Targeted radionuclide therapy for head and neck squamous cell carcinoma: a review.

Head and neck squamous cell carcinoma (HNSCC) is a type of head and neck cancer that is aggressive, difficult to treat, and often associated with poor prognosis. HNSCC is the sixth most common cancer worldwide, highlighting the need to develop novel treatments for this disease. The current standard of care for HNSCC usually involves a combination of surgical resection, radiation therapy, and chemotherapy. Chemotherapy is notorious for its detrimental side effects including nausea, fatigue, hair loss, and more. Radiation therapy can be a challenge due to the anatomy of the head and neck area and presence of normal tissues. In addition to the drawbacks of chemotherapy and radiation therapy, high morbidity and mortality rates for HNSCC highlight the urgent need for alternative treatment options. Immunotherapy has recently emerged as a possible treatment option for cancers including HNSCC, in which monoclonal antibodies are used to help the immune system fight disease. Combining monoclonal antibodies approved by the US Food and Drug Administration, such as cetuximab and pembrolizumab, with radiotherapy or platinum-based chemotherapy for patients with locally advanced, recurrent, or metastatic HNSCC is an accepted first-line therapy. Targeted radionuclide therapy can potentially be used in conjunction with the first-line therapy, or as an additional treatment option, to improve patient outcomes and quality of life. Epidermal growth factor receptor is a known molecular target for HNSCC; however, other targets such as human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, programmed cell death protein 1, and programmed death-ligand 1 are emerging molecular targets for the diagnosis and treatment of HNSCC. To develop successful radiopharmaceuticals, it is imperative to first understand the molecular biology of the disease of interest. For cancer, this understanding often means detection and characterization of molecular targets, such as cell surface receptors, that can be used as sensitive targeting agents. The goal of this review article is to explore molecular targets for HNSCC and dissect previously conducted research in nuclear medicine and provide a possible path forward for the development of novel radiopharmaceuticals used in targeted radionuclide therapy for HNSCC, which has been underexplored to date.

Advancements in cell-based therapies for thermal burn wounds: a comprehensive systematic review of clinical trials outcomes.

BACKGROUND: Burn trauma is one of the major causes of morbidity and mortality worldwide. The standard management of burn wounds consists of early debridement, dressing changes, surgical management, and split-thickness skin autografts (STSGs). However, there are limitations for the standard management that inclines us to find alternative treatment approaches, such as innovative cell-based therapies. We aimed to systematically review the different aspects of cell-based treatment approaches for burn wounds in clinical trials. METHODS: A systematic search through PubMed, Medline, Embase, and Cochrane Library databases was carried out using a combination of keywords, including "Cell transplantation", "Fibroblast", "Keratinocyte", "Melanocyte", or "Stem Cell" with "Burn", "Burn wound", or "Burn injury". Firstly, titles and abstracts of the studies existing in these databases until "February 2024" were screened. Then, the selected studies were read thoroughly, and considering the inclusion and exclusion criteria, final articles were included in this systematic review. Moreover, a manual search was performed through the reference lists of the included studies to minimize the risk of missing reports. RESULTS: Overall, 30 clinical trials with 970 patients were included in our study. Considering the type of cells, six studies used keratinocytes, nine used fibroblasts, eight used combined keratinocytes and fibroblasts, one study used combined keratinocytes and melanocytes, five used combined keratinocytes and fibroblasts and melanocytes, and one study used mesenchymal stem cells (MSCs). Evaluation of the preparation type in these studies showed that cultured method was used in 25 trials, and non-cultured method in 5 trials. Also, the graft type of 17 trials was allogeneic, and of 13 other trials was autologous. CONCLUSIONS: Our study showed that employing cell-based therapies for the treatment of burn wounds have significant results in clinical studies and are promising approaches that can be considered as alternative treatments in many cases. However, choosing appropriate cell-based treatment for each burn wound is essential and depends on the situation of each patient.

Paxbp1 is indispensable for the maintenance of epidermal homeostasis.

