Citations

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Summary Esophageal adenocarcinoma (EAC) develops in a step-wise manner, from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), and ultimately to invasive EAC. However, there remains diagnostic uncertainty about LGD and its risk of progression to HGD/EAC. The aim is to investigate the role of Ki-67, immune-histochemical marker of proliferation, surface expression in patients with confirmed LGD, and risk stratify progression to HGD/EAC. A retrospective cohort study was conducted. Patients with confirmed LGD and indefinite for dysplasia (IND), with a mean follow-up of ≥1 year, were included. Pathology specimens were stained for Ki-67 and analyzed for evidence of surface expression. Our results reveal that 29% of patients with confirmed LGD who stained positive with Ki-67 progressed to HGD/EAC as opposed to none (0%) of the patients who stained negative, a statistically significant result (P = 0.003). Similarly, specimens from patients with IND were stained and analyzed revealing a nonsignificant trend toward a higher rate of progression for Ki-67 positive cases versus Ki-67 negative, 30% versus 21%, respectively. Ki-67 expression by itself can identify patients with LGD at a high risk of progression.

Purpose To investigate the incidence of anteroinferior glenoid rim fractures (AGRFs) after anterior shoulder instability (ASI) in patients aged 50 years or older, identify risk factors for surgical intervention for AGRFs, compare initial treatment strategies, and compare clinical outcomes of patients with and without associated AGRFs. Methods An established geographic medical record system was used to identify patients aged 50 years or older with ASI between 1994 and 2016. Patients with radiographic evidence of AGRFs were identified and matched 1:1 to patients without AGRFs. Outcome measures included recurrent instability, recurrent pain events, conversion to arthroplasty, and osteoarthritis graded with the Samilson‐Prieto classification for post‐instability arthritis. Results Overall, 177 patients were identified, with a mean follow‐up period of 10.8 years. Of these patients, 41 (23.2%) had AGRFs and were matched to 41 control patients without AGRFs. The average age was 58.6 and 58.2 years for the AGRF and control groups, respectively. Rates of surgical intervention (27% vs 49%), recurrent instability (12% vs 20%), progression of osteoarthritis (34% vs 39%), and conversion to arthroplasty (2% vs 5%) were similar between AGRF patients and controls. For patients with AGRFs, increased bone fragment size (odds ratio, 1.1) and increased body mass index (odds ratio, 1.2) correlated with an increased risk of surgery. The cutoff value for an increased risk of surgery in patients with AGRFs was a fragment size 33% of the glenoid width or greater. Conclusions Of patients aged 50 years or older at presentation of ASI, 23.2% presented with an associated AGRF. A fragment size 33% of the glenoid width or greater and a higher patient body mass index were significant factors for surgical intervention; however, most patients did not require surgery and still showed acceptable clinical outcomes, and the most common reason for surgical intervention was a rotator cuff tear. Overall, the presence of an AGRF did not portend a worse prognosis as treatment strategies and long‐term outcomes including recurrent instability, progression of osteoarthritis, and conversion to arthroplasty were similar to those in patients without AGRFs. Level of Evidence Level III, retrospective comparative study.

