Differences in Childhood Growth Parameters Between Patients With Somatic and Heritable Retinoblastoma.

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb. Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005. Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile. Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

Efficacy and safety of anti-angiogenesis agents combined with chemoradiotherapy in the treatment of locally advanced cervical cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Neovascularization is an important factor causing radiotherapy resistance, tumor growth, and metastasis. It may provides a new direction for treatment of cervical cancer. OBJECTIVE AND METHODS: The main objective is to systematically evaluate the clinical efficacy and safety of antiangiogenic therapy combined with CCRT in the treatment of cervical cancer. We searched major Chinese and English databases to collect relevant studies from the database establishment up to April 2022. The experimental group of the studies included used CCRT combined with anti-angiogenic therapy, while another used only CCRT. We used the 'Cochrane Collaboration's tool' to assess risk of bias and RevMan 5.4 to conduct analysis. RESULTS: Twelve studies with 793 patients were included. Use clinical efficiency and adverse reactions as effect indicators. It showed that the combination can improve the ORR (OR = 3.52, P < 0.00001), CR(OR = 2.46, P < 0.00001), DCR (OR = 2.64, P= 0.005), and OS(HR = 0.56, P = 0.03). But it increases the risk of neutropenia (OR = 1.86, P = 0.004) and hypertension (OR = 5.57, P = 0.003). CONCLUSIONS: Combined therapy can improve the clinical efficacy of cervical cancer, but the safety needs to be considered.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

A novel signature to predict the neoadjuvant chemotherapy response of bladder carcinoma: Results from a territory multicenter real-world study.

Background: Although neoadjuvant chemotherapy (NAC) has become the standard treatment option for muscle invasive bladder carcinoma (MIBC), its application is still limited because of the lack of biomarkers for NAC prediction. Methods: We conducted a territory multicenter real-world study to summarize NAC practice in China and its associated clinicopathologic variables with NAC response. Then, we developed and validated a robust gene-based signature for accurate NAC prediction using weighted correlation network analysis (WGCNA), the least absolute shrinkage and selector operation (LASSO) algorithm, a multivariable binary logistic regression model, and immunohistochemistry (IHC). Results: In total, we collected 69 consecutive MIBC patients treated with NAC from four clinical centers. The application of NAC in the real world was relatively safe, with only two grade Ⅳ and seven grade Ⅲ AEs and no treatment-related deaths being reported. Among these patients, 16 patients gave up surgery after NAC, leaving 53 patients for further analysis. We divided them into pathological response and non-response groups and found that there were more patients with a higher grade and stage in the non-response group. Patients with a pathological response could benefit from a significant overall survival (OS) improvement. In addition, univariate and multivariate logistic analyses indicated that tumor grade and clinical T stage were both independent factors for predicting NAC response. Importantly, we developed and validated a five-gene-based risk score for extremely high predictive accuracy for NAC response. Conclusion: NAC was relatively safe and could significantly improve OS for MIBC patients in the real-world practice. Our five-gene-based risk score could guide personalized therapy and promote the application of NAC.

Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study.

To parallelly compare the efficacy of neoadjuvant immunotherapy (tislelizumab), neoadjuvant chemotherapy (gemcitabine and cisplatin), and neoadjuvant combination therapy (tislelizumab + GC) in patients with muscle-invasive bladder cancer (MIBC) and explore the efficacy predictors, we perform a multi-center, real-world cohort study that enrolls 253 patients treated with neoadjuvant treatments (combination therapy: 98, chemotherapy: 107, and immunotherapy: 48) from 15 tertiary hospitals. We demonstrate that neoadjuvant combination therapy achieves the highest complete response rate and pathological downstaging rate compared with neoadjuvant immunotherapy or chemotherapy. We develop and validate an efficacy prediction model consisting of pretreatment clinical characteristics, which can pinpoint candidates to receive neoadjuvant combination therapy. We also preliminarily reveal that patients who achieve pathological complete response after neoadjuvant treatments plus maximal transurethral resection of the bladder tumor may be safe to receive bladder preservation therapy. Overall, this study highlights the benefit of neoadjuvant combination therapy based on tislelizumab for MIBC.

