Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis.

Background: Marfan syndrome (MFS) is a rare genetic disorder caused by mutations in the Fibrillin-1 gene (FBN1) with significant clinical features in the skeletal, cardiopulmonary, and ocular systems. To gain deeper insights into the contribution of epigenetics in the variability of phenotypes observed in MFS, we undertook the first analysis of integrating DNA methylation and gene expression profiles in whole blood from MFS and healthy controls (HCs). Methods: The Illumina 850K (EPIC) DNA methylation array was used to detect DNA methylation changes on peripheral blood samples of seven patients with MFS and five HCs. Associations between methylation levels and clinical features of MFS were analyzed. Subsequently, we conducted an integrated analysis of the outcomes of the transcriptome data to analyze the correlation between differentially methylated positions (DMPs) and differentially expressed genes (DEGs) and explore the potential role of methylation-regulated DEGs (MeDEGs) in MFS scoliosis. The weighted gene co-expression network analysis was used to find gene modules with the highest correlation coefficient with target MeDEGs to annotate their functions in MFS. Results: Our study identified 1253 DMPs annotated to 236 genes that were primarily associated with scoliosis, cardiomyopathy, and vital capacity. These conditions are typically associated with reduced lifespan in untreated MFS. We calculated correlations between DMPs and clinical features, such as cobb angle to evaluate scoliosis and FEV1% to assess pulmonary function. Notably, cg20223687 (PTPRN2) exhibited a positive correlation with cobb angle of scoliosis, potentially playing a role in ERKs inactivation. Conclusions: Taken together, our systems-level approach sheds light on the contribution of epigenetics to MFS and offers a plausible explanation for the complex phenotypes that are linked to reduced lifespan in untreated MFS patients.

Circulating miR-107 as a diagnostic biomarker of osteoporotic vertebral compression fracture increases bone formation in vitro and in vivo.

AIMS: This study aimed to examine the key circulating microRNAs (miRNAs) in the plasma of patients with osteoporotic vertebral compression fracture and assess their potential role as diagnostic biomarkers and explore their function in vitro and in vivo. METHODS: Weighted gene co-expression network analysis (WGCNA) was applied to identify hub miRNAs for subsequent analysis. The candidate miRNAs were tested using plasma from 144 patients and the results were applied to construct receiver operating characteristic (ROC) curves to assess their diagnostic value. In addition, the function of the target miRNA was validated in MC3T3-E1 cells, human bone marrow-derived mesenchymal stromal cells (BMSCs), and an ovariectomized (OVX) mouse model. KEY FINDINGS: Seven modules were obtained by WGCNA analysis. The expression levels of circulating miR-107 in the red module were significantly lower in osteoporotic patients than in healthy controls. In addition, miR-107 provided discrimination with an AUC > 85 % by ROC analyses to differentiate women osteoporosis patients from healthy controls and differentiate women osteoporotic patients with vertebral compression fractures from osteoporotic patients without vertebral compression fractures. In vitro experiments revealed that miR-107 levels were increased in osteogenically induced MC3T3-E1 cells and BMSCs and transfection with synthetic miR-107 could promote bone formation. Lastly, the bone parameters were improved by miR-107 upregulation in OVX mice. SIGNIFICANCE: Our findings show that circulating miR-107 plays an essential role in facilitating osteogenesis and may be a useful diagnostic biomarker and therapeutic target in osteoporosis.

Clinical, Morphological, and Molecular Study on Grade 2 and 3 Pleomorphic Xanthoastrocytoma.

PURPOSE: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. METHODS: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). RESULTS: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). CONCLUSION: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.

Ultrasound Shear Wave Elastography for Evaluation of Diaphragm Stiffness in Patients with Stable COPD: A Pilot Trial.