The mammalian epidermis is a structurally complex tissue that serves critical barrier functions, safeguarding the organism from the external milieu. The development of the epidermis is governed by sophisticated regulatory processes. However, the precise mechanism maintaining epidermal homeostasis remains incompletely elucidated. Recent studies have identified Paxbp1, an evolutionarily conserved protein, as being involved in the developmental regulation of various cells, tissues, and organs. Nonetheless, its role in skin development has not been explored. Here, we report that the targeted deletion of Paxbp1 in epidermal keratinocytes mediated by Keratin14-Cre leads to severe disruption in skin architecture. Mice deficient in Paxbp1 exhibited a substantially reduced epidermal thickness and pronounced separation at the dermo-epidermal junction upon birth. Mechanistically, we demonstrate that the absence of Paxbp1 hinders cellular proliferation, marked by a halt in cell cycle transition, suppressed gene expression of proliferation, and a compromised DNA replication pathway in basal keratinocytes, resulting in the thinning of the skin epidermis. Moreover, molecules and pathways associated with hemidesmosome assembly were impaired in Paxbp1-deficient keratinocytes, culminating in the detachment of the skin epidermal layer. Therefore, our study highlights an indispensable role of Paxbp1 in the maintenance of epidermal homeostasis.

Whole-Body HER2 Heterogeneity Identified on HER2 PET in HER2-Negative, -Low, and -Positive Metastatic Breast Cancer.

Understanding which patients with human epidermal growth factor receptor 2 (HER2)-negative or -low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on 89Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. Methods: In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included. Metastasis HER2 status was determined by immunohistochemistry and in situ hybridization.89Zr-trastuzumab uptake was quantified as SUVmax and SUVmean HER2 immunohistochemistry was related to the quantitative 89Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, uptake heterogeneity, and qualitative scan evaluation. A prediction algorithm for HER2 immunohistochemistry positivity based on uptake was developed. Results: In 200 patients, 89Zr-trastuzumab uptake was quantified in 5,163 metastases, including 186 biopsied metastases. With increasing HER2 immunohistochemistry status, uptake was higher (geometric mean SUVmax of 7.0, 7.6, 7.3, and 17.4 for a HER2 immunohistochemistry score of 0, 1, 2, or 3+, respectively; P < 0.001). High uptake exceeding 14.6 (90th percentile) was observed in one third of patients with a HER2-negative or -low metastasis biopsy. The algorithm performed best when lesion site and size were incorporated (area under the curve, 0.86; 95% CI, 0.79-0.93). Conclusion: HER2 PET had good diagnostic performance in MBC, showing considerable whole-body HER2 heterogeneity and uptake above background in HER2-negative and -low MBC. This provides novel insights into HER2-negative and -low MBC compared with standard HER2 immunohistochemistry on a single biopsy.

The effect of epidermal growth factor receptor mutation on adjuvant chemotherapy with tegafur/uracil for patients with completely resected, non-lymph node metastatic non-small cell lung cancer (> 2 cm): a multicenter, retrospective, observational study as exploratory analysis of the CSPOR-LC03 study.

BACKGROUND: The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03). METHODS: Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1 > 2 cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status. RESULTS: Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P = 0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status. CONCLUSION: In pathologic stage I (>2 cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed.

The Skin Acid Mantle: An Update on Skin pH.

The acid mantle concept refers to the buffer system located in the upper stratum corneum of the skin. By sustaining an acidic environment, the acid mantle contributes to the regulation of the microbiome, structural stability, and inflammation. Skin pH is pivotal in maintaining the integrity of the epidermal barrier. Shifts in pH can disrupt barrier properties, and recent studies have emphasized its impact on dermatologic disease processes. This review explores the complex relationship of mechanisms through which skin pH impacts dermatologic pathologies. Furthermore, we highlight the promising potential of pH-targeted therapies for advancing the management of skin conditions.

FGF7 and FGF10 Promote Fate Transition of Human Epidermal Cell-derived Organoids to an Eccrine Gland Phenotype.

