Epidemiology and economic burden of Von Hippel-Lindau Disease-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in the United States.

BACKGROUND: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited. Therefore, this study characterized the prevalence, healthcare resource utilization (HRU), and economic burden of von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) and pancreatic neuroendocrine tumors (VHL-pNET) in the United States (US). METHODS: Patients with VHL-CNS-Hb or VHL-pNET were identified from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) and matched 1:5 to control patients without VHL disease or CNS-Hb/pNET. Prevalence rates of VHL-CNS-Hb and VHL-pNET (standardized by age and sex) in 2019 were estimated. HRU and healthcare costs (2020 US dollars) were compared between the VHL-CNS-Hb/VHL-pNET and control cohorts. RESULTS: In 2019, US prevalence rates of VHL-CNS-Hb and VHL-pNET were estimated to be 1.12 cases per 100,000 (3,678 patients) and 0.12 cases per 100,000 (389 patients), respectively. Patients with VHL-CNS-Hb (N = 220) had more inpatient, outpatient, and emergency department visits and $49,645 higher annual healthcare costs than controls (N = 1,100). Patients with VHL-pNET (N = 20) had more inpatient and outpatient visits and $56,580 higher annual healthcare costs than controls (N = 100). Costs associated with surgical removal of CNS-Hb and pNET were particularly high. CONCLUSIONS: In this retrospective, claims-based study, both VHL-CNS-Hb and VHL-pNET were associated with substantial HRU and healthcare costs, particularly tumor reduction surgery-related costs. These findings provide important insight for healthcare payers regarding the expected real-world costs that enrollees with VHL-CNS-Hb and VHL-pNET may incur over the course of their disease.

Methods of tissue preparation after EUS-guided tissue acquisition without rapid on-site assessment: Results of a randomized study.

In the absence of rapid on-site evaluation (ROSE), it is not clear which method of tissue preparation is best to process tissue obtained from EUS guidance. Cytological smearing (CS), cell block (CB), and direct histology (DH) are the available techniques. AIM: To compare the diagnostic yield of three techniques of tissue preparation for EUS-guided tissue acquisition without ROSE. METHODS: Patients who were referred for EUS-FNA of peri-gastrointestinal masses were recruited. Without ROSE, each lesion was biopsied with three needle passes, and the order in which tissue is prepared was randomized to either (i) CS + CB, (ii) CB only, or (iii) DH only. The prepared specimens were reviewed. RESULTS: A total of 243 specimens were taken from 81 patients. Tissue diagnosis was achieved in 78/81 (96.3%) of patients, including 63 neoplasms (PDAC [n = 45], pancreatic neuroendocrine tumors [PNET; n = 4], cholangiocarcinoma [n = 5], metastatic disease [n = 4], lymphoma [n = 1], linitis plastica [n = 2], leiomyoma [n = 2]) and 15 benign pathologies (chronic pancreatitis [n = 8], reactive nodes [n = 5], inflammatory biliary stricture [n = 1], and pancreatic rest [n = 1]). The three non-diagnostic cases were found to be PDAC (n = 2) and PNET (n = 1). Sensitivity and diagnostic accuracy was highest with DH (94 and 95%), which was significantly better than that by CS + CB (43 and 54%; P = 0.0001) and CB-only preparations (32 and 48.6%; P < 0.0001). There was no significant difference between the CS + CB and CB-only arms (P > 0.22). CONCLUSION: Without ROSE, our findings suggest that with just a single pass, DH should be the tissue preparation method of choice given its significantly higher diagnostic accuracy compared with CS and/or CB techniques.

Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

Population pharmacokinetics of trabectedin in adolescent patients with cancer.

PURPOSE: To characterize the trabectedin population pharmacokinetics in children and adolescent patients with cancer and compare it with the trabectedin pharmacokinetics in adults. METHODS: Plasma concentrations from ten adolescent and three children with cancer (age range 4.0-17.0 years) treated with trabectedin at doses ranging from 1.1 to 1.7 mg/m2, administered as a 24-h continuous intravenous infusion every 3 weeks, were available for the analysis. An external model evaluation was performed to verify whether a previously developed adult population pharmacokinetic model was predictive of the pediatric plasma concentrations of trabectedin. The maximum a posteriori estimation of the individual pharmacokinetic parameters for pediatric patients was conducted, after successful completion of the external evaluation step. The relationships between pharmacokinetic parameters and body size were evaluated. RESULTS: External evaluation methods showed no major differences between the adult population and children and adolescent patients of this study. The mean ± standard deviation (SD) of the individual estimated clearance and central volume of distribution in these children/adolescent patients was 36.4 ± 16.1 L/h and 13.2 ± 6.54 L, respectively. These values were similar to the typical values reported for adult patients-37.6 L/h and 13.9 L (for females) and 16.1 L (for males). The median area under the plasma concentration versus time curve (AUC) in children/adolescent patients was 55.1 µg h/L, while in the adult population the median AUC was 61.3 µg h/L, both administered a 1.5 mg/m2 dose regimen with mean (range) BSA for adults = 1.86 (0.90-2.80) vs children/adolescent patients = 1.49 (0.66-2.54). CONCLUSIONS: The adult population pharmacokinetic model adequately described the trabectedin plasma concentrations and its variability in the pediatric population of patients involved in this assessment that mostly comprised adolescents. The trabectedin systemic exposure achieved in this population was comparable (within 12%) to the exposure obtained in adult population when the same dose, expressed in mg/m2, was administered.

The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial.

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.