Abstract Introduction Patients with hematologic malignancies (HM) who are eligible for allogeneic hematopoietic cell transplant (allo-HCT) often lack an HLA-matched related donor (MRD) and rely on unrelated donors for a matched or mismatched unrelated donor (MUD or MMUD) or on umbilical cord blood (UCB). It is well known that racial minorities are underrepresented in donor registries. Objective Omidubicel, an advanced cell therapy for allo-HCT, demonstrated superior hematopoietic recovery and clinical outcomes compared with standard UCB (NCT02730299). We hypothesized the impact of omidubicel access on racial and ethnic health disparities in a projection model. Methods A model was developed to project allo-HCT access and clinical outcomes in a hypothetical population of 10,000 allo-HCT-eligible US patients with HM lacking an HLA-MRD. Outcomes associated with omidubicel, MUD, MMUD, haploidentical or UCB HCT, or no transplant were assessed by race/ethnic group. Model inputs, including clinical outcomes for each HCT type, were drawn from clinical trials, public CIBMTR and US Department of Health and Human Services data, and published studies. Increasing omidubicel use was modeled, with proportional reductions in other allo-HCT types or no transplant. Results In a modeled population of 10,000 patients, 5,956 (60%) received allo-HCT utilizing current donor sources (MUD, MMUD, haploidentical, UCB) with no omidubicel (status quo). While 80% of white patients underwent allo-HCT, only 40% of Hispanic, 32% of Asian, and 22% of Black patients underwent allo-HCT. Mean time from selecting graft to HCT was 11.5 weeks. Including those not transplanted, 1-year OS was 62% overall, ranging from 56% (Black) to 65% (White). Modeled increases in omidubicel use in eligible patients were associated with higher proportions of patients undergoing allo-HCT, decreased time to HCT, and increased 1-year OS. Improvements were greatest among racial minorities. Assuming 20% omidubicel use, the proportion of patients receiving allo-HCT increased by 71% in Black, 43% in Asian, 30% in Hispanic, and 5% in White patients. Modeled time to allo-HCT improved as well. Discussion Access to omidubicel is projected to decrease time to allo-HCT, improve outcomes overall, with greatest improvements among racial and ethnic groups underserved by the status quo, thus helping to reduce racial disparities and improving health equity in allo-HCT.

Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

Objectives:Introduction: Wrestling is a physically demanding sport with young athletes prone to anterior cruciate ligament (ACL) injuries. However, there is a paucity of data evaluating the results of ACL reconstruction (ACLR) in this cohort. Purpose: To assess patient-reported outcomes, reoperation rates, graft survival, and return to play (RTP) following ACLR in a large cohort of competitive wrestlers Methods: All competitive wrestlers (high school, collegiate, or professional) with a history of an ACLR at a single institution between 2000 and 2019 were retrospectively identified. Graft failure was defined as a re-tear determined by clinical or advanced imaging evaluation, and/or revision ACL reconstruction. All patients were contacted for determination of reinjury rates, current sport status, visual analog scale (VAS), International Knee Documentation Committee (IKDC) and Tegner activity scores. Results: 118 knees in 114 wrestlers were included at a median follow-up time of 5.8 years (IQR: 3.6 – 10.3). The median age was 17 years (15 – 18) with 116 (98%) males. ACLR was most often performed with bone-patellar tendon-bone (BTB) autograft (n = 64; 54%) or hamstring tendon (HT) autograft (n = 43; 36%). At final follow-up, 80% of athletes were able to RTP at a median of 273 days (IQR: 203 – 379). Graft failure occurred in 17 (14%) patients at a median time of 1.4 years (IQR: 0.8 – 4.7) after the index ACLR. BTB autograft demonstrated a lower failure rate compared to HT autograft (8% vs. 21%; P = 0.044). Kaplan-Meier survivorship free from graft failure for the entire cohort was 95.3% at 1 year, 92.5% at 2 years, 89.8% at 5 years, 84.6 at 10 years, 77.6 at 20 years. BTB autograft was associated with better survival than HT autograft up to 15 years after the index ACLR (90.4% vs. 76.3%; P = 0.030). Conclusions: Return to competitive wrestling was observed in 80% of athletes after ACLR, with 14% of wrestlers experiencing graft failure. BTB autograft reconstruction may serve as a more durable graft for competitive wrestlers with lower rates of failure when compared to HT autograft even up to 15 years after surgery. [Table: see text][Figure: see text][Figure: see text][Figure: see text]