Rationale: Reconstruction of hair follicles (HFs) and eccrine sweat glands (ESGs) is essential for functional skin regeneration. In skin reconstruction research, we found that foreskin-derived epidermal cells reconstructed HF organoids unidirectionally, but not ESG organoids. Methods: To investigate key genes and pathways influencing the fate of ESG and HF, a transcriptome profiling of ESG placode-containing skin and HF placode-containing skin was employed, and key DEGs were identified and validated by RT-qPCR and immunofluorescence staining in mice and rats. Subsequently, adult human epidermal cell-derived organoids were reconstructed to probe functional roles and mechanisms of FGF7 and FGF10 by series of approaches integrating RT-qPCR, immunofluorescence-staining, WB, apoptosis assay, and pathway interference assay. Results: All members of FGF7 subfamily were among the key DEGs screened, the differential expression of FGF7 and FGF10 and their receptors FGFR1/FGFR2 was verified between ESG placode-containing skin and HF placode-containing skin. In vivo and in vitro Matrigel plug models showed that both FGF7 and FGF10 promoted fate transition of human epidermal cell-derived organoids to ESG phenotype organoids, FGF7 and FGF10 had a synergistic effect, and mainly function through the FGFR1/2-MEK1/2-ERK1/2 pathway. Conclusions: Adult epidermal cells can be manipulated to reconstruct personalized HF and ESG to meet different needs.

Pik3c3 Expression Profiling in the Mouse Kidney and Its Role in Proximal Tubule Cell Physiology.

The class 3 phosphatidylinositol 3-kinase (Pik3c3) plays critical roles in regulating autophagy, endocytosis, and nutrient sensing, but its expression profile in the kidney remains undefined. Recently, we validated a Pik3c3 antibody through immunofluorescence staining of kidney tissues from cell type-specific Pik3c3 knockout mice. Immunohistochemistry unveiled significant disparities in Pik3c3 expression levels across various kidney cell types. Notably, renal interstitial cells exhibit minimal Pik3c3 expression. Further, co-immunofluorescence staining, utilizing nephron segment- or cell type-specific markers, revealed nearly undetectable levels of Pik3c3 expression in glomerular mesangial cells and endothelial cells. Intriguingly, although podocytes exhibit the highest Pik3c3 expression levels among all kidney cell types, the renal proximal tubule cells (RPTCs) express the highest level of Pik3c3 among all renal tubules. RPTCs are known to express the highest level of the epidermal growth factor receptor (EGFR) in adult kidneys; however, the role of Pik3c3 in EGFR signaling within RPTCs remains unexplored. Therefore, we conducted additional cell culture studies. The results demonstrated that Pik3c3 inhibition significantly delayed EGF-stimulated EGFR degradation and the termination of EGFR signaling in RPTCs. Mechanistically, Pik3c3 inhibition surprisingly did not affect the initial endocytosis process but instead impeded the lysosomal degradation of EGFR. In summary, this study defines, for the first time, the expression profile of Pik3c3 in the mouse kidney and also highlights a pivotal role of Pik3c3 in the proximal tubule cells. These findings shed light on the intricate mechanisms underlying Pik3c3-mediated regulation of EGFR signaling, providing valuable insights into the role of Pik3c3 in renal cell physiology.

Development of tetravalent antibody-enzyme complexes employing a lactate oxidase and the application to electrochemical immunosensors.

Antibody-enzyme complexes (AECs) are ideal for immunosensing. Although AECs using antibody fragments can be produced by bacterial hosts, their low affinity limits their sensing applications. We have improved the affinity of AECs by combining two antibodies using Catcher/Tag systems; however, it requires multiple antibodies and an enzyme production process. In this study, to realize the production of AECs harboring multiple antibody fragments in a single production process, we report a versatile development method of unique AECs based on a multimeric enzyme structure. Using the homotetrameric enzyme, lactate oxidase (LOx), as a labeling enzyme, tetravalent AECs were developed as an electrochemical immunosensor. Homogeneous tetravalent AECs were successfully fabricated by fusing the anti-epidermal growth factor receptor (EGFR) variable domain of a heavy chain of heavy chain antibody to the N-terminus of LOx. The prepared AECs bound to EGFR, maintain their enzyme activity, and worked well as sensing elements in electrochemical sandwich enzyme-linked immunosorbent assay. Moreover, tetravalent AECs exhibited higher sensitivity than monovalent AECs because of their avidity. The fabricated AECs were successfully used in a wash-free homogeneous electrochemical detection system combined with magnetic separation. Our findings offer new insights into the applications of the LOx tetrameric enzyme for the fabrication of AECs with tetravalent antibodies, which may serve as scaffolds for immunosensors.

