[Clinical observation of the subthreshold micropulse laser combined with ranibizumab for treatment of diabetic macular edema].

Objective: To evaluate the efficacy and safety of the subthreshold micropulse laser (SMPL) combined with ranibizumab in treating diabetic macular edema (DME). Methods: This was a prospective randomized controlled study. Patients diagnosed with DME in the Ophthalmology Department of Beijing Hospital were enrolled from January 2020 to December 2022. Patients were randomized in a ratio of 1∶1 using a table of random numbers into the ranibizumab monotherapy group and the SMPL combined with ranibizumab therapy group. We compared the changes of best-corrected visual acuity, central macular thickness measured by optical coherence tomography and optical coherence tomography angiography parameters, including the vessel density of the superficial and deep capillary plexus (DCP), foveal avascular zone size and peripapillary vessel density, at baseline, 6 and 12 months after the treatment. After 12 months of follow-up, fundus fluorescein angiography results, adverse events, and the number of injections or laser therapies were recorded. The Fisher's exact test and group t-test were used for statistical analysis. Results: Seventy-two patients (72 eyes) were enrolled, with a mean age of (61.1±8.2) years. Patients in the combination therapy group included 19 males and 17 females, while patients in the ranibizumab monotherapy group were 17 males and 19 females. There was no statistically significant difference in baseline characteristics between the two groups (P>0.05). A significant improvement in best-corrected visual acuity was shown in both groups at 6 and 12 months [(58.5±12.9) and (58.2±12.2) ETDRS letters in the combination therapy group, and (63.3±13.1) and (63.8±12.5) ETDRS letters in the ranibizumab monotherapy group]. A significant reduction in central macular thickness was shown in both groups at 6 and 12 months [(451.0±185.5) and (380.4±159.3)µm in the combination therapy group, and (387.5±135.5) and (372.8±146.1)µm in the ranibizumab monotherapy group]. However, there was no significant difference between groups at each timepoint (all P>0.05). At 12 months, the vessel density of the superficial capillary plexus showed no statistical difference compared to the baseline value in each group or between groups (42.6%±5.9% in the ranibizumab monotherapy group and 42.2%±5.5% in the combination therapy group, P>0.05). The vessel density of the DCP in the combination therapy group significantly increased to 47.5%±5.6% at 12 months, significantly different from that in the ranibizumab group (43.4%±5.1%; P<0.05). The foveal avascular zone size in the ranibizumab monotherapy group reduced to (0.32±0.13) mm2, significantly different from that in the combination therapy group [(0.34±0.16) mm2] at 12 months (P<0.05). Patients in the ranibizumab monotherapy group received (7.3±2.5) intravitreal injections, while patients in the combination therapy group received 3 injections. No unfavorable outcomes on fundus fluorescein angiography or systemic or topical severe adverse events were observed during the follow-up. Conclusions: The SMPL combined with intravitreal ranibizumab injections was effective and safe in treating DME patients. The combination treatment significantly reduced the number of injections and improved the vessel density of the DCP and macular ischemia, compared to the ranibizumab monotherapy.

Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma.

Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.

[Efficacy and safety of chimeric antigen receptor T-cell therapy followed by allogeneic hematopoietic stem cell transplantation in 21 patients with Ph-like acute lymphoblastic leukemia].

