Alexander Puzik

Background: Epidermoid and dermoid cysts are one of the most common benign pediatric tumors of the skull. Ultrasonography is usually the diagnostic tool of choice for their evaluation and diagnosis. Although benign, local growth with cosmetic issues, bone erosion, and occasional intracranial involvement generally warrant surgical resection. Since epidermoid and dermoid cysts may be seen by a wide range of medical disciplines, standardized recommendations for optimal diagnosis and treatment are necessary. Case presentation: We report the case of a 14-month-old boy, who underwent neurosurgical removal of a glabellar dermoid cyst classified as an extracranial lesion, and in whom an intracranial lesion was identified on follow-up MRI, represents a rare and unusual clinical course. Ten months after surgery, a surveillance MRI revealed an intracranial lesion in the right frontal parasagittal region, while the child had developed no symptoms. Very careful retrospective review of the initial MRI suggested that an extremely small intracranial part of the lesion might have been faintly visible upon knowledge of the further clinical course. The intracranial lesion was subsequently resected and diagnosed as an epidermoid cyst. In our mini-review, we have compiled evidence that intracranial extension is more common than expected and particularly occurs in craniofacial midline lesions but is definitely not restricted to them. Conclusion: Together, this case and literature review highlight the importance of careful preoperative assessment and interdisciplinary discussion to adequately determine the extent of craniofacial dermoid and epidermoid cysts before surgery. This case illustrates that a subtle intracranial lesion may not be recognizable on initial image interpretation despite MRI having been performed. Imaging follow-up is definitely recommended when intraoperative findings raise concern about deeper extension.

Background: Localized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component. Objective: To evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period. Methods: We conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3–8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety. Results: No patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade ≥3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion. Conclusions: Sirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease with diverse phenotypes. We describe the genetics, phenotypes, and treatment of n = 48 DADA2 patients from Germany, Austria, and Switzerland. We report a high incidence of hematological (83%) and immunological features (85%), a comparatively low anti-tumor necrosis factor full-response rate (58%), and a high decision probability (21%) for hematopoietic cell transplantation (HCT). We establish a correlation between genetic variant ADA2 activity and patient ADA2 activity. Remarkably, lower patient ADA2 activity is predictive of neutropenia and shows a trend toward HCT decision, whereas higher patient ADA2 activity is predictive of vasculitis symptoms. Genetic variants with low residual ADA2 activity are significantly more common among patients receiving HCT. Our study corroborates previous observations connecting ADA2 activity and clinical phenotype, which up to now have been mainly based on in vitro data.

Background: Febrile neutropenia (FN) is a common and potentially life-threatening complication in pediatric oncology. Rapid initiation of empiric antibiotics is critical to improving prognosis. This study evaluated the impact of simple changes to a standard operating procedure (SOP) for FN treatment on the time-to-antibiotic (TTA) in pediatric cancer patients, as well as potential clinical effects. Methods: In this retrospective, single-center, cohort study, children with cancer presenting with FN at the emergency room (pedER) or oncology outpatient department (OD) were included over two one-year periods—before and after SOP adaption. The revised SOP defined a target TTA of ≤30 min. The primary endpoint was to compare median TTA and the proportion of FN episodes meeting target TTA. Secondary endpoints comprised adverse events (AEs) (e.g., ICU admission, need for respiratory or circulatory support, sepsis criteria). Results: After SOP adaption, 32.9% of episodes met target TTA, up from 5.9% before. Median TTA was significantly reduced (44 min vs. 93 min). The improvement persisted during the study period. AE rates showed no significant change. Conclusions: Simple procedural adjustments may significantly improve quality indicators of care, e.g., reducing TTA in pediatric FN patients. These adjustments may be transferable to other pediatric oncology settings.