QSOX1 exerts anti-inflammatory effects in sepsis-induced acute lung injury: regulation involving EGFR phosphorylation mediated M1 polarization of macrophages.

Sepsis is a systemic inflammatory response caused by an infection, which can easily lead to acute lung injury. Quiescin Q6 sulfhydryl oxidase 1 (QSOX1) is a sulfhydryl oxidase involved in oxidative stress and the inflammatory response. However, there are few reports on the role of QSOX1 in sepsis-induced acute lung injury (SALI). In this study, mice model of SALI was constructed by intraperitoneal injection with lipopolysaccharide (LPS). The increased inflammatory response and lactate dehydrogenase activity in bronchoalveolar lavage fluid (BALF) indicated successful modeling. Increased QSOX1 expression was both observed in lung tissues and lung macrophages of sepsis mice accompanied by increased polarization of M1-type macrophages. To explore the role of QSOX1 in the SALI, lentivirus containing QSOX1-specific overexpression or knockdown vectors were used to change QSOX1 expression in LPS-treated RAW264.7 cells. QSOX1 suppressed LPS-induced M1 polarization and further inhibited inflammatory response in RAW264.7 cells. Interestingly, the phosphorylation of epidermal growth factor receptor (EGFR), the promoter of M1 polarization in macrophages, was found to be downregulated upon QSOX1 overexpression in RAW264.7 cells. Mechanically, the binding of QSOX1 to EGFR protein promoted EGFR ubiquitination and degradation, thereby down-regulating EGFR phosphorylation. Moreover, inhibiting EGFR expression or its phosphorylation restored the impact of QSOX1 silencing on M1 polarization and inflammation in the LPS-treated RAW264.7 cells. In summary, QSOX1 may exert anti-inflammatory effects in SALI by inhibiting EGFR phosphorylation-mediated M1 macrophage polarization. This presented a potential target for the treatment and prevention of SALI.

Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies.

Epidermal growth factor receptor (EGFR), which is referred to as ErbB1/HER1, is the prototype of the EGFR family of receptor tyrosine kinases which also comprises ErbB2 (Neu, HER2), ErbB3 (HER3), and ErbB4 (HER4). EGFR, along with other ErbBs, is expressed in the kidney tubules and is physiologically involved in nephrogenesis and tissue repair, mainly following acute kidney injury. However, its sustained activation is linked to several kidney pathologies, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, chronic kidney disease, and renal fibrosis. This review aims to provide a summary of the recent findings regarding the consequences of EGFR activation in several key renal pathologies. We also discuss the potential interplay between EGFR and the reno-protective angiotensin-(1-7) (Ang-(1-7), a heptapeptide member of the renin-angiotensin-aldosterone system that counter-regulates the actions of angiotensin II. Ang-(1-7)-mediated inhibition of EGFR transactivation might represent a potential mechanism of action for its renoprotection. Our review suggests that there is a significant body of evidence supporting the potential inhibition of EGFR/ErbB, and/or administration of Ang-(1-7), as potential novel therapeutic strategies in the treatment of renal pathologies. Thus, EGFR inhibitors such as Gefitinib and Erlinotib that have an acceptable safety profile and have been clinically used in cancer chemotherapy since their FDA approval in the early 2000s, might be considered for repurposing in the treatment of renal pathologies.

Safety and Efficacy of Gefitinib Administration After Osimertinib-Induced Interstitial Lung Disease: A Six-Case Series.