OBJECTIVES: Skeletal muscle dysfunction is one of the most common comorbidities in chronic obstructive pulmonary disease (COPD). The occurrence of respiratory failure in COPD is common and leads to the patient's death. The diaphragm is the most important muscle in the respiratory system and plays a key role in the onset of respiratory failure. This study explores the feasibility of ultrasound shear wave elastography (SWE) to measure diaphragmatic stiffness and evaluates its changes in COPD patients. METHODS: In total, 77 participants (43 patients with stable COPD and 34 healthy controls) were enrolled. All subjects underwent complete diaphragmatic ultrasound SWE measurements and pulmonary function tests. The diaphragmatic stiffness was indicated via diaphragmatic shear wave velocity (SWV) at functional residual capacity (FRC). A trained operator performed the ultrasound SWE examinations of the first 15 healthy controls thrice to assess the reliability of diaphragmatic SWE. RESULTS: A good to excellent reliability was found in diaphragmatic SWV at FRC (ICC = 0.93, 95%CI 0.82-0.98). As compared to the control group, the diaphragmatic SWV at FRC was considerably high in the COPD group (median 2.5 m/s versus 2.1 m/s, P = .008). Diaphragmatic SWV at FRC was linked to forced expiratory volume in one second (r = -0.30, P = .009), forced vital capacity (r = -0.33, P = .003), modified Medical Research Council score (r = 0.30, P = .001), and COPD assessment test score (r = 0.48, P < .001). CONCLUSIONS: Ultrasound SWE may be employed as an effective tool for quantitative evaluation of diaphragm stiffness and can help in personalized management of COPD, such as treatment guidance and follow-up monitoring.

Utility of Point-of-Care Lung Ultrasound for Clinical Classification of COVID-19.

In this study, the utility of point-of-care lung ultrasound for clinical classification of coronavirus disease (COVID-19) was prospectively assessed. Twenty-seven adult patients with COVID-19 underwent bedside lung ultrasonography (LUS) examinations three times each within the first 2 wk of admission to the isolation ward. We divided the 81 exams into three groups (moderate, severe and critically ill). Lung scores were calculated as the sum of points. A rank sum test and bivariate correlation analysis were carried out to determine the correlation between LUS on admission and clinical classification of COVID-19. There were dramatic differences in LUS (p < 0.001) among the three groups, and LUS scores (r = 0.754) correlated positively with clinical severity (p < 0.01). In addition, moderate, severe and critically ill patients were more likely to have low (≤9), medium (9-15) and high scores (≥15), respectively. This study provides stratification criteria of LUS scores to assist in quantitatively evaluating COVID-19 patients.

Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs.

BACKGROUND: As core units of organ tissues, cells of various types play their harmonious rhythms to maintain the homeostasis of the human body. It is essential to identify the characteristics of cells in human organs and their regulatory networks for understanding the biological mechanisms related to health and disease. However, a systematic and comprehensive single-cell transcriptional profile across multiple organs of a normal human adult is missing. RESULTS: We perform single-cell transcriptomes of 84,363 cells derived from 15 tissue organs of one adult donor and generate an adult human cell atlas. The adult human cell atlas depicts 252 subtypes of cells, including major cell types such as T, B, myeloid, epithelial, and stromal cells, as well as novel COCH+ fibroblasts and FibSmo cells, each of which is distinguished by multiple marker genes and transcriptional profiles. These collectively contribute to the heterogeneity of major human organs. Moreover, T cell and B cell receptor repertoire comparisons and trajectory analyses reveal direct clonal sharing of T and B cells with various developmental states among different tissues. Furthermore, novel cell markers, transcription factors, and ligand-receptor pairs are identified with potential functional regulations in maintaining the homeostasis of human cells among tissues. CONCLUSIONS: The adult human cell atlas reveals the inter- and intra-organ heterogeneity of cell characteristics and provides a useful resource in uncovering key events during the development of human diseases in the context of the heterogeneity of cells and organs.

c(RGDyk)-modified nanoparticles encapsulating quantum dots as a stable fluorescence probe for imaging-guided surgical resection of glioma under the auxiliary UTMD.

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.

Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China.

BACKGROUND: Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents' characteristics and cases outcomes. METHODS: A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. RESULTS: Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025-.529). CONCLUSIONS: When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

Inflammatory bowel disease- and Barrett's esophagus-associated neoplasia: the old, the new, and the persistent struggles.

