Effects of apalutamide dose reduction on skin-related adverse events in patients with advanced prostate cancer: A multicenter retrospective study.

BACKGROUND: We aimed to evaluate the effects of apalutamide dose reduction on skin-related adverse events (AEs) and castration-resistant prostate cancer (CRPC)-free survival in patients with advanced prostate cancer (PC). METHODS: We retrospectively evaluated 35 patients with nonmetastatic CRPC and 72 patients with treatment-naïve metastatic castration-sensitive PC (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose reduction on skin-related AEs. The secondary outcomes were the effect of apalutamide dose reduction on skin-related AEs in patients with small body size, postskin AE apalutamide discontinuation rate, and CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. RESULTS: Of the 107 patients, 65 (60.7%) and 42 (39.3%) were treated with full and reduced doses of apalutamide, respectively. The skin-related AE rate was not significantly different between the groups (55% vs. 43%, p = 0.761). In the group receiving reduced apalutamide dose, the incidence of skin-related AEs was significantly lower in patients with small body sizes (body weight <67 kg and body mass index <24 kg/m2 ) than in those with other body sizes. The postskin AE apalutamide discontinuation rate was significantly differed between patients receiving the full (50%) and reduced (16.7%) doses. In the 72 patients with mCSPC, CRPC-free survival was not significantly different between the full and reduced dose groups. CONCLUSION: Apalutamide dose reduction was not significantly associated with the incidence of skin-related AEs. However, dose reduction in patients with small body sizes may alleviate skin-related AEs without sacrificing oncological outcomes.

Trends in the use of local intervention for metastatic hormone-naïve prostate cancer: A multicenter retrospective study.

OBJECTIVE: To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone-naïve prostate cancer (mHNPC) in real-world practice. METHODS: This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC-free survival in the intervention group. RESULTS: The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis-targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate-specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC-free survival. CONCLUSIONS: The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.

Trends in the age of hospitalized patients with urological cancers: A 17-year experience.

OBJECTIVES: To investigate the impact of global aging on the trends in the age of hospitalized patients with a urological cancer diagnosis. METHODS: We retrospectively evaluated a cumulative total of 10 652 cases of referred patients (n = 6637) with a urological disease who were hospitalized in our institution between January 2005 and December 2021. We compared age and the proportion of patients aged ≥80 years among patients who were hospitalized in the urological ward between the period of 2005-2013 and that of 2014-2021. RESULTS: We identified 8168 hospitalized patients with urological cancer. The median age was significantly increased in patients with urological cancer between the periods of 2005-2013 and 2014-2021. The proportion of hospitalized patients with urological cancer aged ≥80 years was significantly increased between the periods of 2005-2013 (9.3%) and 2014-2021 (13.8%). The median ages of the patients with urothelial cancer (UC) and renal cell carcinoma (RCC), but not the median age of those with prostate cancer (PC), were significantly increased between the study periods. The proportion of hospitalized patients with UC, but not the proportions of those with PC and RCC, aged ≥80 years was significantly increased between the study periods. CONCLUSIONS: The age of patients with urological cancer who were hospitalized in the urological ward and the proportion of patients with UC aged ≥80 years significantly increased over the entire study period.

A case of primary CNS embryonal rhabdomyosarcoma with PAX3-NCOA2 fusion and systematic meta-review.

PURPOSE: Primary central nervous system (CNS) rhabdomyosarcoma is a rare mesenchymal tumor predominantly seen in children and associated with a poor outcome. We report a case of primary CNS rhabdomyosarcoma with PAX3-NCOA2 fusion and present a systematic meta-review of primary CNS rhabdomyosarcoma to characterize this rare tumor. METHODS: We present the case of a 6-year-old boy with primary CNS rhabdomyosarcoma in the posterior fossa. In a systematic meta-review, we compare the demographic data of primary CNS rhabdomyosarcoma with data of rhabdomyosarcoma at all sites from the SEER database and analyze clinical factors associated with survival outcome. RESULTS: Our patient underwent gross total resection and received vincristine, actinomycin-D, cyclophosphamide with early introduction of concurrent focal radiation and remained alive with no evidence of disease for 2 years after the end of therapy. Histopathological review revealed embryonal-type rhabdomyosarcoma, and whole-transcriptome analysis revealed PAX3 (EX6)-NCOA2 (EX12) fusion. In all, 77 cases of primary CNS rhabdomyosarcoma were identified through the meta-review. The demographic data of primary CNS rhabdomyosarcoma were similar to data of rhabdomyosarcoma at all sites. Overall and event-free survival outcomes were available for 64 and 56 patients, respectively, with a 3-year OS of 29.0% and a 3-year EFS of 25.7%. The group that received trimodal treatment exhibited better survival outcomes, with a 3-year OS of 57.4% and a 3-year EFS of 46.3%. CONCLUSIONS: Primary CNS rhabdomyosarcoma shares common histological, molecular, and demographic features with non-CNS rhabdomyosarcoma. A trimodal treatment approach with early introduction of radiation therapy may result in favorable survival outcomes.