Objective: To evaluate the efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Ph-like acute lymphoblastic leukemia (Ph-ALL) . Methods: Patients with Ph-ALL who underwent CAR-T therapy followed by allo-HSCT from March 2018 to August 2023 at the First Affiliated Hospital of Soochow University were included, and their clinical data were retrospectively analyzed. Results: Of the 21 patients, 14 were male and 7 were female. The median age at the time of CAR-T therapy was 22 (6-50) years. Seven patients had ABL1-like rearrangements, and 14 had JAK-STAT rearrangements. Prior to CAR-T therapy, 12 patients experienced hematologic relapse; 7 were multiparameter flow cytometry minimal residual disease (MFC-MRD) -positive and 2 were MFC-MRD-negative. CAR-T cells were derived from patients' autologous lymphocytes. Nine patients were treated with CD19 CAR-T cells, and 12 were treated with CD19/CD22 CAR-T cells. After assessment on day 28 after CAR-T therapy, 95.2% of the patients achieved complete remission, with an MRD-negative remission rate of 75%. Nineteen patients developed grade 0-2 cytokine release syndrome (CRS) and 2 patients suffered grade 3 CRS, all cases of which resolved after treatment. All patients underwent allo-HSCT after CAR-T therapy. The median time from CAR-T therapy to allo-HSCT was 63 (38-114) days. Five patients experienced relapse after CAR-T therapy, including four with hematologic relapse and one with molecular relapse. The 3-year overall survival (OS) rates in the ABL1 and JAK-STAT groups were (83.3±15.2) % and (66.6±17.2) %, respectively (P=0.68) . The 3-year relapse-free survival (RFS) rates were (50.0±20.4) % and (55.6±15.4) % in the ABL1 and JAK-STAT groups, respectively. There was no significant difference in 3-year OS or RFS between the two groups. Conclusions: CAR-T therapy followed by allo-HSCT leads to rapid remission in most patients with Ph-ALL and prolongs leukemia-free survival.

[Challenges and strategies in the treatment of neovascular age-related macular degeneration].

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in the elderly, and anti-vascular endothelial growth factor (VEGF) therapy is currently the primary treatment approach. However, the real-world effectiveness of nAMD treatment is not always satisfactory and faces various challenges. Frequent administration and follow-up burdens can lead to decreased patient compliance during long-term treatment, resulting in suboptimal outcomes. Some lesions exhibit poor or no response to anti-VEGF treatment, leading to difficulties in maintaining or even declining visual acuity. Factors such as lesion fibrosis and tissue atrophy can contribute to visual deterioration. Therefore, standardizing and individualizing treatment plans, along with enhancing comprehensive monitoring and management throughout the disease course, are crucial improvement measures. The evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China, released in 2023, provide guidance for standardized clinical diagnosis and treatment. Meanwhile, research and development of new drugs and administration methods are anticipated for the future.

Social Determinants of Outcomes Disparity among Pediatric Patients with Solid Tumor.

BACKGROUND: Socioeconomic factors have a significant impact on healthcare outcomes. Metrics such as area deprivation index (ADI) are used to quantify the anticipated influence of these factors. Here, we sought to assess the impact of socioeconomic factors on clinical outcomes among pediatric patients with solid tumor in our region. STUDY DESIGN: We identified 3,863 pediatric patients who were diagnosed with a malignant solid tumor in the Texas Cancer Registry between 1995 and 2019. ADI was used to quantify socioeconomic determinants of health. These outcome variables were determined: stage of disease at diagnosis, time between diagnosis and treatment initiation, and overall mortality. Statistical analysis was performed using logistic regression, linear regression, Cox proportional hazards regression, and Kaplan-Meier survival curves. RESULTS: A total of 53.5% of patients were male and the average age at diagnosis was 4.5 years. Forty-seven percent of patients were White, 13.3% were Black, 36.2% were Hispanic, 1.7% were Asian, and other rare minority groups made up 1.8%. On multivariable analysis, increased risk of death was associated with Black race, rare minority race, residence in a border county, and increasing ADI score, with the risk of death at 5 years rising 4% with each increasing ADI point. CONCLUSIONS: Social determinants of health are associated with disparate outcomes among pediatric patients with solid tumor. Our results suggest that patients who are part of racial minority groups and those who reside in socioeconomically disadvantaged neighborhoods or regions near the Texas-Mexico border are at an increased risk of death. This information may be useful in strategizing outreach and expanding resources to improve outcomes in at-risk communities.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

WDR5 facilitates recruitment of N-MYC to conserved WDR5 gene targets in neuroblastoma cell lines.

Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC-cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 can be deemed as a "universal" MYC recruiter. Here, we focus on N-MYC amplified neuroblastoma to determine the extent of colocalization between N-MYC and WDR5 on chromatin while also demonstrating that like c-MYC, WDR5 can facilitate the recruitment of N-MYC to conserved WDR5-bound genes. We conclude based on this analysis that N-MYC and WDR5 colocalize invariantly across cell lines at predicted sites of facilitated recruitment associated with protein synthesis genes. Surprisingly, we also identify N-MYC-WDR5 cobound genes that are associated with DNA repair and cell cycle processes. Dissection of chromatin binding characteristics for N-MYC and WDR5 at all cobound genes reveals that sites of facilitated recruitment are inherently different than most N-MYC-WDR5 cobound sites. Our data reveals that WDR5 acts as a universal MYC recruiter at a small cohort of previously identified genes and highlights novel biological functions that may be coregulated by N-MYC and WDR5 to sustain the neuroblastoma state.

Comparison of clinical cure rates from footrot and contagious ovine digital dermatitis using zinc sulphate foot bathing and topical oxytetracycline: A randomised trial.

BACKGROUND: This study reports the clinical cure rates of topical oxytetracycline and 10% zinc sulphate foot bathing for treatment of interdigital dermatitis (ID), footrot (FR) and contagious ovine digital dermatitis (CODD) in lambs. METHODS: The study was a randomised controlled trial of 75 lambs. Group A (n = 38) was foot bathed daily for 5 days in 10% zinc sulphate for 15 minutes and group B was treated with daily topical oxytetracycline for 5 days. On days 0, 7, 14, 28 and 42, lambs were scored for locomotion and foot lesions were recorded. RESULTS: The initial cure rates for ID were 96.20% and 97.00%; for FR, 100% and 95%; and for CODD, 90.09% and 83.33% for zinc sulphate and oxytetracycline, respectively. By day 42, these had changed to 53.16% and 61% for ID; 47.82% and 70% for FR; and 100% and 83.33% for CODD. There were no significant differences in cure rates between the treatments for most time points. LIMITATIONS: The sample size was small, and further studies in larger cohorts and different classes of sheep are required before the findings can be translated into recommendations for clinical practice. CONCLUSION: Both treatments achieved cure rates that are comparable to reported cure rates using systemic antibiotics and could be an effective alternative.

[Effects of laparoscopic hyperthermic intraperitoneal perfusion chemotherapy combined with intraperitoneal and systemic chemotherapy treatment in patients with untreated gastric cancer with peritoneal metastasis].

Objective: To investigate the efficacy of laparoscopic hyperthermic intraperitoneal perfusion chemotherapy combined with intraperitoneal and systemic chemotherapy (HIPEC-IP-IV) in the treatment of peritoneal metastases from gastric cancer (GCPM). Methods: This was a descriptive case series study. Indications for HIPEC-IP-IV treatment include: (1) pathologically confirmed gastric or esophagogastric junction adenocarcinoma; (2) age 20-85 years; (3) peritoneal metastases as the sole form of Stage IV disease, confirmed by computed tomography, laparoscopic exploration, ascites or peritoneal lavage fluid cytology; and (4) Eastern Cooperative Oncology Group performance status 0-1. Contraindications include: (1) routine blood tests, liver and renal function, and electrocardiogram showing no contraindications to chemotherapy; (2) no serious cardiopulmonary dysfunction; and (3) no intestinal obstruction or peritoneal adhesions. According to the above criteria, data of patients with GCPM who had undergone laparoscopic exploration and HIPEC from June 2015 to March 2021 in the Peking University Cancer Hospital Gastrointestinal Center were analyzed, after excluding those who had received antitumor medical or surgical treatment. Two weeks after laparoscopic exploration and HIPEC, the patients received intraperitoneal and systemic chemotherapy. They were evaluated every two to four cycles. Surgery was considered if the treatment was effective, as shown by achieving stable disease or a partial or complete response and negative cytology. The primary outcomes were surgical conversion rate, R0 resection rate, and overall survival. Results: Sixty-nine previously untreated patients with GCPM had undergone HIPEC-IP-IV, including 43 men and 26 women; with a median age of 59 (24-83) years. The median PCI was 10 (1-39). Thirteen patients (18.8%) underwent surgery after HIPEC-IP-IV, R0 being achieved in nine of them (13.0%). The median overall survival (OS) was 16.1 months. The median OS of patients with massive or moderate ascites and little or no ascites were 6.6 and 17.9 months, respectively (P<0.001). The median OS of patients who had undergone R0 surgery, non-R0 surgery, and no surgery were 32.8, 8.0, and 14.9 months, respectively (P=0.007). Conclusions: HIPEC-IP-IV is a feasible treatment protocol for GCPM. Patients with massive or moderate ascites have a poor prognosis. Candidates for surgery should be selected carefully from those in whom treatment has been effective and R0 should be aimed for.

