Citations

AbstractBackground and AimTumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population‐based CRC utilizing a combination of tumor and germline testing approaches.MethodsColorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR‐deficient tumors and a subset of MMR‐proficient CRCs.ResultsOf the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR‐deficient CRC without MLH1 methylation and a gene mutation were considered Lynch‐like and comprised 41.1% and 25.2% of the MMR‐deficient CRCs for the ACCFR and MCCS, respectively.ConclusionsIdentification of MMR gene mutation carriers in Australian CRC‐affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR‐deficient CRCs will have unknown etiology (Lynch‐like) proving problematic for clinical management.

BackgroundClear cell sarcoma typically arises in deep soft tissues of the foot/ankle. Primary head and neck clear cell sarcoma is rare. We report three molecularly confirmed primary head and neck clear cell sarcoma and review the literature.MethodsHead and neck clear cell sarcoma with no primary elsewhere were retrieved from archival/consultation files. English language literature review of all reported head and neck clear cell sarcoma was performed.ResultsThree cases were identified. The tumors, all in men, presented on the scalp of a 33‐year‐old, face of a 20‐year‐old and tongue of a 44‐year‐old. Tumors ranged from 0.6 to 1.4 cm. All had typical features of clear cell sarcoma, including nests of tumor cells divided by fibrous septae. One had multinucleated wreath‐like giant cells. One had a focal junctional component. Immunohistochemistry was positive for S100 (three out of three), HMB45 (three out of three) and Melan‐A (two out of three). All had EWSR1 rearrangements by fluorescence in situ hybridization. Follow up available for one patient revealed no evidence of disease after wide excision and radiation. Seven additional reported cases were identified and tabulated.ConclusionHead and neck clear cell sarcoma is rare but should be considered in the differential diagnosis of nested tumors with fibrous septae. Molecular analysis should be considered for definitive diagnosis regardless of location.

Background: Female soccer players have a well-known risk for anterior cruciate ligament (ACL) injury, but few studies have reported on second ACL injuries in this population. Purpose: To (1) report the rates of subsequent ACL injury (ipsilateral graft rupture or contralateral tear) in competitive female soccer players, (2) compare these rates with those of other female athletes of similar competitive level, (3) determine risk factors for second ACL injury, and (4) report clinical outcome scores in this population. Study Design: Cohort study; Level of evidence, 3. Methods: The medical records at a single institution were reviewed for female patients who were injured during a competitive athletic event and treated with primary ACL reconstruction (ACLR) between 1998 and 2013. Patients were followed for a mean of 68.8 months postoperatively (range, 24-115.2 months). Clinical outcome was obtained via Lysholm and International Knee Documentation Committee (IKDC) scores. Soccer players were matched 1:1 to non-soccer athletes for age, activity level, and graft type. Results: A total of 180 female ACLR patients with a mean ± SD age of 19.6 ± 6.9 years met the study inclusion and exclusion criteria (90 soccer players and 90 non-soccer players). Soccer players sustained more second ACL injuries, including both graft failures (11% vs 1%; P < .01) and contralateral ACL tears (17% vs 4%; P < .01), compared with non-soccer players. Of the 67 patients who returned to soccer after ACLR (mean age, 17.5 years; range, 13-27 years), significantly more had graft tears compared with those who did not return to soccer (15% vs 0%, respectively; P = .04); however, the difference in contralateral ACL tears (19% for returning players vs 9% for those who did not return; P = .34) was not significant. Relatively older age (odds ratio, 1.5 per year; P = .03) was a significant risk factor for ACL graft tear but not for contralateral ACL injury. Both groups had similar mean Lysholm (96 vs 95) and IKDC scores (95 vs 96) at final follow-up. Conclusion: Twenty-eight percent of all female soccer players and 34% of those players who returned to soccer had a second ACL tear. Soccer players had an increased rate of both graft tear and contralateral ACL injury compared with similar non-soccer athletes. Older age and return to soccer were significant risk factors for graft rupture.

BACKGROUNDHealth complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co‐occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co‐occurring RHBs.METHODSLatent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.RESULTSThree RHB clusters were identified: a low‐risk cluster, an insufficiently active cluster, and a high‐risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj], 1.17; 95% confidence interval [95% CI], 1.06‐1.27) and were less likely to be in the high‐risk cluster (ORadj, 0.79; 95% CI, 0.69‐0.88). Risk factors for membership in the high‐risk cluster included psychological distress (ORadj, 2.76; 95% CI, 1.98‐3.86), low educational attainment (ORadj, 7.49; 95% CI, 5.15‐10.88), income <$20,000 (ORadj, 2.62; 95% CI, 1.93‐3.57), being divorced/separated or widowed (ORadj, 1.36; 95% CI, 1.03‐1.79), and limb amputation (ORadj, 1.52; 95% CI, 1.03‐2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.CONCLUSIONSRHBs co‐occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747–2756. © 2016 American Cancer Society.