Shortened ex vivo manufacturing time of EGFRvIII-specific chimeric antigen receptor (CAR) T cells reduces immune exhaustion and enhances antiglioma therapeutic function.

BACKGROUND: Non-viral manufacturing of CAR T cells via the Sleeping Beauty transposon is cost effective and reduces the risk of insertional mutagenesis from viral transduction. However, the current gold standard methodology requires ex vivo numerical expansion of these cells on artificial antigen-presenting cells (AaPCs) for 4 weeks to generate CAR T cells of presumed sufficient quantity and function for clinical applications. METHOD: We engineered EGFRvIII-specific CAR T cells and monitored phenotypic changes throughout their ex vivo manufacturing. To reduce the culture time required to generate the CAR T-cell population, we selected for T cells in peripheral blood mononuclear cells prior to CAR modification (to eliminate the competing NK cell population). RESULTS: While we found increased expression of exhaustion markers (such as PD-1, PD-L1, TIM-3, and LAG-3) after 2 weeks in culture, whose levels continued to rise over time, we were able to generate a CAR+ T-cell population with comparable CAR expression and cell numbers in 2 weeks, thereby reducing manufacturing time by 50%, with lower expression of immune exhaustion markers. The CAR T cells manufactured at 2 weeks showed superior therapeutic efficacy in mice bearing established orthotopic EGFRvIII+ U87 gliomas. CONCLUSION: These findings demonstrate a novel, rapid method to generate CAR T cells by non-viral modification that results in CAR T cells superior in phenotype and function and further emphasizes that careful monitoring of CAR T-cell phenotype prior to infusion is critical for generating an optimal CAR T-cell product with full antitumor potential.

Upfront Therapies and Downstream Effects: Navigating Late Effects in Childhood Cancer Survivors in the Current Era.

PURPOSE OF REVIEW: As survival rates of those diagnosed with childhood cancer improve over time, the number of long-term survivors continues to grow. Advances have not only been made in the upfront treatment of childhood cancer, but also in the identification and treatment of late complications that may arise as a result of the chemotherapy, radiotherapy, or surgical interventions required to provide a cure. RECENT FINDINGS: As new therapies emerge that are often more targeted to cancerous cells while sparing healthy tissues, the hope is that cure can be achieved without the same long-term side effects for survivors. However, much is unknown regarding how these novel interventions will impact patients in the years to come. It is critical that we continue to follow patients treated with new modalities in order to identify and treat the long-term complications that may arise in future childhood cancer survivors.

Dabrafenib for Pilocytic Astrocytoma With BRAF V599ins.

This report highlights the first pediatric case of pilocytic astrocytoma with BRAF V599ins mutation, successfully treated with dabrafenib.

Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.

BACKGROUND: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies. METHODS: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated. RESULTS: Thirty-three patients (18 male; median age, 5 years) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n = 10, 30%). Most tumors were in the cerebral hemispheres (n = 22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3% ±â€…8.3%; the 5-year overall survival (OS) rate was 96.4% ±â€…4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6% ±â€…15.2% (P < .01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways. CONCLUSIONS: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Oncological and functional outcomes of female reproductive organ-sparing radical cystectomy and ileal neobladder construction.

OBJECTIVES: To examine the oncological and urinary functional outcomes of reproductive organ-sparing radical cystectomy (ROS-RC) and U-shaped ileal neobladder construction in females compared with male patients. METHODS: We retrospectively examined 357 patients (281 male and 76 female) with muscle-invasive bladder cancer who were treated with RC plus U-shaped ileal neobladder construction between May 1996 and July 2021. All female patients were treated with ROS-RC. We compared disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and urinary functional outcomes between male and female patients. We evaluated the effect of gender on DFS, CSS, and OS. Furthermore, urinary functional outcomes were evaluated in 140 males and 48 females using a pressure-flow study at 3, 6, 9, and 12 months postoperatively. RESULTS: Female patients were considerably older than male patients at the time of radical cystectomy. No significant difference was noted in the tumor stage preoperatively. The multivariable Cox regression analysis with an inverse probability treatment weighted model revealed that the female gender was not significantly related to DFS, CSS, and OS. Moreover, urinary functions at 12 months were not markedly different between males and females, except for the capacity of the neobladder, detrusor pressure, and maximum urethral closure pressure. CONCLUSIONS: This study demonstrates that female patients with ROS-RC and U-shaped ileal neobladder construction did not significantly correlate with worse oncological outcomes. The combination of ROS-RC and U-shaped ileal neobladder construction might attain adequate urinary function without sacrificing oncologic outcomes.

Congenital corneal staphyloma as a complication of Kabuki syndrome.