High-Risk Neuroblastoma: A Surgical Perspective.

High-risk neuroblastoma requires multimodal treatment including systemic chemotherapy, surgical resection, radiation therapy, stem cell transplant, and immunotherapy. Surgeons play a vital role in obtaining local control of neuroblastoma and must therefore be knowledgeable about this complex pathology. This article provides a review of the optimal timing and extent of resection, the impact of various image-defined risk factors on surgical planning, and surgical approaches and techniques to enhance the resection of tumors in different anatomic locations.

22q11.2 deletion syndrome complicated with pulmonary alveolar proteinosis in a child: a case report.

BACKGROUND: To analyze the clinical data and next generation sequencing (NGS) results from a child with 22q11.2 deletion syndrome (22q11DS) complicated with pulmonary alveolar proteinosis (PAP) who was admitted to the Department of Pediatrics of Fuyang People's Hospital and to present a review of the literature. CASE PRESENTATION: A 9-year-old male child, whose face had a small mandible and high-arched palate, but lacked a cleft palate, had repeated respiratory tract infections and bronchiectasis. Clinical examination, computer tomography, and electronic bronchoscopy were performed. Genetic testing via NGS was undertaken. PAP was confirmed by Periodic Acid Schiff staining of milky white alveolar lavage fluid isolated by electronic bronchoscopy. A deletion of approximately 2.46 Mbp on chromosome 22q11.2 was confirmed by NGS. During hospitalization, anti-infection, nebulization, alveolar lavage, and regular application of thymosin were administered to the patient. The condition of the patient stabilized following treatment. CONCLUSIONS: 22q11DS and PAP are both rare diseases, and the manifestation of 22q11DS combined with PAP has not been previously reported. The diagnosis and treatment of this case will be a reference for future clinical work.

Improving Billing and Collections in a High-Volume Pediatric Surgery Practice: Denials-Based Approach.

BACKGROUND: Despite minimal coding and billing training, surgeons are frequently tasked with both in clinical practice. This often results in denials for reimbursement based on incorrect or insufficient documentation, and reduced collections for work performed. We sought to evaluate how to correct these deficits while improving reimbursement for the most frequently rejected procedures at a high-volume academic center. STUDY DESIGN: Hospital billing data were analyzed for a 4-year period (2018 to 2021) to determine the CPT code denials with the largest overall cost. The denials were then stratified according to payor, reason for denial, and preventability. Assigned ICD-10 codes were categorized based on specificity as related to the procedure. The distribution of denials according to ICD-10 specificity was evaluated using the chi-square test. RESULTS: A total of 8,833 denials representing $11,009,108 in billing were noted during the study period. The CPT code 44970 (laparoscopic appendectomy) was the code associated with the largest financial impact, representing 12.8% of the total denied amount ($1.41M). Of the 823 denials for CPT 44970, 93.3% were associated with nonspecific ICD-10 codes, whereas only 42.0% had been associated with procedure-specific ICD-10 codes. Of the patients with nonspecific codes, 80.7% of denials were due to criteria that could be remedied with supplemental information or timely filing, representing $1,059,968 in collections. CONCLUSIONS: This is the first study to systematically evaluate a pathway for using denial data to improve collections for work performed at a high-volume academic pediatric surgery practice. Using this methodology, targets for improvement in coding and/or documentation can be identified to improve the financial performance of a surgical department. This study also provides evidence that association with nonspecific diagnostic codes is correlated with initial denial of payment by insurance companies.

