Citations

Abstract Epithelial ovarian cancer (EOC) is the most common gynecological cancer, and ranks fifth in cancer deaths among women in the United States. Previous studies have identified several circulating proteins biomarkers for EOC risk, such as CA125 antigen and insulin-like growth factor-1 (IGF-1). However, previous studies on protein biomarkers for EOC were limited with small sample sizes, and only a few proteins investigated. In this study, we integrated genomics and proteomics data to search for novel circulating protein biomarkers for EOC risk. We constructed study instruments using genetic variants for protein quantitative trait loci (pQTL) for over 1,400 circulating proteins. Beta coefficients and standard errors of the selected pQTL variants in relation to EOC risk were obtained from 25,509 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). An inverse-variance weighted method was used to evaluate the association of these genetically predicted protein levels and risk of overall and serous EOC. We identified 35 protein biomarkers, for which their genetically predicted levels were significantly associated with the risk of either overall or serous EOC (false discovery rate <0.05). There are 25 proteins showing significant associations with both overall and serous EOC; most of the associations were stronger for serous EOC than overall EOC. The association for 31 proteins could be attributed, in part, to variants at ABO 9q34.2, a known ovarian cancer susceptibility locus. Five ABO locus-related proteins are in the PI3K-Akt signaling pathway, including insulin-like growth factor 1 receptor, hepatocyte growth factor receptor, interleukin-3 receptor subunit alpha, insulin receptor, and vascular endothelial growth factor receptor 2. Four of these proteins are also in the Rap1 and Ras signaling pathway. These five proteins are all inversely associated with the risk of overall EOC, with odds ratios ranging from 0.64 to 0.93 per unit increase in genetic risk scores (p values: 7.55×10-7 to 5.66×10-2). Four EOC associated proteins which were not influenced by variants in 9q34.2 are microfibrillar-associated protein 2, protein delta homolog 1, semenogelin-2, and netrin-G1, all of which showed significant associations with overall EOC, but not the serous subtype. Our study identifies potential novel biomarkers for ovarian cancer and suggests that genetic variants at locus 9q34.2 may play a role in the relation between levels of these proteins and risk of ovarian cancer. Citation Format: Guochong Jia, Xiang Shu, Xiao-Ou Shu, Jirong Long, Qiuyin Cai, Kirsten B. Moysich, Ellen L. Goode, Thomas A. Sellers, Wei Zheng. Genetically predicted concentration of circulating proteins and epithelial ovarian cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 598.

Abstract Purpose: The majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of ~30%. However, a subset of patients have an extraordinary response to treatment and ~15% survive more than ten years (long-term survivors). The Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG) aims to uncover factors that influence long-term survival of HGSC patients. Here, we investigated the genomic and immunologic determinants of exceptional survival of this deadly disease. Experimental Design: Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline samples (median 39x coverage) of 55 long-term survivors. Primary tumor samples were also characterised by RNA sequencing, DNA methylation profiling and immunohistochemistry. Results: A total 38 (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemo-sensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression-free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls (316 unselected HGSC patients in The Cancer Genome Atlas). Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related) and Signatures 5, 8 and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207; P = 0.001). Staining of adjacent tumor tissue revealed that RB1 loss was associated with increased numbers of PD-1+ tumor-infiltrating lymphocytes (P = 0.015) and MHC class I on tumor cells (P = 0.002). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P < 0.001) compared to patients with RB1 positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P < 0.001). Conclusions: This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations might be associated with enhanced host immune responses and long-term survival. Citation Format: Dale W. Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje C. Wouters, Flurina Saner, Jessica A. Beach, Katy Milne, Catherine J. Kennedy, Joy Hendley, Nadia Traficante, Celeste L. Pearce, Malcolm C. Pike, Multidisciplinary Ovarian Cancer Outcomes Group, Susan J. Ramus, Martin Köbel, Brad H. Nelson, Ellen L. Goode, Anna deFazio, David D. Bowtell. The genomic landscape of high-grade serous ovarian cancer in long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2722.