Purpose (1) To determine the radiographic correction/healing rate, patient‐reported outcomes, reoperation rate, and complication rate after distal femoral osteotomy (DFO) for the valgus knee with lateral compartment pathology. (2) To summarize the reported results of medial closing wedge and lateral opening wedge DFO. Methods We conducted a systematic review of PubMed, MEDLINE, and CINAHL to identify studies reporting outcomes of DFOs for the valgus knee. Keywords included “distal femoral osteotomy,” “chondral,” “cartilage,” “valgus,” “joint restoration,” “joint preservation,” “arthritis,” and “gonarthrosis.” Two authors first reviewed the articles; our study exclusion criteria were then applied, and the articles were included on the basis relevance defined by the aforementioned criteria. The Methodological Index for Nonrandomized Studies scale judged the quality of the literature. Sixteen studies were relevant to the research questions out of 191 studies identified by the original search. Results Sixteen studies were identified reporting on 372 osteotomies with mean follow‐up of 45 to 180 months. All studies reported mean radiographic correction to a near neutral mechanical axis, with 3.2% nonunion and 3.8% delayed union rates. There was a 9% complication rate and a 34% reoperation rate, of which 15% were converted to arthroplasty. There were similar results reported for medial closing wedge and lateral opening wedge techniques, with a higher conversion to arthroplasty in the medial closing wedge that was confounded by longer mean follow‐up in this group (mean follow‐up 100 v 58 months). Conclusions DFOs for the valgus knee with lateral compartment disease provide improvements in patient‐reported knee health–related quality of life at midterm follow‐up but have high rates of reoperation. No evidence exists proving better results of either the lateral opening wedge or medial closing wedge techniques. Level of Evidence Level IV, systematic review of Level IV studies.

Background. Postthoracotomy pain syndrome (PTPS) is unfortunately very common following thoracotomy and results in decreased quality of life. The purpose of this retrospective study was to determine perioperative patient, surgical, and analgesic characteristics associated with the development of PTPS. Methods. Sixty-six patients who presented to the Mayo Clinic Rochester Pain Clinic were diagnosed with PTPS 2 months or more after thoracotomy with postoperative epidural analgesia. These patients were matched with sixty-six control patients who underwent thoracotomy with postoperative epidural analgesia and were never diagnosed with PTPS. Results. Median (IQR) hospital stay was significantly different between control patients (5 days (4, 6)) compared with PTPS patients (6 days (5, 8)), P<0.02. The total opioid equivalent utilized in oral morphine equivalents in milligrams for the first three days postoperatively was significantly different between control patients and PTPS patients. The median (IQR) total opioid equivalent utilized was 237 (73, 508) for controls and 366 (116, 874) for PTPS patients (P<0.005). Conclusion. Patients with a prolonged hospital stay after thoracotomy were at an increased risk of developing PTPS, and this is a novel finding. Patients who utilize higher oral morphine equivalents for the first 3 days were also at increased risk for PTPS.

ABSTRACT Ureaplasma urealyticum and Ureaplasma parvum are pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates of Ureaplasma (202 U. parvum and 48 U. urealyticum isolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% of U. parvum and U. urealyticum isolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of ≥4 μg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations in parC , with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a single U. parvum isolate was tetracycline resistant. tet (M) was found in 10 U. parvum isolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinical Ureaplasma isolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality of Ureaplasma species in the United States.

Abstract Therapeutic monoclonal immunoglobulins (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. As pharmaceutical companies bring more fully humanized therapeutic mAb drugs to the healthcare market analytical platforms that perform therapeutic drug monitoring (TDM) without relying on mAb specific reagents will be needed. In this study we demonstrate that liquid-chromatography?mass spectrometry (LC?MS) can be used to perform TDM of mAbs in the same manner as smaller nonbiologic drugs. The assay uses commercially available reagents combined with heavy and light chain disulfide bond reduction followed by light chain analysis by microflow-LC?electrospray ionization-quadrupole-time-of-flight mass spectrometry (ESI-Q-TOF MS). Quantification is performed using the peak areas from multiply charged mAb light chain ions using an in-house developed software package developed for TDM of mAbs. The data presented here demonstrate the ability of an LC?MS assay to quantify a therapeutic mAb in a large cohort of patients in a clinical trial. The ability to quantify any mAb in serum via the reduced light chain without the need for reagents specific for each mAb demonstrates the unique capabilities of LC?MS. This fact, coupled with the ability to phenotype a patient?s polyclonal repertoire in the same analysis further shows the potential of this approach to mAb analysis.