Craniospinal irradiation with concomitant and adjuvant temozolomide--a feasibility assessment of toxicity in patients with glioblastoma with a PNET component.

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35-40 Gy in 20-24 daily fractions with a focal boost to the tumour of 14-23.4 Gy in 8-13 daily fractions. Concurrent TMZ was administered at 75 mg/m(2) for seven of the cohort, with the other patient receiving 50 mg/m(2). The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

Assessment of muscarinic and nicotinic acetylcholine receptor expression in primitive neuroectodermal tumor/ewing family of tumor and desmoplastic small round cell tumor: an immunohistochemical and Western blot study of tissue microarray and cell lines.

The primitive neuroectodermal tumor (PNET)/Ewing family of tumors (EFT) and desmoplastic small round cell tumor (DSRCT) portend a grave prognosis. Ongoing research in similar neurocrest-derived neoplasms has implicated both the muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in the pathogenesis of these neoplasms. Acetylcholine has been reported to impart a modulatory effect on chemotaxis and proliferation, an effect ameliorated by anticholinergic drugs. The aim of our study is to characterize the pattern of expression of mAChR and nAChR in PNET/EFT and DSRCT, in hopes of discovering a potential target for therapeutic improvements. We examined 34 cases of PNET/EFT and 2 DSRCT retrospectively by immunohistochemical studies. We found that AChRs are overexpressed in a significant number of PNET/EFT and DSRCT. The Western blot analysis of 3 human Ewing sarcoma cell lines confirms the presence of AChRs. Future studies are planned to confirm these results as well as to investigate their potential therapeutic implications.

Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management.

Primitive neuroectodermal tumors are in the Ewing's sarcoma family of tumors and are composed of small round cells. Because of their rare occurrence, optimal therapy is challenging, particularly if they occur in the head and neck. Diagnosis is based on history, immunostaining with at least 2 neural markers, ultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) translocation as the hallmark for the Ewing's sarcoma family. The prognosis in general is poor because of overt metastasis at the time of diagnosis. Of 27 reported patients with primitive neuroectodermal tumors of the head and neck, 23 were less than 20 years of age. Most patients presented with a tumor in the nasal cavity, paranasal sinuses, or neck. Symptoms developed rapidly (3.6 months, on average), and a lethal outcome occurred in 9 patients. This highly malignant tumor requires an aggressive combination of radical resection, chemotherapy, and radiotherapy. A close follow-up with regular radiographic examination for at least 5 years is mandatory.

Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset.

Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate-specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes.

Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells.

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.

Differentiation in paediatric peripheral primitive neuroectodermal tumours of bone. A critical contribution to its assessment.

Differentiation was studied in 73 paediatric peripheral primitive neurorectodermal tumours (pPNETs) of bone observed during 1974 through 1992. The presence of rosettes, pseudorosettes, and/or a rosette-like arrangement of tumour cells (the morphological neural marker, MNM) occurred in 29% of these cases. NSE and N-CAM were expressed by nearly all tumours; synaptophysin was present in 30% of cases, not significantly associated with the MNM status. Neuroendocrine (NE) markers were present in 25% (chromogranin B, secretogranin II) to 40% (chromogranin A, 7B2 protein) of cases. Focal expression of cytokeratins, S100 protein and/or desmin was also noted in a minority of cases. In univariate statistical analysis, only the presence of MNM conferred a significantly higher (about twofold) risk of death than its absence. This study demonstrates the occurrence of at least one immunocytochemical N and/or NE differentiation marker in all pPNETs of bone and a focal expression of cytokeratins, S100 protein and/or desmin in a minority of cases. Synaptophysin and MNM were present each in less than 1/3 of the cases, and no association was noted between them. Statistical analyses highlighted the prognostic role of MNM per se and discourage the sole use of immunocytochemistry in the assessment of neuroectodermal differentiation for prognostic purposes in paediatric pPNETs of bone.

Immunocytochemical study of 12E7 in small round-cell tumours of childhood: an assessment of its sensitivity and specificity.

12E7 is a monoclonal antibody to the MIC2 gene product and can be applied to formalin-fixed, paraffin-embedded tissue. The diagnostic utility of 12E7 as a marker of Ewing's sarcoma and peripheral neuroectodermal tumour was assessed. Immunocytochemical studies were performed on 120 small round-cell tumours from children and adolescents. Immunoreactivity for 12E7 was seen in 13 of 15 Ewing's sarcomas. 14 of 15 peripheral neuroectodermal tumours, four of 14 embryonal rhabdomyosarcoma, seven of 11 T-lymphoblastic lymphomas and one T-cell acute lymphoblastic leukaemia. Immunoreactivity was located on the cell-membrane of Ewing's sarcomas, peripheral neuroectodermal tumours and lymphoid tumours while rhabdomyosarcomas showed weak, cytoplasmic staining in differentiated rhabdomyoblasts. Studies on alveolar rhabdomyosarcomas (n = 10), acute myeloid leukaemias (3), B-lymphoblastic lymphomas (8), blastema-rich nephroblastomas (9), neuroblastomas (20) and retinoblastomas (10) as well as single examples of B-cell acute lymphoblastic leukaemia, Ki-1 anaplastic lymphoma of indeterminate phenotype and intra-abdominal desmoplastic tumour with divergent differentiation were negative. 12E7 is a sensitive marker for the Ewing's sarcoma/peripheral neuroectodermal group of tumours and is useful in distinguishing them from neuroblastoma and blastema-rich nephroblastoma. However, immunopositivity for 12E7 should be interpreted in conjunction with the results of neural and lymphoid markers.