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Pediatric surgical trials are rare and the impact of such trials on the institutions in which they are conducted is unknown. The purpose of this study was to analyze the clinical and financial impact of The Re-MATCH trial, a Phase I clinical trial requiring the biopsy or resection of recurrent medulloblastoma or PNET for enrollment. Inpatient financial and clinical volume information was collected during the 3 years of trial enrollment and the years preceding and following it. The primary endpoints were the difference in direct contribution margin (DCM), or net gain, of study and non-study patients and the difference in surgical volume during the study and non-study periods. The trial enrolled 18 patients; 15 had surgery at the sponsor institution and three had surgery at their home institution, then transferred tumor material to the sponsor institution. There were no differences between the two groups for potentially confounding variables such as neurosurgical procedure work relative value units (P = 0.13) or insurance provider (P = 0.26). There was no difference between the inpatient DCM per case for the institution for non-study patients (mean ± SD, $9039 ± $28,549) and study patients ($14,332 ± $20,231) (P = 0.4819). During the non-study period, there were a mean of 2.78 ± 1.65 pediatric brain tumor resections per month compared to 3.34 ± 1.66 cases per month during the study period, a 17% increase. When the 15 study patients were excluded, there were 2.97 ± 1.64 cases per month, a 7% increase. However, this increase in total case volume including study and non-study patients was not significant (P = 0.121). Phase I investigator-initiated surgically-based clinical trials may increase institutional surgical volume without imposing a financial burden. Finances are unlikely to be a barrier for researchers negotiating for resources to conduct such trials.

Background We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. Methods Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. Results Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). Conclusions Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Background The pathological characteristics, treatment strategies and prognosis of ovarian primary primitive neuroectodermal tumor (PNET) were unclear due to the rarity of PNET. All cases treated at Peking Union Medical College Hospital (PUMCH) between 1975 and 2016 and published in the English literature between 1980 to 2017 were reviewed. Results Finally four cases from PUMCH and 15 cases in the literature were included. The median age was 25 years (range 13–79), and the median diameter of the tumors was 13.4 cm (range 5.0–30.0). The most common initial symptoms were abdominal pain, bloating and a pelvic mass. Diagnosis primarily depended on immunohistochemical and fluorescence in situ hybridization data. Treatment consisted of surgery, various chemotherapy regimens and/or radiotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 15 and 52%, respectively. For patients with OS and PFS > 12 months, the median ages were 21 years (range 13–35) and 17 years (range 13–35), respectively, while for patients with OS < 12 months and PFS < 12 months, the median ages were 48 years (range 14–79) and 25 years (range 18–79), respectively. Conclusions No standard therapy for ovarian primary PNET exists, and an individualized strategy is recommended. Young patients seem to have better prognoses.

Background Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive. Methods Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared. Results Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p  = 0.029), lymph node metastasis (36% vs. 24%; p  = 0.011), and distant metastasis (13% vs. 4%; p  < 0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p  < 0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p  = 0.043). Calcifications remained an independent predictor of RFS on multivariable analysis ( p  = 0.043) controlling for nodal ( p  < 0.001) and distant metastasis ( p  = 0.001). Conclusions Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.

Background Ocular medulloepithelioma (diktyoma) is a rare and potentially malignant paediatric tumour of the non-pigmented ciliary epithelium. Adjuvant chemotherapy can be given in advanced cases, but the indications and regimens remain to be defined. The aim was to identify whether adjuvant chemotherapy offers treatment benefit in advanced ocular medulloepithelioma. Methods This was a retrospective case series of subjects referred to a single specialist ocular oncology centre for advanced ocular medulloepithelioma subsequently treated with enucleation, including those needing adjuvant systemic vincristine, etoposide and carboplatin. A case-note review was performed for included subjects meeting referral criteria. The outcomes were histopathology characteristics, recurrence, metastases and survival. Results Between March 2010 and June 2017, four male patients (mean age 31 months) underwent enucleation for ocular medulloepithelioma. Adjuvant chemotherapy was commenced in 3 patients (75%) due to malignant histopathological features. With a mean follow-up time of 81.5 months (median 71 months, range 49–135 months) none of the patients have had recurrence, metastases or death from the tumour. Conclusions This series is unique in reporting the management of advanced malignant ocular medulloepithelioma with adjuvant systemic vincristine, etoposide and carboplatin for advanced tumours with malignant features. This regimen appears to be safe and may be effective in preventing metastatic spread.

Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors ( n  = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80–100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior.