ABSTRACT Background The clinical course of dementia with Lewy bodies patients is heterogeneous. The ability to more accurately prognosticate survival is important. Objective The objective of this study was to investigate hippocampal volume as a predictor of survival in dementia with Lewy bodies patients. Methods Survival analysis for time from onset of cognitive symptoms to death was carried out using Cox proportional hazards models. Given their age and total intracranial volume, patients were dichotomized into low/medium (0%‐66.7%) and high (66. 7%‐100%) hippocampal volume categories. The models using these categories to predict survival were adjusted for field strength, APOE ε4 status, and estimated onset age of cognitive problems. Results We investigated 167 consecutive patients with dementia with Lewy bodies. The median age at MRI was 72 years (interquartile range 67‐76), and 80% were male. The median time from estimated first cognitive symptom to death was 7.4 years (interquartile range:5.7‐10.2). Lower hippocampal volumes were significantly associated with higher risk of death (hazard ratio 1.28; 95% confidence interval 1.04‐1.58; P = .024). The predicted median survival for participants with onset of cognitive symptoms at age 68 was 10.63 years (95% confidence interval 8.66‐14.54) for APOE ε4 negative, high hippocampal volume participants; 8.89 years (95% confidence interval 7.56‐12.36) for APOE ε4 positive, high hippocampal volume participants; 8.10 years (95% confidence interval 7.34‐11.08) for APOE ε4 negative, low/medium hippocampal volume participants; and 7.38 (95% confidence interval 6.74‐9.29) years for APOE ε4 positive, low/medium hippocampal volume participants. Conclusions Among patients with clinically diagnosed dementia with Lewy bodies, those with neuroimaging evidence of hippocampal atrophy have shorter survival times. © 2016 International Parkinson and Movement Disorder Society

Abstract African American Hereditary Prostate Cancer Study (AAHPC) was developed as a national collaboration to explore the role of genetics in the causation of hereditary prostate cancer (HPC) in African American (AA) men. AAHPC is in partnership with the International Consortium for Prostate Cancer Genetics (ICPCG), which conducts collaborative studies of HPC genetics in multiplex families. As part of an ICPCG sequencing study of 539 affected individuals from 366 HPC pedigrees, we performed whole exome sequencing in 21 ICPCG AA families, of which there were 14 AAHPC affected men from 11 pedigrees. The combined ICPCG AA cohort consisted of N=26 affected members. Post-variant calling quality control (QC) was implemented using Golden Helix SVS 8 software with filters set for removal of variants with Read Depth &lt; 10, Quality Score &lt; 20, Quality Score: Read Depth Ratio &lt; 0.5, Call Rate &lt; 0.75. Variants were additionally filtered by MAF based on the NHLBI ESP650051-V2 exomes variant frequencies for the AA population using a MAF threshold of 5%. Following QC, 176/299 SNVs and 20/39 INDELs remained for further analysis. In these analyses, we focused on 13 known cancer genes (MSR1, AR, BRCA1, BRCA2, BTNL2, EPHB2, CDH1, RNASEL, ELAC2, HOXB13, CHEK2, TP53 and NBN). Three sequenced families had &gt; 1 affected members sequenced (2 or 3 per family) and the remaining 18 families had one member sequenced. Under the dominant model, our preliminary results show that no rare variants in the 13 candidate genes were found in 3/3 affecteds in two families. Rare SNVs in seven candidate genes (AR, CDH1, ELAC2, HOXB13, RNASEL, BRCA2 and EPHB2) were found in 2/3 affecteds for two families and 2/2 affecteds in one family. Several of the remaining 18 affected men (1 sequenced per pedigree) shared the same rare SNV in these candidate genes. For INDELs, rare variants in three candidate genes were found in pedigrees with ≥ 2 affecteds. Several of the remaining 18 affected men (one sequenced per pedigree) shared the same rare INDEL. Additional QC is underway to validate these variants and bioinformatic analyses are being used to predict effects of the variants in an effort to unravel the complex genetic heterogeneity of HPC in AA. Citation Format: Cheryl D. Cropp, Shannon K. McDonnell, Sumit Middha, Melissa DeRycke, Danielle M. Karyadi, Daniel Schaid, Stephen N. Thibodeau, William B. Isaacs, Elaine A. Ostrander, Janet Stanford, Kathleen A. Cooney, Joan E. Bailey-Wilson, John D. Carpten. Rare variant discovery in known cancer genes from whole-exome sequencingof African American hereditary prostate cancer families. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B40.