Objectives: The variability of throwing metrics, particularly elbow torque and ball velocity, during structured long-toss programs is yet to be fully elucidated. The primary aims of this study were to assess various throwing metrics through a structured long-toss program using wearable technology and to quantify the intra and inter thrower variability of these metrics at each stage of throwing. Methods: This was a descriptive laboratory study in which 60 high school and collegiate pitchers participated in a predetermined, structured, progressive long-toss program. All players wore a motusBASEBALL sleeve (Motus Global, Inc.; Rockville Centre, NY), which measured arm slot, arm velocity, shoulder rotation, and elbow varus torque. Radar guns were used to measure ball velocity. These metrics were compared within and between all pitchers at each of the following throwing distances: 90 ft, 120 ft, 150 ft, 180 ft, and maximum effort mound pitching. Intra- and inter- thrower reliabilities were calculated for each throwing metric at every stage of the program. Excellent intra-thrower reliability was defined by an Intra-class coefficient (ICC) >0.750. Acceptable inter-thrower reliability was defined by a Coefficient of Variation (CV) <5%. Results: Ball velocity significantly changed at each progressive throwing distance, but this did not consistently correlate with an increase in elbow torque. Pitching from the mound did not place more torque on the elbow than throwing from 120 ft and beyond. Intra-thrower reliability was excellent throughout the progressive long-toss program for each throwing metric. Ninety-one percent of throwers had acceptable inter-thrower reliability for ball velocity, whereas only 79% of throwers had acceptable inter-thrower reliability for elbow torque. Conclusion: Based on trends in elbow torque, it may be practical to incorporate pitching from the mound earlier in the program (once a player is comfortable throwing from 120 ft). Ball velocity and elbow torque do not necessarily correlate with one another, so a degree of caution should be exercised when using radar guns to estimate elbow torque. Given the variability in elbow torque between throwers, some athletes would likely benefit from an individualized throwing program.

Objectives: Progressive throwing programs are a mainstay of rehabilitating the throwing athlete after injury or surgery. Athletes are commonly asked to throw at reduced levels of effort (i.e. “50% effort”, ”75%,” etc) to minimize stress to healing tissues. However, it is unknown whether players’ perceived exertion matches actual exertion. The purpose of this study was to determine whether decreased effort correlates with decreased throwing metrics, whether metrics decrease to a predictable degree, and to quantify variability of these metrics within a given athlete when attempting to throw at sub-maximal effort. Methods: Sixty healthy, high school and collegiate baseball pitchers participated in a structured throwing program. After warming up, each pitcher was asked to throw five, max effort long toss throws at a distance of 120 feet. Afterwards, they were asked to give 5 throws at both 75% effort and 50% effort from the same distance. A motusBASEBALL sleeve (Motus Global, Inc.; Massapequa, NY) was worn by all players, which measured arm slot, velocity, shoulder rotation, and elbow varus torque (Nm). Ball velocity was measured in miles per hour (MPH) using a radar gun. The observed changes in throwing metrics were compared to one another across each of the throwing scenarios using a general estimating equation to control for multiple comparisons. They were also compared to the expected change to see if a decrease from 100% effort to 75%, and then to 50% resulted in proportional decreases in elbow torque and ball velocity. Intra-thrower variability was determined for each throwing metric at each degree of effort, and these results are reported using intra-class correlation coefficients (ICC) where an ICC > 0.75 was considered to represent excellent agreement. Results: Mean elbow torque decreased as players decreased their perceived effort from 100% (72.7 Nm) to 75% (67.3 Nm) to 50% (62.s Nm) (p<0.001). Mean ball velocity also decreased as they progressed from 100% effort (77.8 MPH) to 75% effort (66.5) to 50% effort (60.3 MPH) throws (p<0.001). However, these observed decreases in torque and velocity were much smaller in magnitude than the decreases in perceived effort. During the 75% effort throws, torque and velocity were not reduced to 75% of max. Instead, elbow torque was only reduced to 93.3% of max, and velocity dropped to 86.1% of max. Similarly, for the 50% effort throws, torque remained 86.5% of max effort torque, while velocity remained 78.1% of max. Accordingly, for every 25% decrease in perceived effort, torque only decreased 7%, and velocity only decreased 11%. These observed differences were all significantly different than the expected differences (p<0.001 for all). Intra-thrower reliability was considered excellent for all metrics within each throwing scenario: max effort, 75% effort, and 50% effort (ICC>0.75 for all). Conclusion: Measured effort was significantly greater than perceived effort during this standardized throwing program for all metrics tested. This is especially true for ball velocity and varus elbow torque. Ultimately, when players throw at what they perceive to be “reduced effort,” their actual throwing metrics do not decrease at the same rate as their perceived exertion. This has significant implications for throwers during the rehabilitation process as their elbows are likely experiencing more stress than desired. Clinicians and coaches must be aware and may want to consider transitioning to more objective measures of effort during rehabilition.

