Publications by authors named "J William Harbour"

236 Publications

Dissecting the Interplay Between Genetic Ancestry and Neighborhood Socioeconomic Status on Triple Negative Breast Cancer.

Ann Surg 2022 Jun 27. Epub 2022 Jun 27.

Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Objective: To investigate the impact of global and local genetic ancestry and neighborhood socioeconomic status (nSES), on breast cancer (BC) subtype, and gene expression.

Summary Of Background Data: Higher rates of aggressive BC subtypes (TNBC) and worse overall BC survival are seen in black women [Hispanic (HB) and non-Hispanic (NHB)] and women from low nSES. However, the complex relationship between genetic ancestry, nSES, and BC subtype etiology remains unknown.

Methods: Genomic analysis was performed on the peripheral blood from a cohort of 308 stage I-IV non-Hispanic White (NHW), Hispanic White (HW), HB and NHB women with BC. Patient and tumor characteristics were collected. Global and local ancestral estimates were calculated. Multinomial logistic regression was performed to determine associations between age, stage, genetic ancestry, and nSES on rates of TNBC compared to ER+/HER2-, ER+/HER2+, and ER-/HER2+ disease.

Results: Among 308 women, we identified a significant association between increasing West African (WA) ancestry and odds of TNBC (OR 1.06,95%CI 1.001-1.126, P=0.046) as well as an inverse relationship between higher nSES and TNBC (OR 0.343,95%CI 0.151-0.781, P=0.011). WA ancestry remained significantly associated with TNBC when adjusting for patient age and tumor stage, but not when adjusting for nSES (OR 1.049, 95%CI-0.987-1.116, P=0.120). Local ancestry analysis revealed nSES-independent enriched WA ancestral segment centered at chr2:42004914 (P=3.70×10-5) in patients with TNBC.

Conclusions: In this translational epidemiologic study of genetic ancestry and nSES on BC subtype, we discovered associations between increasing WA ancestry, low nSES, and higher rates of TNBC compared to other BC subtypes. Moreover, on admixture mapping, specific chromosomal segments were associated with WA ancestry and TNBC, independent of nSES. However, on multinomial logistic regression adjusting for WA ancestry, women from low nSES were more likely to have TNBC, independent of genetic ancestry. These findings highlight the complex nature of TNBC and the importance of studying potential gene-environment interactions as drivers of TNBC.
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June 2022

Pseudoangiomatous retinal gliosis (PARG) treated with iodine plaque in patient with chronic retinal detachment.

Am J Ophthalmol Case Rep 2022 Sep 11;27:101614. Epub 2022 Jun 11.

Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL, USA.

Purpose: To describe a case of a chronic retinal detachment complicated by the development of pre and subretinal hemorrhage secondary to a large pseudoangiomatous retinal gliosis (PARG) that interfered with retinal reattachment. After the lesion was regressed following plaque radiotherapy retinal reattachment was successfully completed.

Observations: A 56y.o healthy man with known history of a chronic inferior rhegmatogenous retinal detachment (RD) of the left eye (OS) presented to the Bascom Palmer Eye Institute (BPEI) emergency department (ED) complaining of new floaters OS. On examination, the patient had a visual acuity of 20/30 right eye (OD) and 20/200 OS. Fundoscopic examination showed a treated tear in OD and dense vitreous hemorrhage OS. Initial B-scan ultrasonography OS showed an inferior RD with diffuse hyperechoic material in the vitreous cavity, preretinal and subretinal space most consistent with hemorrhage. Three days later the patient presented with further vision loss and a repeat B scan showed total RD and increasing subretinal hemorrhage with a solid mass like lesion. At this point, decision was made to proceed with retinal detachment repair, removal of the vitreous hemorrhage, and retina evaluation. During surgery, a total retinal detachment was encountered with poor view of the inferior retina due to a large round vascular lesion in the subretinal space with surrounding hemorrhage and clots. The retina was reattached during surgery, however, the postop was complicated by recurrence of VH, dense hyphema, increased IOP, recurrence of retinal detachment, and growth of the mass like lesion noted during surgery. Consultation with ocular oncology diagnosed the patient with secondary PARG lesion and plaque radiotherapy was given achieving remarkable regression of the lesion. After the lesion had regressed, successful retinal reattachment was achieved, and the patient had excellent visual recovery.

