A neurotropic herpes simplex virus that was genetically inactivated to prevent replication in normal cells was injected into the brain tumors of 12 patients with tumors that had progressed during ...previous treatment. Eleven patients had some radiographic or clinical responses, with inflammation detected in some PET scans. The median survival was 12.2 months, and 4 of 11 patients were still alive 18 months after treatment.
The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within ...clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long‐term safety data are limited, and serious toxicities unique to ...pediatrics may emerge. In a retrospective analysis of patients less than 18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n = 7), we observed slipped capital femoral epiphyses in three of seven patients along with increased linear growth velocity. Clinicians should closely monitor bone health and have a low index of suspicion for serious orthopedic complications including slipped capital femoral epiphyses and inform patients of related risks as part of consent when treating with FGFR TKIs.
The fields of precision medicine and cancer genomics in pediatric oncology are rapidly evolving. Novel diagnostic tools are critical in refining cancer diagnoses, stratifying patient risk, and ...informing treatment decisions. This review is timely and relevant as it discusses advantages and drawbacks of common molecular profiling techniques and highlights novel platforms, which may address select limitations. We discuss recent publications demonstrating utility of large-scale molecular profiling and feasibility and logistics of matching targeted therapies to patients.
We describe the increased accessibility of next-generation sequencing, complementary profiling methods, and strategies to guide treatment decisions. We describe curation and sharing of large genomic datasets and novel mechanisms to obtain matched targeted therapies. Importantly, we discuss relevant publications in distinct disease domains that support indications for evidence-based precision therapy. Lastly, we introduce the incremental analyses that can be obtained via whole-genome and transcriptome sequencing.
Here we highlight high-yield clinical scenarios of precision medicine approaches and identify the ongoing challenges including universally defining clinical actionability, optimizing trial design to account for molecular heterogeneity while acknowledging limitations in patient accrual, expanding access to molecularly targeted therapies, and validating new tools and technology to aid in precision medicine therapeutic approaches.
Background
Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC‐ASCT) and involved ...field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre‐ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival.
Procedure
We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC‐ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24).
Results
The degree of postinduction response prior to ASCT did not affect outcome, with 5‐year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field.
Conclusion
OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma.
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology. The syndrome is characterized by cystic enlargement of the ovaries and a fluid shift from ...the intravascular to the third space due to increased capillary permeability and ovarian neoangiogenesis. Its occurrence is dependent on the administration of human chorionic gonadotrophin (hCG). β-hCG and its analogs, estrogen, estradiol, prolactin, histamine and prostaglandins have all been implicated in OHSS but now it is increasingly better understood that the vasoactivesubstances such as interleukins, tumor necrosis factor-α, endothelin-1, and vascular endothelial growth factor (VEGF) secreted by the ovaries have been implicated in increasing vascular permeability. Enlargement of the ovaries causes abdominal pain, nausea and vomiting. Leakage of fluid from follicles, increased capillary permeability leading to third spacing (due to the release of vasoactive substances), or frank rupture of follicles can all cause ascites. Due to leakage of fluid through the impaired blood vessels both within and outside the ovary there is massive fluid-shift from the intra-vescular bed to the third compartment results in intravascular hypovolemia with concomitant development of edema, ascites, hydrothorax and/or hydropericardium. Low-dose gonadotrophin protocols have been implemented to reduce the risks of fertility treatment in polycystic ovary syndrome patients. Prophylactic albumin administration may interrupt the development of OHSS by increasing the plasma oncotic pressure and binding mediators of ovarian origin. OHSS is significantly lower in an antagonist protocol than in an agonist protocol. Cabergoline inhibits partially the VEGF receptor 2 phosphorylation levels and associated vascular permeability without affecting luteal angiogenesis reduces the 'early' (within the first 9 days after hCG) onset of OHSS. To prevent thrombosis, subcutaneous heparin 5000-7500 U/d is begun on the first day of admission. These patients need a hospital ward where the clinical picture is well understood and the personnel have expertise in its treatment and follow-up. Admission to an intensive care unit is necessary when critical OHSS develops.
Background
Re‐irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation ...(CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF).
Methods
We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT.
Results
Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20–30 Gy in 2‐Gy fractions (n = 6) and 30–36 Gy in 3‐Gy fractions (n = 14). Median age was 5 years (range: 3–14), median interval since initial RT was 8 months (range: 3–20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18 months 95% confidence interval: 17–24. Median OS from start of reRT for HF versus CF was 8.2 and 7.5 months, respectively (p = .20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre‐treatment steroid dose down or off within 2 months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p = .4). No patients developed radionecrosis.
Conclusion
reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.
Concept of a 'therapeutic window' of luteinizing hormone (LH) for successful conception in assisted reproductive technology and ovulation induction has been reviewed in this literature. The separate ...but complementary roles of follicle stimulating hormone and LH in stimulating folliculogenesis and ovulation are well established. Levels under which low LH concentrations may be equally or suboptimally needed for oocyte quality and subsequent embryonic development competence has been reviewed along with the data related to the high levels of LH promoting follicular atresia.
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