Two-step widefield fundus fluorescein angiography-assisted laser photocoagulation in pediatric retinal vasculopathy: A pilot study.

Purpose: To introduce the procedures of two-step fundus fluorescein angiography (FFA) and evaluate its utility in the management of pediatric retinal vasculopathy. Materials and methods: In this retrospective study, medical records of 12 patients who received two-step FFA were studied. The two-step FFA consisted of step 1 [low-dose (LD)] FFA at an intravenous dose of 1.5 mg/kg fluorescein, followed by step 2 [reduced dose (RD)] FFA at a dose of 6.2 mg/kg fluorescein. Demographic data, including age, gender, diagnosis, weight, gestational age, birth weight, and weight on the examination day were taken, were collected. The results of two-step FFA and treatment were recorded. Results: A total of 20 eyes were studied. The top 5 common FFA changes in RD-FFA included peripheral avascular zone (15 eyes), fluorescein leakage (10 eyes), supernumerous vascular branching (10 eyes), neovascularization (NV) (8 eyes), and absence of the foveal avascular zone (6 eyes). LD-FFA was efficient to show all the NV without severe vitreous dye in 8/8 (100.0%) eyes with NV, partial peripheral avascular zone in 11/15 (73.3%) eyes, while RD-FFA always offered more information in all the eyes. Thirteen eyes had laser photocoagulation under the guidance of LD-FFA. In 4 (30.8%) eyes, RD-FFA revealed more lesions and an immediate relaser was performed. Laser photocoagulation was successfully performed in all the 13 eyes in one session without being rearranged. After a median follow-up of 28.1 months, all the eyes were in a stable status. Conclusion: Step-one LD-FFA acted as a pre-FFA to show the NV, and step-two RD-FFA acted as a double-check. The modified strategy may be a helpful clinical adjuvant in the laser photocoagulation of pediatric retinal disorders, especially for young ophthalmologists.

Prophylactic juxtapapillary laser photocoagulation in pediatric morning glory syndrome.

AIM: To determine the anatomic and visual outcomes of prophylactic juxtapapillary laser photocoagulation treatment alone in the prevention of retinal detachment (RD) in a cohort of pediatric patients diagnosed with morning glory syndrome (MGS). METHODS: A total of 24 eyes of 22 consecutive patients aged 0-15y diagnosed with MGS treated with prophylactic juxtapapillary laser photocoagulation alone were reviewed. Data including demographics, ocular examination, anatomic and visual outcomes, following treatment and complications were collected. RESULTS: Two patients had bilateral laser treatment and 20 had monocular laser treatment. The age at treatment of 13 (59.1%) patients was less than 12mo. The presenting symptoms included strabismus (6/22, 27.3%), decreased vision (2/22, 9.1%), and routine fundus screening (14/22, 63.6%). Fifteen (68.2%) patients underwent cranial magnetic resonance imaging (MRI) examinations, and 3 of those 15 (20.0%) had abnormal findings in the nervous system. Based on preoperative wide-field fundus photography and B-scan echography, all (100.0%) eyes had no obvious RD. On postoperative 1mo and 6mo and the following follow-ups, the anatomic outcomes of all eyes remained stable. The mean follow-up duration was 27.7±17.5mo. No severe complications were found. Preoperative visual acuity acquired from 2 (9.1%) patients ranged from light perception to 20/200. Postoperative acuity acquired from 11 (50.0%) patients ranged from light perception to 20/125. CONCLUSION: The preliminary anatomic and visual outcomes of prophylactic juxtapapillary laser treatment alone in pediatric MGS patients are relatively stable in a short-term follow-up. Further long-term clinical observation will be needed to confirm its efficacy and safety.

Dry-Lensectomy Assisted Lensectomy in the Management for End-Stage Familial Exudative Vitreoretinopathy Complicated With Anterior Segment Abnormalities.

Purpose: To report a modified technique of dry-lensectomy assisted lensectomy in the management of end-stage familial exudative vitreoretinopathy (FEVR) complicated with capsule-endothelial, iris-endothelial adhesion and secondary glaucoma. Methods: 24 eyes of 16 patients with severe complications of advanced pediatric total retinal detachment caused by FEVR who received limbus-based dry-lensectomy were studied retrospectively. Preoperative and postoperative clinical information was collected and reviewed. Results: Among the 24 eyes, three eyes (12.50%) underwent lensectomy combined with vitrectomy and membrane peeling simultaneously. 21 (87.50%) eyes underwent lensectomy without membrane peeling due to severe corneal opacity or retinal vascular activity, of which eight underwent another vitrectomy combined with membrane peeling. At the last visit (mean:13.86 ± 5.24 months of follow-up), all eyes had a reconstructed anterior chamber with normal depth. Among 21 eyes having preoperative corneal opacity, 15 (71.43%) had a clearer cornea with reduced opacity, 5 (23.81%) showed similar corneal opacification without deterioration. Among 11 eyes undergone retrolental fibroplasia peeling, seven (63.64%) eyes showed partial retinal reattachment in open-funnel type. Conclusion: Dry-lensectomy offered a simple way to lower the intraocular pressure and simplified the surgery, which helped to solve the severe anterior segment complications and offer a chance for following retrolental fibroplasia peeling and potential visual gain for selected end-stage FEVR patients.

LENS CAPSULAR FLAP TRANSPLANTATION AS PRIMARY TREATMENT FOR CLOSURE OF LARGE MACULAR HOLES.

PURPOSE: To report the long-term outcomes of lens capsular flap transplantation (LCFT) as initial treatment for large macular holes (MHs). METHODS: Thirteen consecutive eyes with large MHs who received LCFT as primary treatment were reviewed retrospectively. All enrolled eyes underwent standard 23-gauge vitrectomy, internal limiting membrane peeling, LCFT, and 15% perfluoropropane tamponade. Autologous whole blood was applied in selected eyes to make the LCT intact. A face-down position maintained for 2 weeks postoperatively. Data including demographic information, medical history, anatomical and functional outcomes, and complications were recorded. RESULTS: The mean preoperative MHs diameter was 979.42 ± 388.28 µm. Eight eyes received autologous LCFT, and the other five eyes received allogenic LCFT. Whole blood was applied in seven eyes. The mean follow-up duration was 19.57 ± 6.24 months (range: 12.0-32.2 months). The macular hole was successfully closed in all cases (13/13). The median best-corrected visual acuity improved from 1.76 (interquartile range, 1.23-1.91) logarithm of the minimum angle of resolution (median Snellen acuity: 20/1,150) preoperatively to 1.16 ± 0.47 logarithm of the minimum angle of resolution (mean Snellen acuity: 20/290) (P < 0.01) at the last visit. No severe complications were noted. CONCLUSION: Lens capsular flap transplantation may help to improve the closure rate and visual outcomes in large MHs, which could be an alternative method as primary treatment for large MHs.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Visualization of the renal vein filled with contrast agent may indicate the renal vein injury during percutaneous nephrolithotomy: two case reports.

BACKGROUND: Intravenous misplacement of a nephrostomy tube is a rare complication of percutaneous nephrolithotomy (PCNL) or percutaneous nephrostomy. The mechanism of misplacement of a nephrostomy tube into the vascular system is seldom investigated. One type of the possible mechanism is that the puncture needle penetrates a major intrarenal tributary of the renal vein and enters the collecting system. However, the guidewire is located outside the collecting system near the large branches of renal vein or perforates into the renal vein. The dilation is performed and causes a large torn injury. Subsequently, the nephrostomy tube is placed inside the vessel when radiological monitoring is not used. However, there is no imaging evidence and the scene of procedure is not demonstrated. This paper reports two cases of visualization of the renal vein filled with contrast agent during PCNL. The findings may be good evidence to support the step of renal vein injury in patients with intravenous nephrostomy tube misplacement. CASE PRESENTATION: We presented two cases with visualization of the renal vein filled with contrast agent during PCNL. In the process of injecting the contrast agent through the puncture needle, we could see the renal vein. Moreover, it was identified that the puncture needle tip was not on the optimal position. The position of puncture needle tip lay outside the collecting system, which was close to the calyceal infundibulum and branches of renal vein. CONCLUSIONS: Visualization of the renal vein filled with contrast agent may be good evidence to verify the renal vein injury in patients with intravenous nephrostomy tube misplacement during PCNL or percutaneous nephrostomy. The suboptimal location of the puncture needle tip and visualization of the renal vein filled with contrast agent indicate the renal vein injury. One type of mechanism of intravenous nephrostomy tube misplacement is as following. Firstly, the guidewire stays outside the collecting system. Subsequently, dilatation directed by the guidewire results in the injury of the vein. Then, the nephrostomy tube migrates into the venous system due to prompt tube inserting and the direction of the sheath and/or the guidewire to the injured vein.

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

BACKGROUND: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. METHODS: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. RESULTS: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). CONCLUSIONS: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

Spectrum of germline mutations in RB1 in Chinese patients with retinoblastoma: Application of targeted next-generation sequencing.

Purpose: Retinoblastoma (RB) is a pediatric ocular malignancy due to biallelic inactivation of the RB1 gene. Genetic testing is critically important for treatment decisions for this disease. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for discovering all types of mutations in the RB1 gene. The aim of this study is the application of targeted NGS in a cohort of Chinese patients with retinoblastoma to identify germline mutations in the RB1 gene. Methods: Blood samples were collected from 149 unrelated probands with retinoblastoma (62 bilaterally and 87 unilaterally) and their parent(s). Genomic DNA was analyzed with custom panel-based targeted NGS, and the panel was designed to include exons 1-27 of the RB1 gene with flanking intronic sequences. Single nucleotide variations (SNVs) and small insertions/deletions (InDels) identified were confirmed with Sanger sequencing. If the Sanger sequencing of a low-frequency variant (LFV) detected with targeted NGS was negative, PCR-based deep NGS was conducted for added confirmation. Copy number variations (CNVs) detected with targeted NGS were confirmed with multiplex ligation-dependent probe amplification (MLPA). Results: Overall, 74 germline mutations were detected in 48.3% of the probands (72/149, 56 bilateral and 16 unilateral cases). The total detection rate in the bilateral cases was 90.3% (56/62). These mutations included 64 SNVs and InDels (25 nonsense, 20 splicing, ten frameshift, eight missense, and one synonymous variants) and ten CNVs. All CNVs were confirmed with MLPA. Twenty-four (32.4%, 24/74) variants detected were novel, including nine splicing, six frameshift, five missense, and four nonsense variants. Eight LFVs (10.8%, 8/74) were found with targeted NGS; six of which were identified with Sanger sequencing, and two were identified with PCR-based deep NGS (13.16% and 3.000% mutant rates, respectively). Conclusions: This study expanded the spectrum of germline mutations in RB1 using targeted NGS technology, which is a cost-saving and efficient method for genetic sequencing of retinoblastoma and may improve the molecular diagnosis of retinoblastoma.

Clinical and Echographic Features of Morning Glory Disc Anomaly in Children: A Retrospective Study of 249 Chinese Patients.

PURPOSE: To report the clinical and echographic features, the prevalence of retinal detachment (RD), and associated visual acuity in a cohort of pediatric patients with morning glory disc anomaly (MGDA). METHODS: This was a retrospective review of 249 pediatric patients with MGDA (271 eyes) seen at the Dept. of Ophthalmology, Xinhua Hospital. Their medical records were reviewed for demographic data and ocular and systemic findings. The maximal depth and width of the cavity were measured using standardized echographic images. The ratios of cavitary depth to axial length, cavitary depth to maximal cavitary width, and the product of cavitary depth and width were calculated and used to indicate the relative size of the excavation. The clinical and echographic findings were correlated with visual acuity and the occurrence of RD of the patient. RESULTS: The relative size of the excavation and the presence of RD were positively associated with increased risk of poor vision (p < 0.05). The presence of persistent fetal vasculature was not associated with the risk of RD and poor vision. The ratio of cavitary depth to axial length more than or equal to 0.25 conferred an increased risk of RD (OR, 2.101; 95% CI, 1.469-3.003). CONCLUSIONS: Clinical and echographic features of MGDA may be used in predicting the risk of RD. Measuring the relative size of excavation via echography may guide the follow-ups and assist in the early diagnosis of RD.