Purpose: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with non-small cell lung cancer harboring EGFR mutations. Although the frequency of osimertinib-induced interstitial lung disease (osi-ILD) is high, the optimal cancer treatment after osi-ILD has not been established. This time, we focused on the safety and efficacy of gefitinib following osi-ILD. Case Presentation: We experienced six cases (five women and one man; median age: 74 years) in which gefitinib was administered after osi-ILD. All six cases had grade 2 or higher osi-ILD and required steroid treatment. The computed tomography imaging pattern of osi-ILD revealed organizing pneumonia in three cases, diffuse alveolar damage in two cases, and hypersensitivity pneumonia in one case. Eastern Cooperative Oncology Group performance status was 1 in four cases, 2 in one case, and 3 in one case. EGFR mutation status was exon 19 deletion in two cases and exon 21 L858R in four cases. Only one patient experienced recurrence of ILD after receiving gefitinib. The best response to gefitinib was partial response in two cases and stable disease in three cases; one case was not evaluable. The median progression-free survival after treatment with gefitinib was 190 days (95% confidence interval: 33-328). Conclusion: The treatment with gefitinib after the development of osi-ILD was safe and effective. Gefitinib may be a promising option for patients who recovered from severe osi-ILD.

Five-Year Follow-Up of Choroidal Metastasis From Lung Adenocarcinoma Harboring Epidermal Growth Factor Receptor (EGFR) Mutation: A Case Report and Literature Review.

This is a long-term follow-up case report of a 71-year-old man with lung adenocarcinoma and choroidal metastasis harboring an epidermal growth factor receptor mutation. Blurry vision, caused by the choroidal metastasis, improved with first-line treatment with afatinib. Thereafter, osimertinib was administered as a second-line treatment, then chemotherapy containing pemetrexed plus bevacizumab as a third-line treatment. For 61 months, recurrence of choroidal metastasis was absent. Only a few reports of lung cancer with choroidal metastasis provide long-term follow-up of more than five years. Therefore, the clinical course of this patient may provide some insights for long-term management in such cases.

Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts.

Purpose: This study aimed to assess the biodistribution and bioactivity of the affibody molecular probe 99mTc-(HE)3ZHER2:V2, prepared by genetic recombination, and to investigate its potential for targeted human epidermal growth factor receptor 2 (HER2) imaging in SKOV3 ovarian cancer and MDA-MB-361 breast cancer xenografts. Methods: Affibody molecules were generated through genetic recombination. The radiochemical purity of the 99mTc-labeled HER2 affibody was determined using reverse phase high performance liquid chromatography (RP-HPLC). Evaluation of HER2 affinity in SKOV3 ovarian cancer cells and MDA-MB-361 breast cancer cells (HER2-positive) was conducted by calculating equilibrium dissociation constants. Biodistribution of the 99mTc-labeled affibody molecular probe was assessed in Balb/c mice bearing SKOV3 tumors. Tumor targeting specificity was evaluated in Balb/c mice using SKOV3, MDA-MB-361, and AT-3 (HER2-negative) xenografts. Results: Affibody (HE)3ZHER2:V2, generated through recombinant gene expression, was successfully labeled with 99mTc, achieving a radiochemical purity of (96.0 ± 1.7)% (n = 3) as determined by RP-HPLC. This molecular probe exhibited specific binding to HER2-positive SKOV3 cells, demonstrating intense radioactive uptake. Biodistribution analysis showed rapid accumulation of 99mTc-(HE)3ZHER2:V2 in HER2-positive tumors post-administration, primarily clearing through the urinary system. Single-photon emission computed tomography imaging conducted 1-3 h after intravenous injection of 99mTc-(HE)3ZHER2:V2 into HER2-positive SKOV3 and MDA-MB-361 nude mouse models confirmed targeted uptake of the molecular probe by the tumors. Conclusions: The molecular probe 99mTc-(HE)3ZHER2:V2 developed in this study effectively targets HER2 for imaging HER2-positive SKOV3 and MDA-MB-361 xenografts in vivo. It exhibits rapid blood clearance without evident toxic effects, suggesting its potential as a valuable marker for detecting HER2 expression in tumor cells.

Prognostic significance of low HER2 expression in gastric cancer: a retrospective, single-center analysis.