Early diagnosis of and adequate therapy for premalignant lesions in patients with inflammatory bowel disease (IBD) and Barrett's esophagus (BE) has been shown to decrease mortality. Endoscopic examination with histologic evaluation of random and targeted biopsies remains the gold standard for early detection and adequate treatment of neoplasia in both these diseases. Although eventual patient management (including surveillance and treatment) depends upon a precise histologic assessment of the initial biopsy, accurately diagnosing and grading IBD- and BE-associated dysplasia is still considered challenging by many general as well as subspecialized pathologists. Additionally, there are continuing updates in the literature regarding the diagnosis, surveillance, and treatment of these disease entities. This comprehensive review discusses the cancer risk, detailed histopathological features, diagnostic challenges, and updates as well as the latest surveillance and treatment recommendations in IBD- and BE-associated dysplasia.

BMP-2 plasmid DNA-loaded chitosan films - A new strategy for bone engineering.

OBJECTIVES: Bone defects are common in every area of medicine and remain a clinical challenge. Tissue engineering has led to promising new strategies in accelerating bone repair. Bone morphogenetic proteins (BMPs) play crucial roles in bone regeneration, but are required in supra-physiological doses, which are expensive and produce severe side effects. METHODS: To address these issues, we prepared BMP-2 plasmid DNA-loaded chitosan films, and examined their effects on mouse osteoblast-like MC3T3-E1 cell morphology, proliferation, and runt-related transcription factor 2 (RUNX2) expression. In vivo testing was performed using calvarial critical-sized defects and histomorphometry in 36 Sprague-Dawley rats. Unloaded chitosan films and empty defects served as controls. RESULTS: In contrast to the controls, cells grown on BMP-2 plasmid DNA-loaded chitosan films had well established filopodia and lamellipodia, significantly higher proliferation 2, 4, and 6 days post-seeding (P ≤ 0.05), and higher nuclear RUNX2 expression. In vivo, new bone growth was significantly greater in the BMP-2 group than in the control groups at 4, 8, and 12 weeks (P ≤ 0.01). CONCLUSIONS: Based on our study findings, BMP-2 plasmid DNA-loaded chitosan films provide an effective strategy for GBR, combining cellular compatibility with biocapability in vivo.

Three-dimensional virtual planning in precise chimeric fibula free flap for metacarpal defects: A case report.

RATIONALE: Metacarpal and phalanx defects with soft tissue loss were suggested to be reconstructed by vascularized bone flap. The fibular osteocutaneous flap is a preferred method. Three-dimensional virtual planning has successfully applied in mandibular reconstruction with fibular free flap. We applied three-dimensional virtual planning in precise fibula flap harvest to maintain the continuity of the fibula and to achieve accurate metacarpal and phalanx reconstruction. PATIENT CONCERNS: A 35-year-old male presented with extensive soft tissue defects and first metacarpal defect involving the first metacarpophalangeal joint. DIAGNOSES: There were 4 cm of first metacarpal defect involving the first metacarpophalangeal joint and soft tissue defects of 5cm × 3cm + 3cm × 2cm. INTERVENTIONS: By combining three-dimensional virtual planning, we harvested a chimeric fibular flap. The precise fibula partial osteotomies were performed with cutting guides designed in virtual planning. OUTCOMES: All the chimeric flaps survived and no significant donor-site morbidity was noted. Michigan Hand Outcome Questionnaire scores indicated acceptable functional results. LESSONS: Our preliminary experience with the approach of three-dimensional virtual planning in precise chimeric fibula free flap is practical and efficient. Although more cases and follow-up are needed to evaluate it, this approach is expected to benefit patients.

Treatment of Tear Trough Deformity: Fat Repositioning versus Autologous Fat Grafting.