Objectives: Little is known about the natural history and long-term outcome of a surgically treated symptomatic lateral discoid meniscus. The goals of this study were to describe the rate and factors associated with recurrent lateral meniscus tears and progression to symptomatic lateral compartment osteoarthritis (OA) in patients surgically treated for a symptomatic lateral discoid meniscus. Patients with surgically treated lateral discoid meniscus have a high incidence of meniscus re-tear and progression to lateral compartment OA. Methods: A large, geographic database was reviewed to identify and confirm patients presenting with symptomatic lateral discoid meniscus between 1998 and 2015. Charts were reviewed to document treatment and outcomes at a minimum clinical follow-up of two years. Results: 70 discoid meniscus patients (30 F, 40 M) with a mean age of 27 years (Range: 2.0-66.0) were followed for an average of 5.8 years (Range 2.0-23.7). Sixty patients underwent surgical management: 49 (82%) patients underwent partial lateral meniscectomy and 11 (18%) underwent meniscus repair (including saucerization). Tear-free survival following surgery was 93% at 2 years, 69% at 5 years, and 40% at 8 years. Overall progression to symptomatic lateral compartment OA in the surgical group was 10% at 2 years, 23% at 5 years, and 48% at 8 years. Of those patients who developed lateral compartment OA, 55% (11/20) had a Kellgren-Lawrence score 2 or greater at last radiographic follow-up. Young age and open growth plates were associated with increased incidence of postoperative re-tear (HR: 0.96, CI: 0.93-0.99, p = 0.01). Increased age at diagnosis and BMI ≥ 30 were associated with increased risk of progression to lateral compartment OA on final radiographs. Conclusion: Patients with a surgically treated lateral discoid meniscus tear had a high rate of recurrent meniscus tear at long-term follow-up (60% at 8 years) that was associated with young age. Approximately 48% of surgically treated patients developed symptomatic lateral compartment OA at eight years from initial presentation. The risk of progression to OA increased with older age at diagnosis and BMI ≥ 30.

Objectives: Meniscus repair is desirable over resection to prevent post-meniscectomy arthritis, especially in young and active patients. However, long-term data is currently lacking following isolated meniscus repair, particularly in the pediatric population. The purpose of this study was to report long-term follow-up of isolated meniscus tears treated by meniscus repair in a pediatric population, and to compare those results to previous mid-term follow-up data reported. We hypothesized that these patients would have satisfactory function and reoperation rates at long-term follow-up. Methods: Patients less than 18 undergoing repair of an isolated (without concomitant ACL injury) meniscus tear performed between 1990 and 2005 were included. At the time of final followup, recurrent tear, reoperations, and IKDC and Tegner scores were determined. With logistic regression, the overall failure between different tear types was calculated. Wilcoxon signed ranks tests were performed to calculate the differences in clinical outcome for different time-points, and Spearman coefficients were calculated for Tegner and IKDC with different variables. Results: At an average followup of 17.6 years (13.1 - 26.0 years), 32 patients with 33 isolated meniscus repairs (29 M: 3F) with an average age of 16.1 (9.9 - 18.7) were included in this study. At early follow-up, complex tears (80%) had a higher overall failure rate compared to simple tears (18.2%). However, no further failures occurred since mid-term follow-up with any tear type. At final follow-up, the average IKDC score was 92.3, which was significantly increased when compared to both preoperative 65.3 (p< 0.0001) and mid-term scores, 90.2 (p= 0.01). However, the average Tegner score (6.5) was significantly lower than both pre-operative 8.3 (p< 0.0001) and mid-term 8.4 (p< 0.0001) scores. There was no correlation for Tegner or IKDC values with any risk factors. Conclusion: In conclusion, this study demonstrates overall good to excellent long-term clinical outcomes following isolated meniscus repair in a pediatric population. Early failure and reoperation rates were variable depending on tear type, with complex multiplanar tears having more failures at short-term follow-up. However, at long-term follow-up, IKDC and Tegner scores were not significantly different for those with complex tears compared to other tear types.

