC. Taken together, the results of the current study demonstrated that miR-19b serves an oncogenic role in the progression of OC, and could potentially act as a biomarker and therapeutic target for OC patients.

Age-related iron deposition in the basal ganglia of controls and Alzheimer disease patients quantified using susceptibility weighted imaging.

This study aimed to investigate age-related iron deposition changes in healthy subjects and Alzheimer disease patients using susceptibility weighted imaging. The study recruited 182 people, including 143 healthy volunteers and 39 Alzheimer disease patients. All underwent conventional magnetic resonance imaging and susceptibility weighted imaging sequences. The groups were divided according to age. Phase images were used to investigate iron deposition in the bilateral head of the caudate nucleus, globus pallidus and putamen, and the angle radian value was calculated. We hypothesized that age-related iron deposition changes may be different between Alzheimer disease patients and controls of the same age, and that susceptibility weighted imaging would be a more sensitive method of iron deposition quantification. The results revealed that iron deposition in the globus pallidus increased with age, up to 40 years. In the head of the caudate nucleus, iron deposition peaked at 60 years. There was a general increasing trend with age in the putamen, up to 50-70 years old. There was significant difference between the control and Alzheimer disease groups in the bilateral globus pallidus in both the 60-70 and 70-80 year old group comparisons. In conclusion, iron deposition increased with age in the globus pallidus, the head of the caudate nucleus and putamen, reaching a plateau at different ages. Furthermore, comparisons between the control and Alzheimer disease group revealed that iron deposition changes were more easily detected in the globus pallidus.

[Effect of chidamide on human B lymphoma cell lines and its mechanisms].

This study was aimed to explore the effects of histone deacetylase inhibitor chidamide on the proliferation, apoptosis of B lymphoma cell lines Raji (Burkitt lymphoma), Maver and Z-138 (mantle cell lymphoma) and its mechanisms. Three B lymphoma cell lines were cultured in vitro with different concentrations of chidamide for different time. The cell proliferation was determined by CCK-8 method; the cell apoptosis and mitochondrial membrane potential were analyzed by flow cytometry; the protein levels of histone H3/H4 acetylation in cells and the activity of caspase-3 were detected by Western blot. The results showed that chidamide inhibited the proliferation of 3 B lymphoma cell lines in time- and concentration-dependent manners, especially in Z-138 cell line earlier and faster; chidamide could induce cell apoptosis and decline of mitochondrial membrane potential, which was more sensitive in Maver and Z-138 cells than that in Raji cells. Chidamide could elevate the histone H3/H4 acetylation level in 3 B lymphoma cell lines and the activity of caspase-3 in Maver and Z-138 cells. It is concluded that chidamide can inhibit proliferation of B lymphoma cell lines and promote cell apoptosis, the increase of histone H3/H4 acetylation induced by chidamide, triggering of mitochondrial pathway and activation of caspase-3 may be considered as possible mechanisms.

[Expression of Notch signal molecules in human lymphoma cells and its significance].

The study was aimed to investigate the expression of Notch signal molecules in human lymphoma cells and its significance. Raji, Maver, Z138 and Jurkat cell lines were used in the study. RT-PCR was used to determine the expression of Notch signaling molecules in these lymphoma cells. Flow cytometry was used to detect the apoptosis and cell-cycle of the lymphoma cells induced by different concentrations of gamma secretase inhibitor DAPT. CCK-8 was used to detect the proliferation of the lymphoma cells treated by DAPT. The results showed that the expression of Notch molecules in the four cell lines was different. Notch1 and Notch2 were found to be expressed in the four lymphoma cell lines, Notch3 predominantly expressed in Jurkat cells, Notch4 only expressed in Raji cells weakly and Hes1 only expressed in Raji and Jurkat cells. Treatment with DAPT could increase the apoptosis ratio of Raji and Jurkat cells. Besides, DAPT could significantly inhibit the proliferation of Raji and Jurkat cells by inducing the cell cycle arrest in G(1) phase, but the effect of DAPT on Maver and Z138 cells was not obvious. The activity of Notch pathway could be inhibited by DAPT treatment through down-regulating the expression of Notch target gene Hes1. It is concluded that the abnormal expression and activation of Notch signal pathway play an important role in the proliferation of lymphoma cells. Notch may be likely a new target for the therapy of lymphoma.

Overall anatomical features and clinical value of the sacral nerve in high resolution computed tomography reconstruction.