Objectives: Distal biceps tendon tears, although rare, significantly impair patient’s elbow mobility and function. There is a paucity of contemporary literature reporting long term outcomes of distal biceps (DB) injuries. Therefore, the authors sought to identify magnetic resonance imaging (MRI) confirmed distal bicep tears and report on (1) patient demographics and injury characteristics of all patients with distal bicep pathology, (2) outcomes of all patients with non-operatively managed DB pathology, and (3) outcomes of all patients with operatively managed DB pathology. Methods: Patients with an MRI-confirmed distal biceps rupture from 1996 to 2016 were identified through an institutional image database. Patients from the initial search were then cross-referenced with the [REDACTED] 1 to ensure record availability. Patients were included if they had complete medical records and ≥5 years of clinical follow-up. Patients with inflammatory arthritis and enthesitis, polytrauma, or incidental findings without clinical assessment were excluded. Medical records were reviewed to confirm the diagnosis of distal biceps tears and obtain further subject details. Results: A total of 158 patients (22 female, 136 male) with a mean age 51.5 years (44.8-61.2) were identified and included. Baseline patient demographics including BMI, smoking status, dominant-handedness, laborer occupation, and gender were gathered (Table 1). Patients had a mean clinical follow-up of almost 14 years (Table 1, range 8.4 -17.8). Outcomes of the 52 non-operative and 106 operatively managed patients, included severe complications, functional outcomes, and health-related productivity loss are reported in Table 2. There were 7 re-operations (4%), 5 re-ruptures (3%), and overall 35% of the operatively treated cohort experienced a complication. Conclusions: Patients with distal bicep pathology tended to be a male laborer in their 50s without clinically significantly associated risk factors. The majority of patients regained full ROM, and 83% were able to return to work without modifications, irregardless of operative or non-operative management. At long term follow up, patients treated operatively were more likely to report missing time from work and averaged more days missed than their non-operatively treated counterparts. Additionally, operative patients had no statistically significant gains functional outcomes, and were subject to potential post-operative complications. Surgeon bias may play a role in deciding treatment for distal biceps tears. As such, careful patient selection for surgical intervention for distal biceps pathology should be employed; surgeons should consider restricting surgical intervention to patients who have significant clinical symptoms or fail non-operative management. [Table: see text][Table: see text]

Objectives: Background: Although they are common, there remains a paucity of data regarding traumatic anterior shoulder dislocations (ASI) associated with anteroinferior glenoid rim fractures (AGRF) in older patients. Purpose: To describe the incidence of AGRF in this population following ASI, identify risk factors for AGRF, compare treatment strategies, and compare clinical outcomes of patients with and without an associated AGRF. Methods: An established geographic medical record system was used to identify patients >50 years of age with ASI between 1994 and 2016. Patients with radiographic evidence of AGRF were identified and matched 1:1 to patients without AGRF. Comparative analysis was conducted to determine differences between groups. Results: Overall, 186 patients were identified with a mean follow-up of 10.4 years (range, 2.0 – 25.4). Of these, 42 (22.6%) had AGRF and were matched to 42 control patients without AGRF. Average age was 58.9 and 58.2 years for the AGRF and control groups, respectively. Rates of surgical intervention (29% vs. 43%), recurrent instability (14% vs. 17%), progression of osteoarthritis (34% vs. 39%), and conversion to arthroplasty (2% vs. 5%) were similar between AGRF and control cohorts. Control patients were more likely to report recurrent pain (p=.046). For patients with AGRF, increased bone fragment size (OR 1.1) and increased BMI (OR 1.2) correlated with an increased risk for surgery. The cut-off value for surgery in patients with AGRF was a fragment size ≥33% of the glenoid width. Conclusions: In patients ≥ 50 years at presentation of ASI, 22.6% presented with an associated AGRF. Increased fragment size and greater patient BMI were significant factors associated with undergoing surgical intervention; however, most patients did not require surgery. Patients without AGRF were more likely to report recurrent pain, possibly due to a higher prevalence of rotator cuff derangement. Overall, the presence of an AGRF did not portend a worse prognosis as treatment strategies and long-term outcomes in terms of recurrent instability, progression of osteoarthritis, and conversion to arthroplasty were similar between patients with and without AGRF at the time of ASI diagnosis.