Conclusion And Importance: PARG lesions are uncommon in particular when associated to chronic retinal detachments. This case highlights the importance of having a high clinical suspicion for the development of these lesions to diagnose them correctly and treat them aggressively with plaque radiotherapy in order to be able to manage the underlying complex retinal detachment.
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September 2022

Hematologic Complications Associated With Intra-arterial Chemotherapy for Retinoblastoma Treatment: A Single Institution Experience.

J Pediatr Hematol Oncol 2022 05 25;44(4):181-185. Epub 2022 Mar 25.

Holtz Children's Hospital, Jackson Memorial Medical Center.

Retinoblastoma (RB) is the most common intraocular pediatric malignancy. Advancements in intra-arterial chemotherapy (IAC) for treatment of RB have resulted in dramatic improvement in eye salvage rates. Data regarding IAC outcomes and associated hematologic toxicities are limited. The objective of this retrospective study was to analyze baseline characteristics, efficacy, and hematologic complications associated with IAC treatment in children with RB at a single international referral institution. Ninety-five sessions of IAC were performed in 28 patients. Mean age at RB diagnosis was 12.5 months (SD, 9.2 mo). Fourteen patients had bilateral RB. IAC agents included melphalan, carboplatin, and topotecan. The most common regimens were triple-agent IAC and single-agent melphalan (66.3% and 15.8%, respectively). Median number of IAC sessions was 3 (mean: 3.39, range: 1 to 9). Eye salvage rate was 83.7% with an overall survival rate of 100% at a median follow-up of 29 months (mean: 29.8 mo, range: 1 to 63 mo). A total of 26 patients (92.9%) experienced at least 1 hematologic toxicity during their treatment course Prevalence of neutropenia, anemia, and thrombocytopenia were 89.3%, 85.7%, and 25%, respectively. While IAC is effective in salvaging most eyes with advanced intraocular RB, over half of patients experienced clinically significant neutropenia and anemia. Clinicians should be vigilant in monitoring patients for IAC-related complications.
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May 2022

Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma.

Mol Cancer Res 2022 Aug;20(8):1260-1271

Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma. Loss-of-function BAP1 mutations are associated with uveal melanoma metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell-cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in uveal melanoma patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAM), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in uveal melanoma cell lines and single-cell RNA-sequencing data from uveal melanoma patient samples. BAP1 reexpression in uveal melanoma cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1-mutant uveal melanoma cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits.

Implications: BAP1 mutations and increased metastasis may be due to upregulation of CAMs.
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August 2022

HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma.

Cancer Gene Ther 2022 Mar 24. Epub 2022 Mar 24.

The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.

We previously demonstrated that pan-HDAC inhibitors could limit escape from MEK inhibitor (MEKi) therapy in uveal melanoma (UM) through suppression of AKT and YAP/TAZ signaling. Here, we focused on the role of specific HDACs in therapy adaptation. Class 2 UM displayed higher expression of HDACs 1, 2, and 3 than Class 1, whereas HDACs 6, 8, and 11 were uniformly expressed. Treatment of UM cells with MEKi led to modulation of multiple HDACs, with the strongest increases observed in HDAC11. RNA-seq analysis showed MEKi to decrease the expression of multiple HDAC11 target genes. Silencing of HDAC11 significantly reduced protein deacetylation, enhanced the apoptotic response to MEKi and reduced growth in long-term colony formation assays across multiple UM cell lines. Knockdown of HDAC11 led to decreased expression of TAZ in some UM cell lines, accompanied by decreased YAP/TAZ transcriptional activity and reduced expression of multiple YAP/TAZ target genes. Further studies showed this decrease in TAZ expression to be associated with increased LKB1 activation and modulation of glycolysis. In an in vivo model of uveal melanoma, silencing of HDAC11 limited the escape to MEKi therapy, an effect associated with reduced levels of Ki67 staining and increased cleaved caspase-3. We have demonstrated a novel role for adaptive HDAC11 activity in UM cells, that in some cases modulates YAP/TAZ signaling leading to MEKi escape.
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March 2022