Atypical choroidal nevus in a subject with a germline PALB2 pathogenic variant.

Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.

Assessing the phacoemulsification learning curve using duration of each step.

PURPOSE: To assess the phacoemulsification learning curve for ophthalmology residents using duration for each step. SETTING: Single tertiary, training site hospital. DESIGN: Cross-sectional study. METHODS: Emory ophthalmology postgraduate year (PGY) 3 and PGY-4 residents operating at Grady Memorial Hospital between April 2017 and February 2018 were eligible to participate. Duration in seconds for each step of surgery was calculated for incisions, continuous curvilinear capsulorhexis (CCC), hydrodissection, nucleus disassembly, quadrant removal, cortical cleanup, intraocular lens insertion, and closure, and this outcome was analyzed as a function of different experience levels. RESULTS: A total of 528 surgeries were included of 549 total surgeries recorded. 6 categories of experience levels were established as A to F, increasing by increments of 50. There was an overall downward trend across various steps across the 8 case categories, and several adjacent categories demonstrate statistically significant differences. The 3 most time-intensive steps early in training were nucleus disassembly (336.5 ± 16.5 seconds), quadrant removal (275.1 ± 18.0 seconds), and cortical cleanup (244.2 ± 24.6 seconds). There was a sustained drop in mean duration for all steps through at least category D, with most steps showing a drop through category F. CONCLUSIONS: There is a benefit to a higher caseload, well above the Accreditation Council for Graduate Medical Education-mandated 86 cases. Improvements in efficiency were observed after 250 cases, with nuclear disassembly and CCC demonstrating a significant decrease in operative time.

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

Reverse total shoulder arthroplasty provides stability and better function than hemiarthroplasty following resection of proximal humerus tumors.

BACKGROUND: Tumors may necessitate resection of a substantial portion of the proximal humerus and surrounding soft tissues, making reconstruction challenging. We evaluated outcomes in patients undergoing treatment of tumors of the proximal humerus with reverse total shoulder arthroplasty (rTSA) or shoulder hemiarthroplasty. METHODS: Patients who underwent rTSA (n = 10) or shoulder hemiarthroplasty (n = 37) for tumors of the proximal humerus in 2009 to 2017 were reviewed. Of these patients, 27 had died, leaving 20 for review. The mean follow-up period of the survivors was 27.1 months. They were evaluated clinically and contacted to determine the American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, and visual analog scale score. RESULTS: Postoperative complications occurred in 13 hemiarthroplasty patients (34%). Tumor recurrence occurred in 3 hemiarthroplasty patients (7.9%), whereas in the rTSA group, 1 patient (10%) had a postoperative complication, with no recurrences. One hemiarthroplasty patient required revision surgery with rTSA to improve shoulder function. Six dislocations and two subluxations occurred in the hemiarthroplasty group, whereas no subluxations occurred in the rTSA group (P = .14). Mean range of motion was 85° of forward flexion for rTSA patients (n = 10) compared with 28° for hemiarthroplasty patients (P < .001). The mean American Shoulder and Elbow Surgeons score was 63 for hemiarthroplasty patients (n = 5) and 59 for rTSA patients (n = 4). The mean Simple Shoulder Test scores were 3.8 and 2.4, respectively. The mean visual analog scale pain scores were 2.4 and 2.5, respectively. CONCLUSION: Reverse total shoulder arthroplasty can reproducibly reconstruct the shoulder in patients requiring oncologic proximal humerus resection. Patients have good outcomes, better range of motion, and no increase in instability rates compared with hemiarthroplasty.

Surgical treatment outcomes after primary vs recurrent anterior shoulder instability.

