Citations

Abstract Introduction: Efforts to improve clear cell renal cell carcinoma (ccRCC) mortality have focused primarily on evaluating prognostic biomarkers in primary tumors in order to identify indicators of response to treatment and targets for novel therapies. To date little attention has been paid to the status of these biomarkers in the more therapeutically-relevant metastatic tumor. Thus, we evaluated concordance of expression of four key prognostic ccRCC biomarkers (BAP1, PBRM1, Ki-67 and TOPOIIa) in a large cohort of patient-matched primary ccRCC and metastatic tumors. Methods: We identified 114 patients treated surgically for ccRCC between 1990 and 2005 who had synchronous (M1) or metachronous (M0) metastases, underwent metastasectomy for at least one metastatic lesion and had archived tissue available from the primary and at least one metastatic tumor. We performed IHC on all primary and metastatic tumors for BAP1, PBRM1, Ki-67, and TOPOIIa using previously-published protocols. BAP1 and PBRM1 expression was categorized as positive or negative and Ki-67 and TOPOIIa was quantified as the number of positive cells per mm2. For BAP1 and PBRM1, we calculated the concordance between patient-matched primary and metastatic tumors as the percentage of pairs where the primary and metastatic tumor had the same designation (i.e., positive or negative). For TOPOIIa and Ki-67, we assessed concordance using Spearman correlation coefficient. Analysis of variance was used to evaluate if concordance between primary-metastatic tumor pairs for TOPOIIa and Ki-67 was associated with metastatic site, metastatic timing (M0/M1), metastatic tumor grade, metastatic tumor necrosis, and metastatic tumor sarcomatoid differentiation. Results: There were a total of 161 patient-matched metastatic tumors available for the 114 patients: 78 patients had only a single metastasis while 36 patients had two or more metastases. While sites of metastases varied, pulmonary metastases were the most common (44% of all metastases). Loss of BAP1 expression was observed in19% of the primary ccRCC and 98.6% of the tumor pairs had concordant BAP1 status between the paired primary and metastatic tumors. Loss of PBRM1 was observed in 56% of the primary ccRCC tumors and 89.3% of tumor pairs showed concordant PBRM1 status. By comparison, median expression of Ki-67 was 65.0mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.43. The difference in Ki-67 expression between primary-metastatic tumor pairs was associated with necrosis in the metastatic tumor (p=0.014). Median expression of TOPOIIa was 2.6mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.25. The difference in TOPOIIa expression between primary-metastatic tumor pairs was associated with metastatic site (p=0.0006) and metastases to the heart were significantly different than pulmonary metastases (p<0.0001). Additionally, synchronous metastases had larger differences from their patient-matched primary tumors in comparison to metachronous metastases (p=0.012), as did necrotic metastases (p=0.028). Conclusion: We observed high concordance for loss of BAP1 and PBRM1 expression between primary ccRCC and metastatic tumors in the same patient. Conversely, we noted high discordance in protein expression of Ki-67 and TOPOIIa between patient-matched primary-metastatic tumor pairs. Moreover, this discordance varied by key pathological features. Our results suggest that using the status of a biomarker in primary ccRCC as a guide for the status in metastatic tumors is not always appropriate and needs to be evaluated on a marker-by-marker basis. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, John C. Cheville, Thai H. Ho, Sue M. Harrington, Tracy Hilton, Christine Lohse, Amanda Shreders, Payal Kapur, James Brugarolas, R Houston Thompson, Bradley C. Leibovich, Eugene D. Kwon, Richard W. Joseph, Alexander S. Parker. Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 10.