Since 2013, North American Neuroendocrine Tumor Society (NANETS) consensus-guidelines have endorsed consideration of surgical intervention for pancreatic- neuroendocrine tumors (PNET) with liver metastases. Patients with non-functional PNET with liver only metastases from 2010 to 2019 were identified from the National Cancer Database. 34.7% underwent surgical intervention (13% PNET resection, 2.1% surgical management of liver metastases (SMLM), 19.5% PNET resection ​+ ​SMLM). In multivariable analysis, government insurance, year of diagnosis>2013, increasing primary tumor size were associated with lower rate of surgical intervention. Receiving treatment at an academic center (OR 3.59, 95%CI 1.81–7.11; P ​< ​0.001) or integrated cancer network (OR 3.21, 95%CI 1.57–6.54; P ​= ​0.001) was associated with a higher rate of surgical intervention. The overall rate of surgical intervention decreased from 45.7% in 2010 to 23.0% in 2019. Despite guideline recommendations and the suggested survival benefits, only one-third of patients underwent surgical intervention, potentially influenced by the rising utilization of systemic therapy in the past decade. •One-third of patients with PNET and liver metastases received surgical intervention.•Overall rate of surgical intervention for patients with PNET +liver metastases decreased from 45.7% in 2010 to 23.0% in 2019.•Treatment in community centers compared to academic centers was associated with lower chance of surgical intervention.•5-year OS non-surgical patients 40.4%, vs. PNET resection 74.4% vs. both SMLM and PNET resection 75.9%.

IntroductionPancreatic neuroendocrine tumours (pNETs) have an excellent long-term survival after resection, but are associated with a high recurrence rate. Identification of prognostic factors affecting recurrences would enable identifying subgroup of patients at higher risk of recurrences, who may benefit from more aggressive treatment.MethodsA retrospective analysis of prospectively maintained database of patients undergoing pancreatectomy with curative intent for grade I and II pNETs between July 2007 and June 2021 was performed. Perioperative and long-term outcomes were analysed.ResultsA total of 68 resected patients of pNETs were included in this analysis. Fifty-two patients (76.47%) underwent pancreaticoduodenectomy, 10 (14.7%) patients had distal pancreatectomy, and 2 (2.9%) patients underwent median pancreatectomy, while enucleation was performed in 4 patients (5.8%). The overall major morbidity (Clavien-Dindo III/IV) and mortality rates were 33.82% and 2.94%, respectively. At a median follow-up period of 48 months, 22 (32.35%) patients had disease recurrence. The 5-year overall survival and 5-year recurrence-free survival (RFS) rates were 90.2% and 60.8%, respectively. While OS was unaffected by different prognostic factors, multivariate analysis showed that lymph node involvement, Ki-67 index ≥5%, and presence of perineural invasion (PNI) were independently associated with recurrence.ConclusionsWhile surgical resection gives excellent overall survival in grade I/II pNETs, lymph node positivity, higher Ki-67 index, and PNI are associated with a high risk for recurrence. Patients with these characteristics should be stratified as high risk and evaluated for more intensive follow-up and aggressive treatment strategies in future prospective studies.

Embryonal tumor with multilayered rosettes (ETMR), C19MC-altered was introduced to the World Health Organization classification of central nervous system tumors in 2016. It is characterized by amplification or fusion of the chromosome 19 microRNA cluster (C19MC) locus at 19q13.42. Medulloepithelioma also an ETMR but lacks C19MC alteration. We report a rare case of spinal medulloepithelioma in a 2-year-old boy and review the literature.

Over 90% of Ewing sarcoma/primitive neuroectodermal tumors (PNETs) feature an 11;22 translocation leading to an EWSR1–FLI1 fusion. Less commonly, a member of the ETS-transcription factor family other than FLI1 is fused with EWSR1 . In this study, cytogenetic analysis of an extraskeletal Ewing sarcoma/PNET revealed a novel chromosomal translocation t(4;22)(q31;q12) as the sole anomaly. Following confirmation of an EWSR1 rearrangement by the use of EWSR1 breakpoint flanking probes, a fluorescence in situ hybridization positional cloning strategy was used to further narrow the 4q31 breakpoint. These analyses identified the breakpoint within RP11-481K16, a bacterial artificial chromosome (BAC) clone containing two gene candidates FREM and SMARCA5 . Subsequent RACE, RT–PCR, and sequencing studies were conducted to further characterize the fusion transcript. An in-frame fusion of the first 7 exons of EWSR1 to the last 19 exons of SMARCA5 was identified. SMARCA5 encodes for hSNF2H, a chromatin-remodeling protein. Analogous to EWSR1–ETS-expressing NIH3T3 cells, NIH3T3 cells expressing EWSR1–hSNF2H exhibited anchorage-independent growth and formed colonies in soft agar, indicating chimeric protein tumorigenic potential. Conversely, expression of EWSR1–hSNF2H in NIH3T3 cells, unlike EWSR1–ETS fusions, did not induce EAT-2 expression. Mapping analysis demonstrated that deletion of the C-terminus (SLIDE or SANT motives) of hSNF2H impaired, and deletion of the SNF2_N domain fully abrogated NIH3T3 cell transformation by EWSR1–SMARCA5 . It is proposed that EWSR1–hSNF2H may act as an oncogenic chromatin-remodeling factor and that its expression contributes to Ewing sarcoma/primitive neuroectodermal tumorigenesis. To the best of our knowledge, this is the first description of a fusion between EWSR1 and a chromatin-reorganizing gene in Ewing sarcoma/PNET and thus expands the EWSR1 functional partnership beyond transcription factor and zinc-finger gene families.