BACKGROUND: Fat-preserving lower blepharoplasty techniques and filling techniques using autologous or non-autologous materials are increasingly used to treat tear trough deformity. However, there has been no definitive comparison of the results of fat repositioning versus autologous fat grafting for this condition. The authors used statistical analysis to compare the results of the two methods. METHODS: From October 2013 to September 2015, a total of 101 patients, aged 20-43 years, underwent fat repositioning or autologous fat grafting in our department. Group 1 (51 patients, 102 eyes) underwent intraorbital fat repositioning with septal reset by transconjunctival lower blepharoplasty. Group 2 (50 patients, 100 eyes) underwent autologous fat grafting by lipoinjection. RESULTS: No significant complications occurred in any patient postoperatively. Four of 102 eyes in Group 1 and seven of 100 eyes in Group 2 had no improvement; the rest had different degrees of improvement. In Grade II and III deformities, fat repositioning resulted in significantly greater improvement of grade compared with autologous fat grafting. The surgical method of Group 1 resulted in better curative effects than that of Group 2. CONCLUSION: In patients with tear trough deformity and without obvious skin or orbicularis oculi muscle laxity, both fat repositioning and autologous fat grafting are acceptable for mild deformity. In patients with higher-grade deformities, fat repositioning produced superior results than autologous fat grafting. LEVEL OF EVIDENCE IV: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Pharyngoesophageal Reconstruction With the Medial Sural Artery Perforator Flap After Total Laryngopharyngectomy: A New Method.

BACKGROUND: The medial sural artery perforator (MSAP) flap has become a popular target in head and neck reconstruction. This flap has many advantages compared with other free flaps but has not yet been used in the reconstruction of circumferential haryngoesophageal defects. METHODS: Reconstruction of pharyngoesophageal circumferential defects using the MSAP flap was performed in 4 patients. The design of the flap was based on the perforators, which were confirmed by endoscopy. The MSAP flap was tubed and anastomosed end to end to the esophagus. The artery was anastomosed to the superior thyroid arteries, whereas the vein was anastomosed to the internal jugular vein. RESULTS: All the flaps survived. All 4 patients gained acceptable speech and swallow function. One patient developed an infection at the donor site, a second developed fistulas, and a third experienced stricture. All complications were successfully treated. CONCLUSIONS: Here, we demonstrated the use of the MSAP flap in reconstruction of circumferential pharyngoesophageal defects. Further application and follow-up studies should be performed.

In vitro remineralization of hybrid layers using biomimetic analogs.

Resin-dentin bond degradation is a major cause of restoration failures. The major aim of the current study was to evaluate the impact of a remineralization medium on collagen matrices of hybrid layers of three different adhesive resins using nanotechnology methods. Coronal dentin surfaces were prepared from freshly extracted premolars and bonded to composite resin using three adhesive resins (FluoroBond II, Xeno-III-Bond, and iBond). From each tooth, two central slabs were selected for the study. The slabs used as controls were immersed in a simulated body fluid (SBF). The experimental slabs were immersed in a Portland cement-based remineralization medium that contained two biomimetic analogs (biomineralization medium (BRM)). Eight slabs per group were retrieved after 1, 2, 3, and 4 months, respectively and immersed in Rhodamine B for 24 h. Confocal laser scanning microscopy was used to evaluate the permeability of hybrid layers to Rhodamine B. Data were analyzed by analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) tests. After four months, all BRM specimens exhibited a significantly smaller fluorescent area than SBF specimens, indicating a remineralization of the hybrid layer (P≤0.05). A clinically applicable biomimetic remineralization delivery system could potentially slow down bond degradation.

Expression of hepatocyte growth factor and c-Met is characteristic of α-fetoprotein-producing colorectal adenocarcinoma: A report of three cases.

