Bracketed Localization in Breast-Conserving Surgery: Indications and Success Rates From a Single, High Volume, Academic Breast Cancer Center.

BACKGROUND: Bracketed localization is a technique used to help localize lesions for breast-conserving surgery (BCS). To date, there are no guidelines for when bracketed localization should be used in clinical practice. Based on our experience, we aim to provide criteria that should prompt surgeons to consider bracketing. METHODS: A single-institution retrospective chart review was performed on patients who underwent bracketed localization for BCS between 2015 and 2021. Lesion characteristics were recorded including lesion span, number of lesions, histology type on core needle biopsy and surgical specimen, margin status, and need for additional surgery. RESULTS: One hundred and thirteen cases were analyzed. Imaging showed an average lesion span of 5.0-cm. Multifocal lesions represented 45% of cases. Ductal carcinoma in situ (DCIS) was a histological component in 64% of core needle biopsies and 76% of surgical specimens. Negative margins were achieved in 82% of patients on the first excision. Additional surgery was performed in 17% of patients. Invasive lobular carcinoma had the highest additional surgery rate at 23%. Negative margins with BCS were achieved in 96% of cases, including those with successful re-excision. DISCUSSION: This descriptive study shows that bracketed localization was most often employed for patients with large lesion spans, multifocality, and a DCIS or invasive lobular component. While these characteristics are typically associated with higher rates of positive margins, our cohort's rate of additional surgery was comparable to the national average for all BCS operations. These results argue that surgeon utilization of bracketed localization may be beneficial in these clinical scenarios.

Likelihood of germline mutation with solitary retinoblastoma based on tumour location at presentation.

BACKGROUND/AIMS: To evaluate the likelihood of germline mutation in patients presenting with solitary retinoblastoma based on tumour location at first examination. METHODS: Retrospective analysis of solitary unilateral retinoblastoma for likelihood of germline mutation (family history of retinoblastoma and/or genetic testing indicating germline RB1 mutation and/or development of additional new or bilateral tumours) based on tumur location at presentation (macular vs extramacular). RESULTS: Of 480 consecutive patients with solitary retinoblastoma, 85 were in the macula (18%) and 395 were extramacular (82%). By comparison (macular vs extramacular tumours), macular tumours had smaller basal diameter (12.7 mm vs 18.9 mm, p<0.001) and smaller tumour thickness (6.1 mm vs 10.7 mm, p<0.001). Patients with macular tumours demonstrated greater likelihood for germline mutation (23% vs 12%, OR=2.18, p=0.011), specifically based on family history of retinoblastoma (13% vs 2%, OR=4.64, p=0.004), genetic testing showing germline RB1 mutation (27% vs 15%, OR=2.04 (95% CI 1.04 to 4.01), p=0.039), development of new tumours (13% vs 3%, OR=5.16 (95% CI 2.06 to 12.87), p=0.001) and/or development of bilateral disease (9% vs 2%, OR=4.98 (95% CI 1.70 to 14.65), p=0.004). CONCLUSIONS: Among patients with solitary unilateral retinoblastoma, those presenting with macular tumour (compared with extramacular tumour) show 2.18 times greater likelihood for germline mutation and an even higher likelihood of development of subsequent tumours. Solitary macular retinoblastoma should raise an index of suspicion for likely germline mutation and multifocal disease.

Likelihood of Germline Mutation With Solitary Unilateral Retinoblastoma Based on Patient Age at Presentation: Analysis of 482 Consecutive Patients.

PURPOSE: To evaluate the likelihood of germline retinoblastoma in patients presenting with solitary unilateral retinoblastoma, based on age at presentation. METHODS: This retrospective case series of 482 consecutive patients presenting with solitary unilateral retinoblastoma analyzed the likelihood of germline retinoblastoma, defined as family history of retinoblastoma, germline retinoblastoma mutation documented on genetic testing, and/or development of bilateral disease and/or additional new tumors. This analysis was based on age at presentation (0 to 12 months vs older than 12 to 24 months vs older than 24 to 36 months vs older than 36 months) and a sub-study was conducted on infant age at presentation (0 to 3 months vs older than 3 to 6 months vs older than 6 to 9 months vs older than 9 to 12 months). RESULTS: Of the overall group (482 consecutive patients) with solitary unilateral retinoblastoma, there were significantly different findings in the youngest age group (0 to 12 months old) with greater family history of retinoblastoma (10% vs 2% vs 1% vs 2%, P = .004), smaller median basal diameter (18.0 vs 20.0 vs 20.0 vs 20.0 mm, P = .014), smaller median tumor thickness (8.7 vs 10.0 vs 11.5 vs 10.0 mm, P = .002), greater macular tumor location (33% vs 16% vs 10% vs 8%, P < .001), and greatest likelihood of germline mutation (29% vs 17% vs 8% vs 9%, P = .001). By comparison, patients 1 year and younger (vs older than 1 year) demonstrated a 2.96 odds ratio (OR) (P = .001) for likelihood of germline retinoblastoma. For those classified as infants (1 year and younger) (n = 132 consecutive patients), the youngest patients (0 to 3 months old) demonstrated the greatest likelihood for germline mutation (61% vs 20% vs 24% vs 22%, P = .009) and greatest odds ratio (5.52, P = .002) compared to patients older than 3 to 12 months. CONCLUSIONS: The youngest patients with solitary unilateral retinoblastoma showed the greatest likelihood of germline disease when evaluating all patients (1 year and younger vs older than 1 year of age) (OR = 2.96) and the substudy of infants (3 years and younger vs older than 3 to 12 months old) (OR = 5.52). [J Pediatr Ophthalmol Strabismus. 2021;58(6):355-364.].