BACKGROUND: Sacral nerve injury is a common complication of pelvic or sacral fractures. As the sacral nerve courser within the sacrum and has a complex relationship with the surrounding tissues, different parts of the sacral plexus injury have similar clinical symptoms and signs. Since lack of specific imaging technique in the diagnosis of sacral nerve injury, especially on multi-segment, multi-site, how to determine the preoperative location and extent of the sacral nerve injury accurately becomes a concern of the general orthopaedic and images practitioners. This study was conducted to gain an insight into the overall anatomical features of the sacral nerve (SN) on the same slice in high resolution computed tomography (HRCT) reconstruction and to determine the value of this information for the clinical diagnosis of related diseases. METHODS: Fifty healthy volunteers and 30 patients (40 sides) with SN lesions confirmed by surgery were scanned using a 16-slice helical CT scanner (Light Speed, GE, USA). Among the patients, 6 with intervertebral disk hernia (6 sides), 8 with spinal stenosis (12 sides), 11 with pelvic trauma (14 sides), 4 with pelvic malignancies (6 sides), and 1 with sacral vertebral tuberculosis (2 sides). The SN multiplanar reconstruction was performed using a UNIX-based SCD4.1 workstation where the image was set on the same slice. All images were stored in the Digital Imaging and Communications in Medicine format. The display of nerves in different sections was analyzed using a five-graded scale with coordinate curves of each individual score. The overall anatomic features visible on the slice were analyzed and the abnormalities of the lesions were studied. RESULTS: The image of the same slice clearly revealed the shape, running direction, thickness, tension and adjacent anatomy of the S1-S4 nerves. The rank of display rates in different sections was: outward-rotated oblique sagittal > outward-rotated oblique coronal > oblique coronal plane > coronal > sagittal > transverse section. The S5 nerve was partially displayed from the starting point to the segment around the posterior sacral foramen. The overall anatomy of the triangular sacral plexus was only revealed in the oblique outward-rotated sagittal section, while 100% of its individual rami, as well as two or three of the adjacent rami, were displayed from their starting points to the anterior border of the piriformis. The abnormalities included 39 sides of morphological change (97.5%), 38 sides of compression (95.0%), 35 sides of adhesion (87.5%), 32 sides of displacement (80.0%), 34 sides of shrinkage (85.0%), 6 sides of thickening (15.0%), and 2 sides of abruption (5.0%). CONCLUSIONS: The 16-slice CT multiplanar reconstruction was able to reveal the overall anatomic features of the SN on the same slice. The section of reconstruction was a crucial factor in determining the display capability of various sacral nerves. This technology was valuable in the diagnosis and management of related diseases.

[Study on the overall anatomical features and clinical value of lumbar nerve root, plexus and branches in CT reconstruction].

OBJECTIVE: To identify the overall anatomical characteristics and the clinical value of the lumbar nerves under CT multiplanar reconstruction. METHODS: Fifty normal subjects and 30 patients with LN diseases (51 sides) were selected, including 10 patients with lumber intervertebral disk hernia, eight patients with spinal stenosis, 5 patients with spondylolisthesis, 1 patient with tethered cord syndrome, 1 patient with lumbar scoliosis, and 5 patients with spinal trauma The 16-slice helical CT (Light Speed, GE Company) was used for scanning the lumbar vertebra with multiplanar reconstruction in Workstation (ADW4.1) with UNIX System in DICOM format. The image was set on the same slice for the overall anatomy and manifestations of the lesions. RESULTS: The same-slice imaging showed the strip-like LN slightly lower than the surrounding muscle in density. Each LN went out of the dural sac at an acute angle. The course of the lumbar plexus and its major branches, including the obturator nerve, femoral nerve and reproductive nerve, and their relations to the adjacent structures were clearly revealed. The percentage of the segments displayed was well associated with the reconstruction angle, with the order being oblique coronal > outward-rotated oblique coronal > oblique sagittal > coronal > sagittal section. The major manifestations of abnormal LN included compression and displacement (50 sides, 98.0%), morphological changes (49 sides, 96.1%), adhesion (41 sides, 80.4%). CONCLUSIONS: The CT multiplanar reconstruction is ideal for the imaging of the overall size, shape, running and tension of the LN root; it is valuable in clinical diagnosis.

Receptor-binding domain of SARS-Cov spike protein: soluble expression in E. coli, purification and functional characterization.

AIM: Spike protein of coronavirus is responsible for virus binding, fusion and entry, and is a major inducer of neutralizing antibodies. This paper was to find a soluble and functional recombinant receptor-binding domain of severe acute respiratory syndrome-associated coronavirus (SARS-Cov), and to analyze its receptor binding ability. METHODS: Three fusion tags (glutathione S-transferase, GST; thioredoxin, Trx; maltose-binding protein, MBP), which preferably contributes to increasing solubility and to facilitating the proper folding of heteroprotein, were used to acquire the soluble and functional expression of RBD protein in Escherichia coli (BL21(DE3) and Rosetta-gamiB(DE3) strains). The receptor binding ability of the purified soluble RBD protein was then detected by ELISA and flow cytometry assay. RESULTS: RBD of SARS-Cov spike protein was expressed as inclusion body when fused as TrxA tag form in both BL21 (DE3) and Rosetta-gamiB (DE3) under many different cultures and induction conditions. And there was no visible expression band on SDS-PAGE when RBD was expressed as MBP tagged form. Only GST tagged RBD was soluble expressed in BL21(DE3), and the protein was purified by AKTA Prime Chromatography system. The ELISA data showed that GST/RBD antigen had positive reaction with anti-RBD mouse monoclonal antibody 1A5. Further flow cytometry assay demonstrated the high efficiency of RBD's binding ability to ACE2 (angiotensin-converting enzyme 2) positive Vero E6 cell. And ACE2 was proved as a cellular receptor that meditated an initial-affinity interaction with SARS-Cov spike protein. The geometrical mean of GST and GST/RBD binding to Vero E6 cells were 77.08 and 352.73 respectively. CONCLUSION: In this paper, we get sufficient soluble N terminal GST tagged RBD protein expressed in E.coli BL21(DE3); data from ELISA and flow cytometry assay demonstrate that the recombinant protein is functional and binding to ACE2 positive Vero E6 cell efficiently. And the recombinant RBD derived from E.coli can be used to developing subunit vaccine to block S protein binding with receptor and to neutralizing SARS-Cov infection.