INTRODUCTION: The aim of this study is to compare the outcomes of surgical management after primary anterior shoulder dislocation to the outcomes of patients who have surgical stabilization after recurrent anterior shoulder instability. METHODS: A Medline (PubMed) search was performed in November of 2016 using the following key terms: shoulder, labrum, Bankart, instability, repair, outcome, recurrent. In May 2017 a Cochrane search was performed using similar key terms to ensure we included all studies. Only level I and II studies were included. RESULTS: There were three studies that compared primary repair to delayed repair. In all three studies, the rate of recurrence was higher in group R than group S. When pooled, there was not a statistically significant difference between these groups, but there was a slightly higher odds of recurrence in group R (pooled OR 2.08, CI 0.69-6.26, p = 0.19). No significant differences were appreciated in functional outcomes or complications in these two groups. CONCLUSION: Further level I and level II studies to compare surgical treatment after first time and recurrent instability are needed. This study failed to find a statistically significant difference in recurrence rates in patients who had stabilization acutely after a single episode compared to patients with recurrent instability events, although results suggest there may be a small benefit in primary stabilization.

Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer.

Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included. Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification. BAP1 expression in unaffected choroid tissue from a patient with UM was assessed by quantitative RT-PCR and methylation by pyrosequencing. Twenty-eight patients had one or more germline sequence variants in BAP1; seven of these were pathogenic. One hundred forty patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected. In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of ≥2 BAP1-related cancers 6/16 (38%), age of onset <35 years 4/21 (19%) and familial UM 6/34 (18%). One of 19 non-tumor choroid tissues tested showed uncharacteristically low expression as compared to the controls decrease in BAP1 RNA expression but no evidence of constitutional promotor hypermethylation was detected. UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.

Oncologic reconstruction of the proximal humerus with a reverse total shoulder arthroplasty megaprosthesis.

BACKGROUND AND PURPOSE: Both malignant and benign tumors of the proximal humerus may necessitate resection of a substantial portion of the proximal humerus, making reconstruction options challenging. While hemiarthroplasty has been a classic treatment, reverse total shoulder replacement may provide better pain relief and function for these patients. METHODS: We utilize a two-surgeon approach for these challenging cases. The orthopedic oncologist resects the tumor. A shoulder-trained surgeon implants the reverse shoulder replacement. Modern implants, with large glenospheres and modular components, can allow reliable, straightforward reconstructions for these patients. We prefer 6 weeks of postoperative immobilization to decrease the risk of instability. RESULTS: We have completed 13 reverse total shoulder replacements for oncologic shoulder resections, with acceptable clinical outcomes and no complications to date. CONCLUSION: Reverse total shoulder replacement with long-stem, modular components can reliably and reproducibly reconstruct the shoulder in patients with oncologic resections of the proximal humerus.

The Rho-GEF Gef3 interacts with the septin complex and activates the GTPase Rho4 during fission yeast cytokinesis.

Rho GTPases, activated by Rho guanine nucleotide exchange factors (GEFs), are conserved molecular switches for signal transductions that regulate diverse cellular processes, including cell polarization and cytokinesis. The fission yeast Schizosaccharomyces pombe has six Rho GTPases (Cdc42 and Rho1-Rho5) and seven Rho GEFs (Scd1, Rgf1-Rgf3, and Gef1-Gef3). The GEFs for Rho2-Rho5 have not been unequivocally assigned. In particular, Gef3, the smallest Rho GEF, was barely studied. Here we show that Gef3 colocalizes with septins at the cell equator. Gef3 physically interacts with septins and anillin Mid2 and depends on them to localize. Gef3 coprecipitates with GDP-bound Rho4 in vitro and accelerates nucleotide exchange of Rho4, suggesting that Gef3 is a GEF for Rho4. Consistently, Gef3 and Rho4 are in the same genetic pathways to regulate septum formation and/or cell separation. In gef3∆ cells, the localizations of two potential Rho4 effectors--glucanases Eng1 and Agn1--are abnormal, and active Rho4 level is reduced, indicating that Gef3 is involved in Rho4 activation in vivo. Moreover, overexpression of active Rho4 or Eng1 rescues the septation defects of mutants containing gef3∆. Together our data support that Gef3 interacts with the septin complex and activates Rho4 GTPase as a Rho GEF for septation in fission yeast.