[Application of transbronchial cryobiopsy in the diagnosis of postoperative complications after lung transplantation: a report of 6 cases].

Objective: To investigate the efficacy and safety of transbronchial cryobiopsy (TBCB) after lung transplantation. Methods: The clinical characteristics, TBCB procedure, diagnosis and treatment, and outcomes of lung transplant recipients of 6 patients (all male, aged 33-67 years) with TBCB in China-Japan Friendship Hospital from May to November 2021 were retrospectively analyzed. Results: Among the 6 patients diagnosed by TBCB, there were 2 cases of organizing pneumonia, 1 acute cellular rejection, 1 antibody-mediated rejection, and 1 bronchiolitis obliterans, and 1 diffuse alveolar damage. After the clinical diagnosis was confirmed, the condition improved after adjustment of the treatments followed. There were no serious complications related to the TBCB procedure. Conclusion: TBCB is valuable and relatively safe in the diagnosis of complications after lung transplantation, but the indications need to be strictly controlled.

Increased Sparc release from subchondral osteoblasts promotes articular chondrocyte degeneration under estrogen withdrawal.

OBJECTIVE: The incidence of osteoarthritis (OA) in menopausal women is significantly higher than in same-aged men. Investigating the role of subchondral osteoblasts in estrogen deficiency-induced OA may help elucidate the pathological mechanism, providing new insights for the diagnosis and treatment of menopausal OA. METHODS: A classical ovariectomy-induced OA (OVX-OA) rat model was utilized to isolate primary articular chondrocytes and subchondral osteoblasts, which were identified and then cocultured in Transwell. The expression of chondrocyte anabolic and catabolic indicators was evaluated. The differentially expressed proteins in the conditioned medium (CM) of osteoblasts were identified by Liquid Chromatograph-Mass Spectrometer (LC-MS/MS). Normal chondrocytes were treated with osteoblast CM, and then RNA sequencing was performed on the treated chondrocytes. KEGG was used to identify significant enrichment of signaling pathways, and Simple Western was used to verify the expression of related proteins in the signaling pathways. RESULTS: Coculture of OVX-OA subchondral osteoblasts with chondrocytes significantly downregulated the expression of the anabolic indicators and upregulated the expression of the catabolic indicators in chondrocytes. 1,601 proteins were identified in both normal and OVX osteoblast culture supernatants. Protein-protein interaction network analysis revealed that Sparc was one of the hub proteins. The AMPK/Foxo3a signaling pathway of chondrocytes was downregulated by OVX-OA osteoblasts CM. AICAR, the AMPK agonist, partially reversed the catabolic effect of OVX-OA osteoblasts on chondrocytes. CONCLUSIONS: Sparc secreted by OVX-OA subchondral osteoblasts can downregulate the AMPK/Foxo3a signaling pathway of chondrocytes, thereby promoting chondrocyte degeneration.

Anti-GRP-R monoclonal antibody antitumor therapy against neuroblastoma.

Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.

Combination bromo- and extraterminal domain and poly (ADP-ribose) polymerase inhibition synergistically enhances DNA damage and inhibits neuroblastoma tumorigenesis.