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations.

Psychiatric symptoms in children with low-grade glioma and craniopharyngioma: A systematic review.

The presentation of psychiatric symptoms in pediatric low-grade brain tumors is challenging because this can delay proper diagnosis and treatment. We performed a systematic review of psychiatric presenting symptoms of low-grade brain tumors in pediatric patients. We searched the PubMed and Web of Science databases of studies published in English from 1977 until 2019 reporting patients aged ≤21 years at the time of tumor diagnosis who exhibited psychiatric/behavioral symptoms before diagnosis of low-grade glioma (LGG), pilocytic astrocytoma (PA), or craniopharyngioma (CP). Our systematic search strategy coupled each tumor type with patient age and presenting symptoms by using different variations of the search terms "childhood" and "psychiatric symptoms" or "behavioral symptoms." We identified six unique articles that met our inclusion criteria in the LGG search, 27 in the PA search, and 32 in the CP search. Six patients were included in the LGG articles (age range, 3-16 years), 75 in the PA articles (age range, 0.5-21 years), and 87 in the CP articles (age range, 0.67-21 years). The most common presenting symptoms included eating disorders (n = 64) and behavioral changes (n = 49). Our findings demonstrate the need to establish clear criteria for neuroimaging indications for pediatric patients exhibiting eating disorders.

Humoral response after SARS-CoV-2 mRNA vaccination in patients with prostate cancer using steroids.

OBJECTIVES: The effect of concomitant steroid use on the antibody response to a SARS-CoV-2 vaccine in patients with prostate cancer (PC) remains unknown. We aimed to evaluate the rates of antispike immunoglobulin G (IgG) antibody response to the BNT162b2 mRNA vaccine in patients with PC using steroids. METHODS: This cross-sectional study conducted from June 21, 2021 to January 5, 2022 included 215 patients with PC who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of titers of IgG antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein. We compared the rate of anti-SARS-CoV-2 S IgG ≥15 U/mL between patients with or without concomitant steroid use. RESULTS: Of 215, we identified 33 patients who had concomitant steroid use. Of these, 12 and 21 patients were metastatic castration-sensitive PC and castration-resistant PC (CRPC), respectively. Patients with concomitant steroid use had a significantly lower rate of antibody titer ≥15 U/mL than those without steroid use (82% vs. 95%, P = 0.021). Patients with CRPC with concomitant steroid use (n =21) also had a lower rate of antibody titer ≥15 U/mL (71%) than those without steroid use (93%, P = 0.051), although this was not statistically different. Increased number of systemic treatments administered after diagnosis of CRPC (3 lines or more) were significantly associated with antibody titers <15 U/mL (97% vs. 77%, P <0.001). CONCLUSION: The humoral response to the BNT162b2 mRNA vaccine was significantly lower in patients with concomitant steroid use. Anti-SARS-CoV-2 S antibody titers were affected by CRPC status, the accumulation of post-CRPC treatments, and steroid use.

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors.

Although BRAF inhibition has demonstrated activity in BRAFV600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis.

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series. METHODS: We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes. RESULTS: The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group. CONCLUSIONS: Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity.

Predicting outcomes of neonates born to GBS-positive women who received inadequate intrapartum antimicrobial prophylaxis.

We determined the predicting factors of early-onset group B streptococcal (EOGBS) infection in neonates who were born to GBS carrier mothers with inadequate intrapartum antibiotic prophylaxis (IAP). Medical records of all neonates born from January 1, 2008 to April 1, 2010 were reviewed. Inadequate IAP was defined as delivery less than 4 hours (h) after the first administration of antimicrobial. Of 1910 neonates, 273 were born from mothers colonized with GBS, including 69 who received inadequate IAP. Of 69 neonates, nine showed symptoms, including respiratory distress, fever, tachycardia, vomiting, and irritability. Abnormalities in complete blood count (CBC) and C-reactive protein (CRP) were noted in three and four neonates, respectively. Three infants were diagnosed with EOGBS infection confirmed by positive rectal and throat cultures, and all three presented with respiratory distress and CRP abnormalities. Respiratory distress (p=0.0004) and CRP (p=0.0001) offered reliable indicators for detecting EOGBS infections.

Hypoglycemia associated with L-asparaginase in acute lymphoblastic leukemia treatment: a case report.

A patient with acute lymphoblastic leukemia repeatedly developed hypoglycemia during chemotherapy. Comparison of serum glucose trends between chemotherapy with and without L-asparaginase (L-Asp) demonstrated a strong association between L-Asp and hypoglycemia. Critical blood sampling during hypoglycemia indicated hyperinsulinism, suggesting that L-Asp induced hypoglycemia in the patient through inappropriate insulin secretion. Identification of hypoglycemia as an adverse effect will enable clinicians to understand and develop appropriate strategies for L-Asp use in chemotherapy regimens.