Expanding genotype-phenotype correlations in FOXG1 syndrome: results from a patient registry.

BACKGROUND: We refine the clinical spectrum of FOXG1 syndrome and expand genotype-phenotype correlations through evaluation of 122 individuals enrolled in an international patient registry. METHODS: The FOXG1 syndrome online patient registry allows for remote collection of caregiver-reported outcomes. Inclusion required documentation of a (likely) pathogenic variant in FOXG1. Caregivers were administered a questionnaire to evaluate clinical severity of core features of FOXG1 syndrome. Genotype-phenotype correlations were determined using nonparametric analyses. RESULTS: We studied 122 registry participants with FOXG1 syndrome, aged < 12 months to 24 years. Caregivers described delayed or absent developmental milestone attainment, seizures (61%), and movement disorders (58%). Participants harbouring a missense variant had a milder phenotype. Compared to individuals with gene deletions (0%) or nonsense variants (20%), missense variants were associated with more frequent attainment of sitting (73%). Further, individuals with missense variants (41%) achieved independent walking more frequently than those with gene deletions (0%) or frameshift variants (6%). Presence of epilepsy also varied by genotype and was significantly more common in those with gene deletions (81%) compared to missense variants (47%). Individuals with gene deletions were more likely to have higher seizure burden than other genotypes with 53% reporting daily seizures, even at best control. We also observed that truncations preserving the forkhead DNA binding domain were associated with better developmental outcomes. CONCLUSION: We refine the phenotypic spectrum of neurodevelopmental features associated with FOXG1 syndrome. We strengthen genotype-driven outcomes, where missense variants are associated with a milder clinical course.

Role of Lactate Dehydrogenase in Identifying Relapse for Patients With Stage I Testicular Cancer on Surveillance.

PURPOSE: Tumor markers alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase assume a key role in the management of testicular germ cell tumors. While alpha-fetoprotein and human chorionic gonadotropin have modest sensitivity and specificity for germ cell tumors, lactate dehydrogenase has weak sensitivity and specificity. We explored the utility of lactate dehydrogenase in identifying relapse among stage I seminomatous and nonseminomatous germ cell tumors on surveillance. MATERIALS AND METHODS: Patients with a history of stage I testicular germ cell tumors were identified from a prospectively maintained database at the Princess Margaret Cancer Centre from December 1980 to May 2021 and surveyed according to established institutional algorithm guidelines. The utility of lactate dehydrogenase elevation to independently detect germ cell tumor relapse was examined. RESULTS: Among 1,014 seminoma and 676 nonseminomatous germ cell tumor patients, 176 and 176 patients relapsed with a median time to relapse of 13.6 and 8.9 months, respectively. Imaging alone was the most common mode of relapse detection in 144 and 74 of seminoma and nonseminomatous germ cell tumor patients, respectively. Lactate dehydrogenase was elevated in 49 cases of seminoma and 38 cases of nonseminomatous germ cell tumors at relapse, but was never the sole relapse indicator. Among 350 seminoma and 311 nonseminomatous germ cell tumor patients who never relapsed, 210 and 233, respectively, had at least 1 elevated lactate dehydrogenase value. CONCLUSIONS: Lactate dehydrogenase alone did not independently contribute to early relapse detection in stage I seminoma or nonseminomatous germ cell tumor. Elevated lactate dehydrogenase values were documented in a high proportion of nonrelapsing seminoma and nonseminomatous germ cell tumor cases.

Salvage lymph node dissection for prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-identified oligometastatic disease.

INTRODUCTION: The availability of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) imaging, particularly in the setting of rising prostate-specific antigen (PSA) after definitive treatment, has led to oligometastatic prostate cancer being increasingly identified. Despite the enthusiasm surrounding treating oligometastatic disease, it has been relatively understudied. We sought to review our salvage lymphadenectomy experience in the PSMA PET/CT era. METHODS: We retrospectively reviewed patients undergoing lymphadenectomy following curative-intent primary therapy with rising PSA who had undergone a PSMA PET/CT identifying oligometastatic disease (defined as ≤5 PSMA-avid lesions) between January 2016 and April 2020. The primary endpoint was complete response, defined as achieving a PSA <0.2 ng/ml without concomitant androgen deprivation therapy (ADT). RESULTS: Twenty-two patients were included. Primary curative therapy included radical prostatectomy (86.4%) and brachytherapy (13.6%). Median PSA at salvage surgery was 1.72 ng/ml. Pelvic lymph node dissection was the most performed procedure (72.7%). Median node yield was 10.5, with a median of 1.5 positive nodes on pathology. Eight patients (36.4%) achieved PSA <0.2, with six (27.3%) remaining with PSA <0.2 after a median followup of 23.1 months. Nine (40.9%) had an initial PSA decline, but nadired ≥0.2, and in five (22.7%) the PSA rose immediately after surgery. Overall, ADT was started in seven patients (31.8%) at a median of 10.1 months post-salvage surgery. CONCLUSIONS: In our series of salvage dissection for PSMA-PET-detected nodal oligometastases, approximately a third achieved PSA <0.2; yet, it was only durable in 27%. Prospective trials of salvage nodal radiation are ongoing, however, more prospective trials of salvage node dissection are needed.

Utility of Serum miR-371a-3p in Predicting Relapse on Surveillance in Patients with Clinical Stage I Testicular Germ Cell Cancer.

BACKGROUND: Optimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown. OBJECTIVE: To explore the association between serum miR-371a-3p and CSI surveillance relapse. DESIGN, SETTING, AND PARTICIPANTS: Serial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse. RESULTS AND LIMITATIONS: Thirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p = 0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p = 0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87-2.02, p = 0.18; NSGCT: OR 0.45, 95% CI 0.21-1.00, p = 0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p = 0.05). Limitations include small numbers of relapses and variable time points of serum collection. CONCLUSIONS: In our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy. PATIENT SUMMARY: The promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.