INTRODUCTION: Mutated human epidermal growth factor receptor 2 (HER2) is an oncogene with critical pathogenic roles in breast cancer. HER2-low-positive breast cancer is a recently described subtype. We aimed to explore the clinical and molecular characteristics of gastric cancer with low HER2 expression, drawing on recent developments in breast cancer subtypes. MATERIALS AND METHODS: This retrospective study involved 129 patients with HER2-non-amplified gastric cancer treated in Iwate prefectural Iwai Hospital from 2013 to 2019. Tumors were classified as HER2-null or low-positive based on immunohistochemistry score 0 or 1 + or 2 + with HER2 negativity in situ hybridization, respectively. Statistical analyses, including Kaplan-Meier analyses and Cox proportional hazards model were conducted. RESULTS: Low HER2 expression was present in 26% (33/129) of the patients. Clinicopathological characteristics were not significantly different between the HER2-low and null groups. Kaplan-Meier analysis of overall survival was significantly longer in the HER2-low group than in the HER2-null group (P = 0.01). In multivariate Cox regression analysis, HER2-null status was associated with worse survival (hazard ratio 3.01; 95% confidence interval 1.18-7.65; and P = 0.02). CONCLUSION: This study highlights the prognostic importance of low HER2 expression in gastric cancer, similar to that observed in HER2-low-positive breast cancer, and suggests reclassification of gastric cancer to improve personalized treatment. Future studies should elucidate the molecular underpinnings of low HER2 expression in gastric cancer to guide novel therapeutic strategies and improve outcomes.

Association of mammographic and sonographic findings with prognostic molecular factors and hormone receptor expression in malignant breast lesions.

Background: The aim of this study was to determine whether mammographic and sonographic features of malignant breast lesions are correlated with tumor histologic grade, hormonal receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67 status. Materials and Methods: In this retrospective study, imaging and histopathological findings of 187 biopsy-proven breast cancer cases from November 2019 to February 2021 were reviewed. The Chi-square test was used to examine the potential correlation between mammographic and sonographic characteristics with histopathological features such as hormonal receptor, HER2 status, Ki-67 labeling index, and histological grade. Results: We observed that microlobulated margin as well as oval/round morphology in mammograms correlate with triple-negative intrinsic subtype (P = 0.006 and P = 0.004). The presence of calcification in sonography was significantly higher in the luminal-B subtype (P = 0.002). Furthermore, ill-defined margins in mammography were significantly higher in amplified HER2 expression (P = 0.004) in the same manner as an oval/round shape in higher levels of Ki-67 (P = 0.030). Conclusion: Mammography and sonography features may reflect the biological behavior of various subtypes of breast cancer and can detect more aggressive breast cancers that can mimic benign or less malignant appearing lesions. These findings may be an excellent predictor for some subtypes like triple-negative breast cancer. Studying the range of these imaging characteristics may help in better understanding the prognosis, choosing a treatment strategy, and predicting response to treatment.

Clitoral Hemangioma in Adults: A Case Report and Literature Review.

Hemangiomas are benign vascular tumors commonly seen in early childhood, typically occurring on the face, scalp, chest, or back. Clitoral hemangiomas, especially in adults, are exceptionally rare. This case report describes a unique presentation of clitoromegaly due to a cavernous hemangioma of the clitoris in a 39-year-old woman who presented with a progressive and worsening swelling of the clitoris for five years. A surgical excision of the cyst was performed, and a histological examination confirmed a cavernous hemangioma.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation: A multicenter, case-series study in China.

Objective: To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor (EGFR) 21L858R mutant non-small cell lung cancer (NSCLC) patients in China and to explore the factors influencing the efficacy and safety. Methods: A longitudinal, consecutive case-series, multicenter study with mixed prospective and retrospective data was conducted. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included duration of treatment (DOT), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included. The median follow-up time for these patients was 20.4 months. Among 134 patients with evaluable lesions, the ORR was 70.9% and the DCR was 96.3%. The median PFS was 16.3 [95% confidence interval (95% CI), 13.7-18.9] months. Multivariate Cox regression analysis suggested that the baseline brain metastasis (BM) status [with vs. without BM: hazard ratio (HR), 1.331; 95% CI, 0.720-2.458; P=0.361] and initial doses (45 mg vs. 30 mg: HR, 0.837; 95% CI, 0.427-1.641; P=0.604) did not significantly affect the median PFS. The median DOT was 21.0 (95% CI, 17.5-24.6) months and the median OS was not reached. Genetic tests were performed in 64 patients after progression, among whom 29 (45.3%) patients developed the EGFR 20T790M mutation. In addition, among the 46 patients who discontinued dacomitinib treatment after progression, 31 (67.4%) patients received subsequent third-generation EGFR-tyrosine kinase inhibitors. The most common grade 3-4 adverse events were rash (10.4%), diarrhea (9.1%), stomatitis (7.1%) and paronychia (4.5%). The incidence of grade 3-4 rash was significantly higher in the 45 mg group than that in the 30 mg group (21.9% vs. 7.5%, P=0.042). Conclusions: First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Clinicopathological characteristics of neural epidermal growth factor-like 1 protein-associated membranous glomerulonephritis.

