Summary Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the ...liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene ( LIPA ) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM−1G>A ), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM−1G>A homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy.
Pompe disease is a lysosomal storage disease due to deficient acid α-glucosidase (GAA) activity. Infants with the classic infantile-onset subtype present with severe hypotonia and cardiomegaly, and ...most expire in the first year of life, whereas the severity of the muscle-based manifestations in patients with the late infantile/juvenile and adult-onset subtypes depends on the level of GAA residual enzymatic activity. The clinical features of later-onset Pompe disease are still emerging, and even the natural history and progression of muscle weakness and respiratory failure, hallmarks of the later-onset subtypes, are not well documented. For example, we report here three later-onset patients who had chronic diarrhea, postprandial bloating and abdominal pain, previously unrecognized manifestations of later-onset Pompe disease. Two patients had intestinal incontinence and one reported synchronous vomiting and diarrhea on a daily basis. These symptoms significantly interfered with their quality of life, often limiting their ability to leave home. All gastrointestinal symptoms resolved within the first six months of enzyme replacement therapy (ERT) with recombinant human alglucosidase alpha (rhGAA). All three patients gained weight and remain symptom free, two for over four years. Thus, gastrointestinal symptoms occur in later-onset patients with Pompe disease and are resolved with ERT.
Purpose: Patients with metastatic or recurrent Ewing’s sarcoma family of tumors and alveolar rhabdomyosarcoma have <25% 5-year survival
in most studies. This study administered a novel immunotherapy ...regimen aimed at consolidating remission in these patients.
Experimental Design: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing’s sarcoma family of tumors or alveolar rhabdomyosarcoma
underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard
multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts
received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific
translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2
(rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2.
Results: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation
breakpoint peptides occurred in 39%, and only 25% of HLA-A2 + patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall
survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients
initiating immunotherapy.
Conclusions: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into
a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable
survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally
limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic
cells.
BackgroundPatients with high-risk pediatric solid tumors experience poor outcomes and require improved treatments. NK cell immunotherapies hold promise for potential anti-tumor activity; however, ...clinical translation faces challenges of NK expansion, persistence, and inhibition. Interleukin-15 (IL-15) fosters NK cell development, homeostasis, lytic capacity, and survival. Preclinical data demonstrate that NK cells expanded ex vivo by IL15 and 4–1BBL are largely resistant to inhibitory signals and mediate potent tumor killing in vitro, suggesting efficacy against solid tumors.Methods and Study Design In this single-institution Phase I trial (NCT01875601), we enrolled children and young adults with refractory solid tumors, including brain tumors, to evaluate the feasibility of manufacturing and safety of infusing activated NK cells. Using a 3+3 design for dose escalation, NK cells were administered after lymphodepleting cyclophosphamide. Artificial antigen-presenting cells (aAPC) expressing human 4–1BBL and human IL-15Rα were used to stimulate and expand autologous NK cells ex vivo. Three dose levels (DL) (1x106 cells/kg, 1x107 cells/kg, 1x108 cells/kg) of NK cells were explored for Cohort A. Cohort B evaluated administration of 1x107 NK cells/kg followed by a ten-day rhIL-15 infusion with 4 DLs planned (0.25 mcg/kg/day, 0.5 mcg/kg/day, 1 mcg/kg/day, 2 mcg/kg/day).ResultsSixteen patients enrolled, with median age of 16.1 years. The average ex vivo NK cell expansion was 19.4 fold, readily supporting DLs up to 1x107 cells/kg. Expansion was insufficient to achieve the top DL of 1x108 cells/kg. Following administration, partial responses per RECIST criteria were observed in 3 patients with refractory osteosarcoma, Ewing sarcoma, and medulloblastoma, two in DL1 of Cohort A, and one in DL1 of Cohort B. The remaining 13 patients had stable disease.The most common adverse events were hematologic toxicities, likely chemotherapy-related. Symptoms of cytokine release syndrome occurred in 2/12 patients in Cohort A, one being a dose limiting toxicity. Four patients received rhIL-15 at the 0.25 mcg/kg/day DL with one dose limiting toxicity related to pericardial tamponade and capillary leak syndrome, prior to pause of enrollment for supply issues.ConclusionsHarvesting, expanding, and administering 1x107 cells/kg of aAPC-activated autologous NK cells is feasible and safely tolerated. The addition of rhIL-15 shows potential promise although further exploration is necessary to identify if higher dose levels would be beneficial. Anti-tumor activity was observed following administration of aAPC-activated autologous NK cells with three partial responses in heavily pretreated patients. Correlative studies are underway to better understand the immunological impact of NK cells and explore differences between responders and non-responders.Trial RegistrationClinicalTrials.gov Identifier: NCT01875601Ethics ApprovalThe study was approved by the National Institutes of Health Intramural Institutional Review Board, approval number was NCT01875601. Written informed consent was obtained from the patient or guardian before taking part in the trial.ConsentWritten informed consent was obtained from the patient or guardian for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, ...advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2-77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0-36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%-35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials.
This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.
Because of increasing uptake of cancer genetic testing and the improving survival of young patients with cancer, health care practitioners including oncologists will increasingly be asked about ...options for assisted reproduction by members of families affected by hereditary cancer syndromes. Among these reproductive options, preimplantation genetic diagnosis (PGD) offers the opportunity to select embryos without familial cancer-predisposing mutations.
A review of the published literature supplemented by a survey of PGD centers in the United States.
Prenatal diagnosis and/or embryo selection after genetic testing has already been performed in the context of more than a dozen familial cancer syndromes, including the common syndromes of genetic predisposition to colon and breast cancer.
While constituting new reproductive options for families affected by cancer, the medical indications and ethical acceptance of assisted reproductive technologies for adult-onset cancer predisposition syndromes remain to be defined. Continued discussion of the role of PGD in the reproductive setting is needed to inform the responsible use of these technologies to decrease the burden of heritable cancers.
Purpose: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children
and young adults with sarcomas treated with dose-intensive ...combination chemotherapy.
Experimental Design: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c.,
daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two
cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, ≤500/mcL) during cycles
1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell
mobilization were studied on cycle 1. Growth factor–related toxicity, transfusions, and episodes of fever and neutropenia
and infections were collected for cycles 1 to 4.
Results: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range)
duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim ( P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim ( P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim
concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults.
Conclusion: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration
of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment
with VDC and IE. (Clin Cancer Res 2009;15(23):7361–7)
Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol.
This study examined safety, ...pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity.
Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma).
Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.
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