α-fetoprotein (AFP)-producing colorectal adenocarcinoma is rare and typically not well recognized. In the present study, 3 cases of AFP-producing colorectal cancer are described. All 3 of these cases demonstrated increased levels of blood AFP associated with disease progression. Only case 2 exhibited classical histological hepatoid features. Following immunohistochemical tissue staining, all 3 cases were observed to be positive for AFP expression. In addition, the expression of hepatocyte growth factor (HGF), c-Met receptor and the transcription factor c-Myc were identified to be associated with the expression of AFP. The 3 cases demonstrated resistance to multiple drugs, including epidermal growth factor receptor inhibitors, despite the presence of wild-type Kirsten rat sarcoma viral oncogene homolog (K-RAS; codons 12 and 13), neuroblastoma-RAS (codons 12 and 13) and B-Raf proto-oncogene, serine/threonine kinase (V600E). We propose that hepatoid histological features or a positive AFP finding by immunohistochemistry are sufficient for a diagnosis of AFP-producing colorectal adenocarcinoma. Furthermore, we speculates that autocrine HGF/c-Met activation may be capable of inducing the dedifferentiation of common adenocarcinoma cells, reverting them to a cancer stem cell state and producing AFP or hepatoid differentiation. Consequently, therapy targeted to the HGF/c-Met signaling pathway may potentially be effective for the treatment of AFP-producing colorectal adenocarcinoma.

A Case Report of Gastrointestinal Hemorrhage and Perforation During Apatinib Treatment of Gastric Cancer.

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which shows good efficacy and safety in clinical trials for chemotherapy-refractory gastric cancer patients. Till now, there is no case report after apatinib came in the market. We presented a 55-year-old Chinese woman with advanced gastric cancer, who received apatinib after failure of second-line chemotherapy. On the 19th day of apatinib administration, she suffered from gastrointestinal hemorrhage. Then, her condition rapidly deteriorated to gastrointestinal perforation. Although the patient received timely medical and surgical treatment, she finally died of septic shock. Although apatinib shows exciting efficacy and good tolerance in phase II and III clinical trials, this novel targeted drug should be prescribed carefully and close clinical monitoring is needed when using it.

Metachronous Primary Adenocarcinoma of Lung During Adjuvant Imatinib Mesylate Therapy for Gastrointestinal Stromal Tumor of Stomach: A Case Report.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in gastrointestinal tracts; however, the synchronous or metachronous coexistence of GIST with additional primary malignancy is not common.Here, we present an unusual case of gastric GIST with metachronous primary lung adenocarcinoma diagnosed during his adjuvant treatment with oral receptor tyrosine kinase inhibitor imatinib mesylate (400 mg daily). After 6-month use of imatinib, the patient suffered from dry cough and dyspnea. Subsequent lung biopsy demonstrated adenocarcinoma with diffuse interstitial changes.Our research emphasizes the possibility of an additional primary tumor with GIST, and reminds the clinicians to strengthen the surveillance of the additional cancer during the follow-up of GIST patients.

Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo.

Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2- overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.

Transsacral excision with pre-operative imatinib mesylate treatment and approach for gastrointestinal stromal tumors in the rectum: A report of two cases.

Gastrointestinal stromal tumors (GISTs) are rare in the rectum. Radical surgery, such as an abdominoperineal resection, is necessary for large rectal GISTs, which can result in the loss of function of involved organs. Imatinib mesylate can be used as perioperative therapy and may reduce tumor size, and it is now approved for use in the adjuvant therapy of locally resected anorectal GISTs. The present study describes two cases of large rectal GISTs, for which abdominoperineal resections were initially planned. The two patients received pre-operative imatinib mesylate treatment, and the therapeutic response was assessed by magnetic resonance imaging. Finally, transsacral local resection was successfully performed for these two GISTs. A macroscopically complete resection was achieved, and microscopically, the resection margin was negative. One patient experienced the complication of rectal leakage, which was successfully managed by drainage. No recurrence occurred in the two patients after more than two years. Pre-operative imatinib mesylate therapy with subsequent transsacral local resection for selected rectal GISTs is a feasible treatment modality and can prevent extended surgery.

Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells.

Cancer stem cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence that they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ATP-binding cassette subfamily G member 2 (ABCG2) confers chemoresistance to CSCs, where it serves as a potential biomarker and therapeutic target. Here, we show that afatinib, a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4, preferentially eliminated side population cells with CSC character, in both cell lines and patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells, afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA-damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome, or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication.