Photoreceptor nanotubes mediate the in vivo exchange of intracellular material.

Emerging evidence suggests that intracellular molecules and organelles transfer between cells during embryonic development, tissue homeostasis and disease. We and others recently showed that transplanted and host photoreceptors engage in bidirectional transfer of intracellular material in the recipient retina, a process termed material transfer (MT). We used cell transplantation, advanced tissue imaging approaches, genetic and pharmacologic interventions and primary cell culture to characterize and elucidate the mechanism of MT. We show that MT correlates with donor cell persistence and the accumulation of donor-derived proteins, mitochondria and transcripts in acceptor cells in vivo. MT requires cell contact in vitro and is associated with the formation of stable microtubule-containing protrusions, termed photoreceptor nanotubes (Ph NTs), that connect donor and host cells in vivo and in vitro. Ph NTs mediate GFP transfer between connected cells in vitro. Furthermore, interfering with Ph NT outgrowth by targeting Rho GTPase-dependent actin remodelling inhibits MT in vivo. Collectively, our observations provide evidence for horizontal exchange of intracellular material via nanotube-like connections between neurons in vivo.

Pou2f1 and Pou2f2 cooperate to control the timing of cone photoreceptor production in the developing mouse retina.

Multipotent retinal progenitor cells (RPCs) generate various cell types in a precise chronological order, but how exactly cone photoreceptor production is restricted to early stages remains unclear. Here, we show that the POU-homeodomain factors Pou2f1/Pou2f2, the homologs of Drosophila temporal identity factors nub/pdm2, regulate the timely production of cones in mice. Forcing sustained expression of Pou2f1 or Pou2f2 in RPCs expands the period of cone production, whereas misexpression in late-stage RPCs triggers ectopic cone production at the expense of late-born fates. Mechanistically, we report that Pou2f1 induces Pou2f2 expression, which binds to a POU motif in the promoter of the rod-inducing factor Nrl to repress its expression. Conversely, conditional inactivation of Pou2f2 in RPCs increases Nrl expression and reduces cone production. Finally, we provide evidence that Pou2f1 is part of a cross-regulatory cascade with the other temporal identity factors Ikzf1 and Casz1. These results uncover Pou2f1/2 as regulators of the temporal window for cone genesis and, given their widespread expression in the nervous system, raise the possibility of a general role in temporal patterning.This article has an associated 'The people behind the papers' interview.

Treatment outcomes for response-based radiotherapy in children and adolescents with central nervous system germinoma: a prospective study.

PURPOSE: The optimal dose and range of radiotherapy for central nervous system (CNS) germinoma have not yet been established. This study aimed to investigate the effects of individualized radiotherapy on the prognosis of patients with germinoma. METHODS: Based on imaging examination, tumor markers, and pathologic results, patients with germinoma received different radiotherapy strategies, including R1 (24 Gy whole ventricular irradiation + tumor-bed boost to 40 Gy), R2 (24-30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy), R3 (24 Gy craniospinal irradiation + tumor-bed boost to 40 Gy), and R4 (30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy with 45 Gy to spinal metastasis). RESULTS: A total of 77 patients were enrolled in this study between January 2015 and March 2021. The 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 94.7% ± 2.6% and 96.0% ± 2.3%, respectively. The 3-year EFS for patients with localized and metastatic disease were 96.6% ± 2.4% and 89.2% ± 7.2%, respectively. The 3-year EFS of patients receiving R1, R2, R3, and R4 radiotherapy were 100%, 94.1% ± 5.7%, 100%, and 86.2% ± 9.1%, respectively. CONCLUSION: Good prognosis was still achieved after reducing dose and extent of radiation for the patients who achieved complete response (CR) after induction chemotherapy or pathological CR after second-look surgery.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

Novel fully human anti-CD47 antibodies stimulate phagocytosis and promote elimination of AML cells.

Although most patients with acute myeloid leukemia (AML) enter remission after induction chemotherapy, the risk of relapse remains considerable. Therefore, some novel therapeutic strategies are still required. This study found that the overexpression of CD47 on AML cells was at least twofold more than that on normal bone marrow (NBM) cells in 81% (17/21) of the investigated patients; no patients had lower expression level of CD47 compared with healthy donors. The study also demonstrated that blocking the CD47/SIRPα (signal regulatory protein α) signal with the established novel fully human anti-CD47 monoclonal antibodies increased the phagocytosis of AML cells by macrophages in vitro. Furthermore, in vivo experiments showed that the novel fully human anti-CD47 monoclonal antibodies could significantly prolong the survival time of mice. Overall, the novel fully human anti-CD47 antibodies could block CD47/SIRPα interaction, increase macrophage-mediated phagocytosis, and enhance the elimination of AML cells.

Comparison of SARS-CoV-2 indirect and direct RT-qPCR detection methods.

BACKGROUND: Sensitive, rapid, and accessible diagnostics continue to be critical to track the COVID-19 pandemic caused by the SARS-CoV-2 virus. RT-qPCR is the gold standard test, and comparison of methodologies and reagents, utilizing patient samples, is important to establish reliable diagnostic pipelines. METHODS: Here, we assessed indirect methods that require RNA extraction with direct RT-qPCR on patient samples. Four different RNA extraction kits (Qiagen, Invitrogen, BGI and Norgen Biotek) were compared. For detection, we assessed two recently developed Taqman-based modules (BGI and Norgen Biotek), a SYBR green-based approach (NEB Luna Universal One-Step Kit) with published and newly-developed primers, and clinical results (Seegene STARMag RNA extraction system and Allplex 2019-nCoV RT-qPCR assay). We also tested and optimized direct, extraction-free detection using these RT-qPCR systems and performed a cost analysis of the different methods evaluated here. RESULTS: Most RNA isolation procedures performed similarly, and while all RT-qPCR modules effectively detected purified viral RNA, the BGI system provided overall superior performance (lower detection limit, lower Ct values and higher sensitivity), generating comparable results to original clinical diagnostic data, and identifying samples ranging from 65 copies to 2.1 × 105 copies of viral genome/µl. However, the BGI detection system is more expensive than other options tested here. With direct RT-qPCR, simply adding an RNase inhibitor greatly improved detection, without the need for any other treatments (e.g. lysis buffers or boiling). The best direct methods detected ~ 10 fold less virus than indirect methods, but this simplified approach reduced sample handling, as well as assay time and cost. CONCLUSIONS: With extracted RNA, the BGI RT-qPCR detection system exhibited superior performance over the Norgen system, matching initial clinical diagnosis with the Seegene Allplex assay. The BGI system was also suitable for direct, extraction-free analysis, providing 78.4% sensitivity. The Norgen system, however, still accurately detected samples with a clinical Ct < 33 from extracted RNA, provided significant cost savings, and was superior to SYBR green assays that exhibited reduced specificity.

Comparison of chemotherapy with or without asparaginase for extranodal nasal NK/T-cell lymphoma in children and adolescents.

PURPOSE: As extranodal natural killer/T-cell lymphoma (ENKTL) occurs rarely in children and adolescents, standardized therapy is yet to be determined. This study aimed to describe the clinical features and determine the optimal chemotherapy regimen for childhood ENKTL. METHODS: The treatment outcomes of radiotherapy combined with asparaginase-based (P-GEMOX or P-GMED) or asparaginase-absent chemotherapy regimens (CHOP, EPOCH, or NHL-BFM-90/95) in patients aged ≤18 years with newly diagnosed ENKTL from December 2006 to December 2018 were compared. RESULTS: Among the 34 patients included in the study, 21 had stage I/II disease. The overall response rates of chemotherapy with or without asparaginase were 85.0% and 78.6%, respectively. With a median follow-up of 54 months, the 5-year event-free survival (EFS) rates of patients with stage I/II and III/IV disease were 66.2 ± 11.3% and 26.0 ± 12.8%, respectively (P = .027). In stage III/IV patients treated with asparaginase-based or asparaginase-absent regimens, the 5-year EFS rates were 40.0 ± 17.4% and 0%, respectively (P = .236). The 5-year EFS rates of stage III/IV patients who received or did not receive hematopoietic stem cell transplant were 66.7 ± 27.2% and 11.1 ± 10.5%, respectively (P = .054). In addition, chemotherapy-associated side effects were significantly less in patients treated with asparaginase-based regimens as compared to asparaginase-absent regimens in this cohort. CONCLUSION: P-GEMOX and P-GMED regimens are effective and safe for treating childhood ENKTL.

Multimodal Treatment of Children With Sacrococcygeal Yolk Sac Tumor: Retrospective Analysis of Clinicopathology Characteristics and Relapse-free Survival.

The aim of the study was to explore the clinicopathologic characteristics of sacrococcygeal yolk sac tumor (SYST) associated with relapse and the role of sensitivity to neoadjuvant chemotherapy in predicting outcome. The authors investigated prognostic factors of age, stage, initial tumor size, pathologic response to neoadjuvant chemotherapy, and alfa fetoprotein. A total of 26 patients with SYST were enrolled. Neoadjuvant chemotherapy was administered to 20 cases. Six patients underwent resection as initial therapy. Recurrence occurred in 12 patients. Nine patients with specimens exhibiting no malignant component after chemotherapy did not experience recurrence. By contrast, relapses occurred in 7 of 11 patients with viable residual tumor after neoadjuvant chemotherapy. All relapsed patients still achieved partial remission or complete remission after salvage therapy. Five-year relapse-free survival and overall survival rates were 55.2% and 100%, respectively (median follow-up, 59.5 mo; range, 16 to 155). Patients with complete necrosis after neoadjuvant chemotherapy had a better outcome compared with children with viable residual tumor. Relapse-free survival of pediatric SYSTs in this cohort were still low and warrants the multidisciplinary effort.

The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China.

PURPOSE: This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). METHODS: We collected and analyzed clinical data concerning patients aged <15 years with favorable histology (FH) WTs treated at the Sun Yat-Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. RESULTS: We enrolled 97 patients with FH WTs (median follow-up, 71.5 months; range, 22.2-170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P = .010). Five-year event-free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5-year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P = .001) and OS (P = .017). CONCLUSIONS: Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT-diagnosed prechemotherapy may have prognostic relevance. Further research into other potential confounding variables are required to determine whether such patients warrant altered risk-stratified therapy.

Rituximab is highly effective in children and adolescents with Burkitt lymphoma in Risk Groups R2 to R4.

Data regarding the use of rituximab in children and adolescents with Burkitt's lymphoma (BL) is limited. This study retrospectively analyzed the effect of rituximab on children and adolescents with BL in risk group (R) 2 to R4. Patients underwent chemotherapy according to the revised NHL-BFM-95 protocol. Rituximab was administered at the dose of 375 mg/m2 on day 0 of each cycle. A total of 106 patients were included. Stratified by the number of doses of rituximab, there were 49, 16, and 41 patients in group 1 (no rituximab), group 2 (1-3 doses of rituximab) and group 3 (≥4 doses of rituximab), respectively. The 3-year event-free survival (EFS) rates were 83.2% (95% CI = 72.6%-93.8%), 81.2% (95% CI = 52.3%-93.5%) and 96.8% (95% CI = 78.8%-99.6%) in group 1, group 2 and group 3, respectively (p = 0.077). In R2/R3, the relapse rates were 0 in patients treated with rituximab and 11.8% in those treated without rituximab (p = 0.516). In R4, the relapse rates were 18.8%, 21.4% and 3.0% in group 1, group 2 and group 3, respectively (p = 0.048). Rituximab is highly effective in children and adolescents with BL in R2 to R4. The optimal number of doses was 4-6 in patients with BL in R4.

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era.

BACKGROUND: Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL). METHODS: We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels. RESULTS: Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0-1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001). CONCLUSIONS: The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

Effect of chemotherapy alone with adult chemotherapy regimens on prognosis of children and adolescents with Hodgkin's disease.

OBJECTIVE: A current focus on the treatment of children and adolescents with Hodgkin's disease is identification of subgroups of patients for whom radiotherapy can be omitted without compromising clinical outcome. We evaluated the feasibility of using adult chemotherapy regimens alone to treat children and adolescents with Hodgkin's disease. METHODS: Recruitment inclusion criteria were children and adolescents ≤18 years old who were newly diagnosed as Hodgkin's disease. Chemotherapy comprised four cycles of ABVD, six cycles of ABVD or COPP/ABV and six cycles of BEACOPP/ABVD chemotherapy regimens in the low-, intermediate- and high-risk groups, respectively. Radiotherapy was omitted for patients with low-risk, nonbulky disease who had achieved complete remission after chemotherapy and patients who failed to undergo the scheduled radiotherapy due to various reasons beyond the disease. RESULTS: Seventy-five children and adolescents were recruited, including 28, 24 and 23 patients in the low-, intermediate- and high-risk groups, respectively. With a median follow-up of 48 months, 4-year event-free survival and 4-year overall survival were 77.6% ± 5% and 95.3% ± 3%, respectively, in the whole cohort. The 4-year event-free survival in the low-, intermediate- and high-risk groups were 88.2% ± 6%, 78.1% ± 9% and 66.2% ± 11%, respectively (P = 0.062). Sixteen patients (21.3%) relapsed and four died from tumor progression. CONCLUSIONS: Over three-quarters of children and adolescents with Hodgkin's disease achieved long-term event-free survival after receiving chemotherapy alone with adult chemotherapy regimens, and radiotherapy-related toxicity was avoided.

Clinical presentation and CT/MRI findings of alveolar soft part sarcoma: a retrospective single-center analysis of 14 cases.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a relatively rare malignant tumor and early diagnosis and appropriate treatment for ASPS are essential for a good prognosis. PURPOSE: To retrospectively review the clinical presentation and computed tomography (CT) and magnetic resonance imaging (MRI) findings of ASPS so as to improve the accuracy of imaging diagnosis. MATERIAL AND METHODS: Fourteen patients with pathologically proven ASPS were enrolled. Their clinical and imaging findings were retrospectively reviewed. RESULTS: The median age of the patients was 29 years (range, 13-37 years). Most tumors were located in the soft tissues of the trunk and lower limbs. The median maximal diameter of the masses was 91 mm. Thirteen masses presented with ovoid or irregular shapes. Eleven masses had less clear boundaries. Compared with the adjacent muscles, the masses were isodense or hypodense on CT, hypo-, iso-, or hyperintense on T1-weighted images, and heterogeneous hyperintense on T2-weighted images. Intense enhancement was seen after contrast agent administration, with prominent intra- or peri-tumoral feeders on CT or flow voids on MRI. By the end of the last follow-up, 13 patients had distant metastasis and three patients had local recurrence. CONCLUSION: ASPS should be included in the differential diagnosis when a bulky, heterogeneous soft tissue mass in the trunk and the lower limbs with intense enhancement after contrast administration and prominent intra- or peri-tumoral feeders on CT or flow voids on MRI is seen, particularly in young patients.

Survival analysis of children with stage II testicular malignant germ cell tumors treated with surgery or surgery combined with adjuvant chemotherapy.

For children with stage II testicular malignant germ cell tumors (MGCT), the survival is good with surgery and adjuvant chemotherapy. However, there is limited data on surgical results for cases in which there was no imaging or pathologic evidence of residual tumor, but in which serum tumor markers either increased or failed to normalize after an appropriate period of half-life time post-surgery. To determine the use of chemotherapy for children with stage II germ cell tumors, we analyzed the outcomes (relapse rate and overall survival) of patients who were treated at the Sun Yat-sen University Cancer Center between January 1990 and May 2013. Twenty-four pediatric patients with a median age of 20 months (range, 4 months to 17 years) were enrolled in this study. In 20 cases (83.3%), the tumors had yolk sac histology. For definitive treatment, 21 patients underwent surgery alone, and 3 patients received surgery and adjuvant chemotherapy. No relapse was observed in the 3 patients who received adjuvant chemotherapy, whereas relapse occurred in 16 of the 21 patients (76.2%) treated with surgery alone. There were a total of 2 deaths. Treatment was stopped for 1 patient, who died 3 months later due to the tumor. The other patient achieved complete response after salvage treatment, but developed lung and pelvic metastases 7 months later and died of the tumor after stopping treatment. For children treated with surgery alone and surgery combined with adjuvant chemotherapy, the 3-year event-free survival rates were 23.8% and 100%, respectively (P = 0.042), and the 3-year overall survival rates were 90.5% and 100%, respectively (P = 0.588). These results suggest that adjuvant chemotherapy can help to reduce the recurrence rate and increase the survival rate for patients with stage II germ cell tumors.

Brain metastasis in children with stage 4 neuroblastoma after multidisciplinary treatment.

INTRODUCTION: Brain metastasis is common in relapsed neuroblastoma patients, but the characteristics of brain metastasis remain largely unknown. This study aimed to investigate the status of brain metastasis with neuroblastoma in South China. METHODS: In this retrospective case-based study, 106 patients with stage 4 neuroblastoma from the Department of Pediatric Oncology in Sun Yat-sen University Cancer Center between January 2004 and May 2013 were included. The incidence, risk factors, and survival status of these patients were reviewed and analyzed. RESULTS: Of the 106 patients, 11 (10.4%) developed brain metastasis, accounting for 20.0% of 55 patients with relapse or progression. The age at initial diagnosis of the 11 patients ranged from 2 to 10 years (median 4 years), which was younger than that of the patients without brain metastasis (median 5 years, range 1-10 years, P=0.073). The male to female ratio of the 11 patients was 8:3, which was not significantly different from that of the patients without brain metastasis (P=0.86). Patients with brain metastasis had higher lactate dehydrogenase levels than those without brain metastasis, but the differences were not significant (P=0.076). Eight patients died, and 3 patients survived. The median interval from the initial diagnosis to the development of brain metastasis was 18 months (range 6-32 months). The median survival was 4 months (range 1 day to 29 months) after the diagnosis of brain metastasis. The median interval from the manifestation of brain metastasis to death was 3 months (range 1 day to 11 months). CONCLUSIONS: High-risk factors for brain metastasis in cases of neuroblastoma include bone marrow involvement and a younger age at initial diagnosis. Nevertheless, multiple treatment modalities can improve disease-free survival.

Treatment outcome of Chinese children with anaplastic large cell lymphoma by using a modified B-NHL-BFM-90 protocol.

Pediatric anaplastic large cell lymphoma (ALCL) has rarely been reported in Chinese pediatric patients. This study evaluated the clinical characteristics and treatment outcome of Chinese pediatric patients with ALCL. Between October 2002 and October 2012, 39 untreated pediatric patients with ALCL were enrolled at a single institution. The patients were stratified into three groups (R1, R2, and R3) based on the stage of the disease, clinical risk factors, and chemotherapeutic response, and received different intensive chemotherapy regimens based on a modified B-NHL-BFM-90 protocol. Of the 39 patients, 22 were boys, and 17 were girls, with a median age at diagnosis of 10 years (range 2-16 years), 91.2% were anaplastic lymphoma kinase (ALK)-positive. The patient groups R1, R2, and R3 accounted for 12.8%, 30.4%, and 56.4% of the total, respectively. 87.2% of patients were stage III/IV. At a median follow-up period of 52 months (range 15-136 months), seven patients relapsed and three patients died of their disease. The 5-year event-free survival for all patients was 81.4% ± 6.4%, with 100%, 83.3% ± 10% and 75.3% ± 9.8% for groups R1, R2, and R3, respectively. The overall survival for all patients was 92.2% ± 4.3%. Our study demonstrates that a risk-stratified treatment with a modified B-NHL-BFM-90 protocol is efficacious for Chinese children with ALCL.

The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors.

Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.

Treatment Outcome of Response-Based Radiation Therapy in Children and Adolescents With Central Nervous System Nongerminomatous Germ Cell Tumors: Results of a Prospective Study.

PURPOSE: The optimal dose and range of radiation therapy for central nervous system nongerminomatous germ cell tumors (NGGCTs) have not been uniformly established. Therefore, this study aimed to investigate the effect of individualized radiation therapy, based on the response to induction chemotherapy combined with surgery, on the prognosis of patients with NGGCTs. METHODS AND MATERIALS: Based on the imaging examination and tumor markers after induction chemotherapy and pathologic results of second-look surgery, patients with NGGCT received different radiation therapy strategies, including 30.6 Gy whole ventricular irradiation + tumor-bed boost to 54 Gy, 30.6 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, 36 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, and 36 Gy craniospinal irradiation + 54 Gy tumor-bed boost with 45 Gy to metastatic spinal lesions. RESULTS: A total of 51 patients were enrolled between January 2015 and March 2021, with a median age of 10.3 years. The 3-year event-free survival and overall survival (OS) of the entire cohort were 70.2% ± 6.9% and 77.5% ± 6.0%, respectively. The 3-year OS of patients achieving partial response after induction chemotherapy was higher than that of patients with stable disease (P = .03) or progressive disease (P = .002). The 3-year event-free survival and OS of the 18 patients receiving 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed boost were 88.9% ± 7.4% and 94.4% ± 5.4%, respectively. CONCLUSIONS: The results suggest that an individualized radiation therapy strategy based on response to induction chemotherapy and surgery is a feasible and promising means of achieving reduction in dose and extent of radiation in patients while still providing good response.

PD-L1-expressing natural killer cells predict favorable prognosis and response to PD-1/PD-L1 blockade in neuroblastoma.

T/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.

The dual HDAC and PI3K inhibitor, CUDC­907, inhibits tumor growth and stem­like properties by suppressing PTX3 in neuroblastoma.

Neuroblastoma (NB) is one of the common solid tumors in childhood and poses a threat to the lives of children. Patients with advanced­stage or recurrent NB have a poor prognosis. CUDC­907, as a novel dual­target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol­3­kinase (PI3K), has been proven to play an antitumor role in several types of tumors. However, the exact role of CUDC­907 in NB remains unclear. In the present study, in vivo and in vitro assays were performed to investigate the anti­NB activity of CUDC­907. Pentraxin 3 (PTX3) small interfering RNA (siRNA) and PTX3 overexpression plasmid were transfected into cells to define the underlying mechanisms of CUDC­907. Tumor tissues and clinical information were collected and immunohistochemistry (IHC) was conducted to analyze the association between the expression of HDAC1, HDAC2, HDAC3 and CD44, and the prognosis of patients with NB. The results indicated that CUDC­907 significantly inhibited the proliferation and migration, and induced the apoptosis of NB cells, downregulating the expression level of MYCN, and suppressing the PI3K/AKT and MAPK/ERK pathways. Furthermore, CUDC­907 suppressed the stem­like properties of NB cells by inhibiting PTX3, a ligand and upstream protein of CD44. IHC revealed that the high expression of HDAC1, 2, 3 and CD44 was associated with a poor prognosis of patients with NB. On the whole, these findings indicate that CUDC­907 may be developed into a possible therapeutic approach for patients with NB.