Intra-arterial chemotherapy for retinoblastoma in 341 consecutive eyes (1,292 infusions): comparative analysis of outcomes based on patient age, race, and sex.

PURPOSE: To evaluate tumor control and globe salvage following intra-arterial chemotherapy (IAC) for retinoblastoma based on International Classification of Retinoblastoma (ICRB) and patient demographics. METHODS: The medical records of 313 patients (341 eyes) treated with IAC were reviewed retrospectively. Chemotherapy agents included melphalan, topotecan, and carboplatin. Comparative analysis was performed for tumor control and globe salvage based on ICRB and patient demographics including age (≤12 vs >12 months), race (white vs nonwhite), and sex. RESULTS: Of the 341 eyes treated with 1,292 consecutive infusions of IAC as primary or secondary therapy for retinoblastoma, Kaplan-Meier 5-year estimates of globe salvage was 74%. Of those treated with IAC as primary therapy (n = 160 eyes; 655 infusions), 5-year globe salvage overall was 76%: and more specifically, 100% for groups B and C, 86% for group D, and 55% for group E. Of those treated with IAC as secondary therapy (n = 207 eyes; 859 infusions), 5-year globe salvage was 71%. Comparative analysis by race and sex demonstrated no differences in outcomes, but analysis by age revealed that younger patients had a higher rate of globe salvage (77% vs 72%; P < 0.001). Complications (per catheterization) included retina ischemia (1%), choroidal ischemia (1%), neovascularization of the disk, retina, iris (NVI), glaucoma (about 1% each), and central/peripheral systemic ischemia (<1%). Younger patients showed less NVI (P = 0.028), white patients showed less retinal ischemia (P = 0.037), and no difference by sex. There were no patients with metastatic disease or death. CONCLUSIONS: Our results suggest that IAC provides substantial tumor control for advanced and/or recurrent retinoblastoma with a high rate of globe salvage and few complications. There was little difference in outcomes per age, race, and sex.

The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells.

Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and ß-thalassemia. To identify new HbF regulators that might be amenable to pharmacologic control, we screened a protein domain-focused CRISPR-Cas9 library targeting chromatin regulators, including BTB domain-containing proteins. Speckle-type POZ protein (SPOP), a substrate adaptor of the CUL3 ubiquitin ligase complex, emerged as a novel HbF repressor. Depletion of SPOP or overexpression of a dominant negative version significantly raised fetal globin messenger RNA and protein levels with minimal detrimental effects on normal erythroid maturation, as determined by transcriptome and proteome analyses. SPOP controls HbF expression independently of the major transcriptional HbF repressors BCL11A and LRF. Finally, pharmacologic HbF inducers cooperate with SPOP depletion during HbF upregulation. Our study implicates SPOP and the CUL3 ubiquitin ligase system in controlling HbF production in human erythroid cells and may offer new therapeutic strategies for the treatment of ß-hemoglobinopathies.

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8.

BACKGROUND: The Zc3h8 gene encodes a protein with three zinc finger motifs in the C-terminal region. The protein has been identified as a component of the Little Elongation Complex, involved in transcription of small nuclear RNAs. ZC3H8 is overexpressed in a number of human and mouse breast cancer cell lines, and elevated mRNA levels are associated with a poorer prognosis for women with breast cancer. METHODS: We used RNA silencing to decrease levels of expression in mouse mammary tumor cells and overexpression of ZC3H8 in cells derived from the normal mouse mammary gland. We measured characteristics of cell behavior in vitro, including proliferation, migration, invasion, growth in soft agar, and spheroid growth. We assessed the ability of these cells to form tumors in syngeneic BALB/c mice. ZC3H8 protein was visualized in cells using confocal microscopy. RESULTS: Tumor cells with lower ZC3H8 expression exhibited decreased proliferation rates, slower migration, reduced ability to invade through a basement membrane, and decreased anchorage independent growth in vitro. Cells with lower ZC3H8 levels formed fewer and smaller tumors in animals. Overexpression of ZC3H8 in non-tumorigenic COMMA-D cells led to an opposite effect. ZC3H8 protein localized to both PML bodies and Cajal bodies within the nucleus. ZC3H8 has a casein kinase 2 (CK2) phosphorylation site near the N-terminus, and a CK2 inhibitor caused the numerous PML bodies and ZC3H8 to coalesce to a few larger bodies. Removal of the inhibitor restored PML bodies to their original state. A mutant ZC3H8 lacking the predicted CK2 phosphorylation site showed localization and numbers of ZC3H8/PML bodies similar to wild type. In contrast, a mutant constructed with a glutamic acid in place of the phosphorylatable threonine showed dramatically increased numbers of smaller nuclear foci. CONCLUSIONS: These experiments demonstrate that Zc3h8 expression contributes to aggressive tumor cell behavior in vitro and in vivo. Our studies show that ZC3H8 integrity is key to maintenance of PML bodies. The work provides a link between the Little Elongation Complex, PML bodies, and the cancer cell phenotype.