PURPOSE: JQ1 is a bromo- and extraterminal (BET) domain inhibitor that downregulates MYC expression and impairs the DNA damage response. Poly (ADP-ribose) polymerase (PARP) inhibitors prevent DNA damage sensing and repair. We hypothesized that JQ1 would promote a DNA repair-deficient phenotype that sensitizes neuroblastoma cells to PARP inhibition. METHODS: Four human neuroblastoma cell lines were examined: two MYCN-amplified (BE(2)-C and IMR-32), and two non-MYCN-amplified (SK-N-SH and SH-SY5Y). Cells were treated with JQ1 (BET inhibitor), Olaparib (PARP inhibitor), or in combination to assess for therapeutic synergy of JQ1 and Olaparib. Treated cells were harvested and analyzed. Quantitative assessment of combination treatment synergy was performed using the median effect principle of Chou and Talalay. RESULTS: Combination treatment with Olaparib decreased the IC50 of JQ1 by 19.9-fold, 2.0-fold, 12.1-fold, and 2.0-fold in the BE(2)-C, IMR-32, SK-N-SH, and SH-SY5Y cell lines, respectively. In the MYCN-amplified cell lines, BE(2)-C and IMR-32, combination treatment decreased gene expression of MYCN relative to single-drug treatment alone or control. Combination treatment decreased protein expression of DNA repair proteins Ku80 and RAD51, led to accumulation of DNA damage marker phospho-histone H2A.X, and increased caspase activity. In the non-MYCN-amplified cell lines, SK-N-SH and SH-SY5Y, combination treatment induced G0/G1 cell cycle arrest. CONCLUSIONS: Combination BET and PARP inhibition synergistically inhibited neuroblastoma tumorigenesis in vitro. In MYCN-amplified neuroblastoma cells, this effect may be induced by downregulation of MYCN transcription, defects in DNA repair, accumulation of DNA damage, and apoptosis. In non-MYCN-amplified cell lines, combination treatment induced cell cycle arrest.

[The impact of different comprehensive treatment models on patients with adenocarcinoma of esophagogastric junction based on propensity score matching: a single center cohort study].

Objective: To compare the prognostic influence and postoperative pathology of different comprehensive treatment models for adenocarcinoma of esophagogastric junction. Methods: Between January 2012 and December 2017, a total of 219 patients with adenocarcinoma of esophagogastric junction underwent surgery in Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute and were enrolled in this study. The clinicopathological data of these patients were collected. The patients were categorized into 3 groups according to different treatment models: surgery-first group, neoadjuvant chemotherapy (NAC) group and neoadjuvant chemoradiotherapy (nCRT) group. A trimatch propensity score analysis was applied to control potential confounders among the three groups by using R language software. A total of 7 covariates including gender, age, comorbidity, body mass index, clinical T stage, clinical N stage and Siewert type were included, and the caliper value was taken as 0.2. After matching, a total of 87 patients were included for analysis with 27 patients for each group. There were 82 males and 5 females, with a median age of 63 years (range: 38 to 76 years). The effect of preoperative treatment on postoperative tumor pathology among the three different comprehensive treatment models was explored by χ2 test, ANOVA or Wilcoxon rank sum test. Mann-Whitney U test or χ2 test were used to undergo pairwise comparisons. Kaplan-Meier method and Log-rank test were used to analyze the overall survival and progression-free survival. Results: The proportion of vascular embolism in the surgery-first group was 72.4% (21/29), which was significantly higher than NAC group (37.9% (11/29), χ2=6.971, P=0.008) and nCRT group (6.9% (2/29), χ2=26.696, P<0.01). The proportions of pathological T3-4 stage in nCRT group and NAC group were 55.2% (16/29) and 62.1% (18/29), respectively, which were significantly lower than the surgery-first group (93.1% (27/29), χ2=10.881, P=0.001; χ2=8.031, P=0.005). Compared with the NAC group (55.2% (16/29), χ2=6.740, P=0.009) and nCRT group (31.0% (9/29), χ2=18.196, P<0.01), the proportion of lymph node positivity 86.2% (25/29) were significantly higher in the surgery-first group. The 5-year overall survival rates were 62.1%, 68.6% and 41.4% for the surgery-first group, NAC group and nCRT group, respectively (χ2=4.976, P=0.083). The 5-year progression-free survival rates were 61.7%, 65.1% and 41.1% for the surgery-first group, NAC group and nCRT group, respectively. The differences in overall survival (χ2=4.976, P=0.083) and progression-free survival (χ2=4.332, P=0.115) among the three groups were nonsignificant. Conclusions: Postoperative pathology is significantly different among the three groups. Neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy could decrease the proportions of vascular embolism, pathological T3-4 stage and lymph node positivity to achieve local tumor control. The prognosis of overall survival and progression-free survival are not significantly different among the three groups.

Multimodality treatment of pediatric Ewing sarcoma: A single-center 10-year analysis of outcomes.

BACKGROUND: Ewing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control. METHODS: Patients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis. RESULTS: Sixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status. CONCLUSION: There was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.