Background: Infantile hemangiomas (IH) are the most common benign vascular tumor in infants. Despite their spontaneous regression, IH can cause aesthetic, functional, and vital organ complications. Hepatic involvement requires particular attention in infants with multiple cutaneous hemangiomas. While magnetic resonance imaging (MRI) is the established diagnostic standard, contrast-enhanced ultrasound (CEUS) emerges as a promising alternative. Objective: To compare the diagnostic accuracy of CEUS and MRI in hepatic IH detection and characterization, and to evaluate potential diagnostic imaging markers. Materials and Methods: A retrospective multicenter analysis was conducted to identify infants diagnosed with hepatic IH who underwent CEUS, MRI, or both between 2016 and 2024. Lesion size and count were compared in patients who underwent both imaging modalities. Data from 24 patients was included in the analysis. Results: Of 24 patients, 15 underwent only CEUS, 3 underwent only MRI, and 6 received both imaging modalities. CEUS findings were comparable to MRI regarding lesion size and number, with CEUS demonstrating capability to detect lesions as small as 4 mm. Treatment decisions were predominantly based on CEUS findings. Conclusion: CEUS showed diagnostic accuracy comparable to MRI in hepatic hemangioma evaluation, without compromising disease severity assessment. CEUS advantages include real-time imaging and avoidance of sedation or anesthesia in young patients. These findings support CEUS as a viable, less invasive, and resource-efficient alternative to MRI for hepatic IH evaluation, enabling optimization of diagnostic and treatment protocols. SUMMARY STATEMENT: CEUS provides accurate diagnosis and monitoring of hepatic IH, demonstrating comparable or potentially superior detection capabilities to MRI, while offering practical advantages for infants. KEY RESULT: Diagnostic Accuracy: CEUS accurately detects lesion number and size. Vascular Detailing: CEUS may offer superior real-time visualization of vascular patterns. Clinical Benefits: CEUS is non-invasive, cost-effective, and suitable for repeated assessments in non-sedated patients, making it an ideal diagnostic modality for the assessment of suspected hepatic IH.

Objective Abdominal lymphatic malformations (ALM) are benign macro-, microcystic or mixed lesions that originate from defects in vascular development. Depending on size and location, clinical symptoms vary from asymptomatic to potentially life-threatening. Standardized diagnostic and therapeutic guidelines for ALM do not exist. Current literature focuses on imaging characteristics rather than symptoms for indication of invasive treatment strategies, including sclerotherapy and surgery. Sirolimus is evolving as a medical treatment option, while a watchful waiting approach for asymptomatic and low-risk ALM patients is not yet established as a conservative strategy. Methods We retrospectively characterized a multicenter cohort of 21 ALM treated 1996 - 2024. Items included clinical symptoms, imaging findings, and management strategies, including resection, sclerotherapy, sirolimus or a watchful waiting approach. Results ALM patients were categorized based on symptoms and lesion characteristics with potentially associated complications depending on lesion size and anatomical location: 9/21 (43%) patients were observed in the asymptomatic and low-risk group with regular clinical and radiological follow-up intervals. Acutely symptomatic (7/21; 33%), symptomatic or high-risk patients (5/21; 24%) underwent resection (10/21; 48%), sclerotherapy (1/21, 5%), or were treated with sirolimus (1/21, 5%). All patients had favorable long-term outcomes. Conclusions We developed a multidisciplinary diagnostic and therapeutic algorithm for ALM based on clinical presentation and lesion characteristics to ensure a standardized, yet patient-centered symptom- and risk-based approach for the most beneficial treatment and outcome. Importantly, our study is the first to demonstrate that watchful waiting is an adequate strategy for asymptomatic ALM patients with a low anticipated risk for complications. Validation of our proposed algorithm is warranted in a prospective study.

This study lays the groundwork for future lentivirus-mediated gene therapy in patients with Diamond Blackfan anemia (DBA) caused by mutations in ribosomal protein S19 ( RPS19 ), showing evidence of a new safe and effective therapy. The data show that, unlike patients with Fanconi anemia (FA), the hematopoietic stem cell (HSC) reservoir of patients with DBA was not significantly reduced, suggesting that collection of these cells should not constitute a remarkable restriction for DBA gene therapy. Subsequently, 2 clinically applicable lentiviral vectors were developed. In the former lentiviral vector, PGK.CoRPS19 LV , a codon-optimized version of RPS19 was driven by the phosphoglycerate kinase promoter ( PGK ) already used in different gene therapy trials, including FA gene therapy. In the latter one, EF1 α .CoRPS19 LV , RPS19 expression was driven by the elongation factor alpha short promoter, EF1 α (s) . Preclinical experiments showed that transduction of DBA patient CD34 ⁺ cells with the PGK.CoRPS19 LV restored erythroid differentiation, and demonstrated the long-term repopulating properties of corrected DBA CD34 ⁺ cells, providing evidence of improved erythroid maturation. Concomitantly, long-term restoration of ribosomal biogenesis was verified using a potentially novel method applicable to patients’ blood cells, based on ribosomal RNA methylation analyses. Finally, in vivo safety studies and proviral insertion site analyses showed that lentivirus-mediated gene therapy was nontoxic.

Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.

Background: Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research. Case presentation: We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH. Conclusion: Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.

Background: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. Methods: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15–39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. Discussion: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. Trial registration: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).