Neural epidermal growth factor-like 1 protein (NELL1) is the second most common target antigen in membranous glomerulonephritis (MGN). However, data regarding the clinicopathological characteristics of NELL1-associated MGN are limited owing to its low prevalence. This study examined the prevalence and clinicopathological characteristics of NELL1-associated MGN in a Japanese cohort. Additionally, we compared the clinicopathological features of NELL1-positive MGN, phospholipase A2 receptor 1 (PLA2R1)-positive MGN, and MGN negative for all three antigens (NELL1, PLA2R1, and thrombospondin type-1 domain-containing 7A). Among 257 consecutive patients pathologically diagnosed with MGN at two centers in Japan, 24 (9.3%) were immunohistochemically positive for NELL1. Clinically, patients with NELL1-positive MGN were significantly older (p < 0.001) and had a higher frequency of bucillamine use (vs PLA2R1-positive MGN, p < 0.01). Histologically, NELL1-positive MGN exhibited significantly lower detection of spikes and crater formation (p < 0.001), higher prevalence of segmental spike distribution (vs PLA2R1-positive MGN: p < 0.001), and higher prevalence of stage I cases on electron microscopy (p < 0.01). There were no significant differences in the prognoses among the three groups. The characteristic histological feature of segmental distribution in NELL1-positive MGN may be related to bucillamine use and the early phase of the disease. Further investigations with larger numbers of patients may offer further insight into the prognosis of patients with NELL1-positive MGN.

In silico assessments of the small molecular boron agents to pave the way for artificial intelligence-based boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a highly targeted, selective and effective technique to cure various types of cancers, with less harm to the healthy cells. In principle, BNCT treatment needs to distribute the 10boron (10B) atoms inside the tumor tissues, selectively and homogeneously, as well as to initiate a nuclear fission reaction by capturing sufficient neutrons which releases high linear energy particles to kill the tumor cells. In BNCT, it is crucial to have high quality boron agents with acceptable bio-selectivity, homogeneous distribution and deliver in required quantity, similar to chemotherapy and other radiotherapy for tumor treatment. Nevertheless, boron drugs currently used in clinical trials yet to meet the full requirements. On the other hand, BNCT processing has opened up the era of renaissance due to the advanced development of the high-quality neutron source and the global construction of new BNCT centers. Consequently, there is an urgent need to use boron agents that have increased biocapacity. Artificial intelligence (AI) tools such as molecular docking and molecular dynamic simulation technologies have been utilized to develop new medicines. In this work, the in silico assessments including bioinformatics assessments of BNCT related tumoral receptor proteins, computational assessments of optimized small molecules of boron agents, are employed to speed up the screening process for boron drugs. The outcomes will be applicable to pave the way for future BNCT that utilizes artificial intelligence. The in silico molecular docking and dynamic simulation results of the optimized small boron agents, such as 4-borono-l-phenylalanine (BPA) with optimized proteins like the L-type amino acid transporter 1 (LTA1, also known as SLC7A5) will be examined. The in silico assessments results will certainly be helpful to researchers in optimizing druggable boron agents for the BNCT application. The clinical status of the optimized proteins, which are highly relevant to cancers that may be treated with BNCT, has been assessed using bioinformatics technology and discussed accordingly. Furthermore, the evaluations of cytotoxicity (IC50), boron uptake and tissue distribution of the optimized ligands 1 and 7 have been presented.