Objectives: Following ACL reconstruction, objective measurements of functional testing are often incorporated into the decision-making process with regard to clearance for return to sport (RTS), in order to reduce the risk of second ACL injury. However, there is limited data to assess the predictive value of functional testing to risk of second ACL injury. Therefore, the purpose of this study was to determine whether performance on functional testing following primary ACL reconstruction can predict second ACL injuries. Methods: Patient records were retrospectively analyzed for individuals who presented with an ACL injury at a single institution from 1990-2010. A total of 335 patients who underwent primary ACL reconstruction, had functional testing at the six month ± one month time point postoperatively, and had a minimum of two year post-operative follow-up were included in this study. Functional testing included vertical jump, single leg hop, and triple leg hop. Functional testing is represented as a measure of limb symmetry and was calculated as the involved limb divided by the uninvolved limb providing a percentage relative to the uninvolved limb. Statistical analysis was performed to determine the significance of functional test limb symmetries between those with and without a secondary tear by sex, then by age. Unpaired T-tests with an alpha level less than 0.05 was performed with JMP 13 (SAS Institute Inc., Cary, NC). Group distributions as well as effect sizes were calculated. Results: 335 patients with a mean age of 25 (SD 9.76) at an average time of 9.05 years (SD 3.54) of follow-up after ACL reconstruction met inclusion criteria and underwent statistical analysis (females= 150, male= 185). Of the cohort, 53 patients (18%) experienced second tears (female= 26, male= 27) at an average time of 44.19 months (6.03- 168.4) following ACL reconstruction with 34 occurring on the contralateral side and 19 on the ipsilateral side. Results at six month post ACL reconstruction indicate a significant difference between those who experienced a second ACL injury and those who didn’t with respect to single hop limb symmetry (95% ±7% vs.90% ± 12%, P<0.01). Triple hop limb symmetry was also significantly different between those who suffered a second ACL tear and those who did not (94% ± 6% vs. 90% ±11%, P<0.01). No significant differences were found in limb symmetry of vertical jump. When data was analyzed by sex, significant differences were found in females in the single hop limb symmetry (96% ± 8%, vs. 89% ± 14%, P<0.05) as well as triple hop limb symmetry (95% ± 5% vs. 90% ± 12%, P< 0.05). No significant differences were found in vertical jump for neither females nor males. No significant differences were found when data was categorized by age or sex and age. Conclusion: Overall, at an average of 9.05 years follow-up, 18% of a young and active population of primary ACL reconstructions had a second ACL injury. Contralateral ACL injuries were observed at an increased frequency relative to subsequent ipsilateral ACL tears. Patients with greater limb symmetry on single hop or triple hop functional testing at 6 months are at an increased risk for second ACL tears. When functional testing is used for return-to-sport decisions, physicians should caution patients about the risk of subsequent ACL injury for high performing patients.

Background Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. Methods We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. Results Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16–82 years), and the median time from PA to PC transformation was 5 years (range 1–29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. Conclusions PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.

AbstractBackgroundGlioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date.MethodsRetrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.ResultsOf the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.ConclusionsWhile our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.

Is tau load associated with long-term outcomes of TBI? By using PET to assess tau deposits in patients with chronic TBI, Takahata et al. reveal elevated tau load compared to age-matched controls, and show that the abundance of tau in white matter is associated with late-onset neuropsychiatric symptoms.