Abstract Background: Mutations in BRCA1 and BRCA2 influence the molecular pathogenesis of breast cancer. However, little is known about the association between mutations, response to therapy, and prognosis. We therefore analysed these associations in triple negative breast cancer (TNBC) patients in the neoadjuvant GeparQuinto Study. Methods: The GeparQuinto study recruited 1956 patients with HER2 negative disease including a prespecified group of 671 TNBC patients with untreated breast cancer. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w), with or without bevacizumab (15 mg/kg). Here we present the analysis for both randomization arms combined. Sufficient blood was available of 482 TNBC patients. BRCA1 and BRCA2 genotyping was successful in 469 patients with available germline DNA and was conducted by SureSelect custom capture and sequencing on HiSeq 2500. Mutation status was correlated with pathological complete response rates (pCR) and disease free survival (DFS). Results: A total of 74 (15.8%) mutations in BRCA1 (n=61) and BRCA2 (n=13) were detected after initial sequencing. A pCR (ypT0/ypN0) was observed in 50% (n=37) of mutation carriers but only 31.1% (n=123) of patients without mutations (p=0.002). Similar results were observed for pCR (pT0is/pN0) (52.7% vs. 36.5%; p=0.010). pCR (ypT0/ypN0) was predictive of disease free survival (DFS) in all patients (Hazard Ratio, HR=0.23; 95%CI: 0.15-0.37; p<0.001) and in patients without BRCA mutations pCR (ypT0/ypN0) (HR= 0.20; 95%CI: 0.11-0.34; p<0.001). However in mutation carriers this effect was reduced (HR=0.48; 95%CI: 0.18 1.27; p=0.129). Conclusion: TNBC Patients with BRCA mutations showed a higher frequency of pCR than patients without BRCA mutations after treatment with epirubicin, cyclophosphamide and docetaxel (+/ bevacizumab), suggesting that BRCA mutations may influence pCR in response to treatment regimens that do not include platin chemotherapy. pCR as a surrogate marker for DFS was also confirmed in patients without BRCA mutations. In addition, the effect of pCR on prognosis seemed to be smaller among the mutation carriers, although the number of mutation carriers was too low to test for differences between mutation carriers and wildtype patients. The project has partly been funded within NIH-NIGMS U19 GM61388 and the Breast Cancer Research Foundation. Citation Format: Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm TN, Huober J, Liedtke C, Müller V, Nekljudova V, Weber K, Rack B, Rübner M, Wang L, Ingle JN, Weinshilboum RM, von Minckwitz G, Couch F. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-06.

Abstract Background: Chemotherapy-related amenorrhea (CRA) impacts quality of life and reproductive options, and may play a role in treatment decision-making for young breast cancer patients. Although age, increasing doses of alkylating agents, and tamoxifen are known to increase the risk of chemotherapy-related amenorrhea (CRA), it is difficult to predict which women will develop CRA in order to inform fertility preservation and treatment decisions. We sought to investigate whether single nucleotide polymorphisms (SNPs) that have been associated with a younger age at natural menopause and ovarian reserve in non-oncologic populations were predictive of CRA in two large German clinical trials that administered gonadotoxic chemotherapy. Methods: A total of 1322 premenopausal participants under age 50 who enrolled in SUCCESS B (a phase 3 trial of FEC-docetaxel-trastuzumab +/- gemcitabine for high risk early stage breast cancer) or SUCCESS C (a phase 3 trial of FEC-docetaxel-cyclophosphamide vs. docetaxel-cyclophosphamide that also tested the efficacy of a weight loss intervention in early stage breast cancer patients) were eligible for this study. We excluded patients who were receiving ovarian suppression. On these trials, menstrual status was self-reported as amenorrheic or not every three months after chemotherapy. Bloods were stored and patients provided consent for DNA analysis. We genotyped nine candidate SNPs in six genes (rs2002555 and rs11170547 in AMHR2, rs6166 in FSHR, rs10852344 <60kb from TNFRSF17/RUNDC2A/ GSPT1, rs12461110 in NLRP11, rs1801133 in MTHFR, rs2066470 in MTHRF, rs3810682 in BMP15, and rs615942 in COASY), and examined their association with CRA at 12-month and 24-month time points using logistic regression adjusted for age, BMI, and tamoxifen. Results: Of the 554 eligible women with SNP data and menstrual data at 12 months, 70% reported CRA; of the 458 eligible women with SNP data and menstrual data at 24 months, 69% reported CRA. The two SNPs in AMHR2 showed suggestive associations with CRA at 12 and 24 months. [Final results pending]. Conclusions: Genetic variation in AMHR2 may be associated with CRA. Additional research will be needed to validate these findings in other breast cancer survivors and to identify additional SNPs that may be associated with CRA. Together with other clinical factors, genetic variation may improve our ability to predict who will experience CRA, and may inform reproductive and treatment decision-making in cancer patients. Citation Format: Ruddy KJ, Rack B, Schwitulla J, Lambrechts D, Haeberle L, Schramm A, Trapp E, Scholz C, Beutler AS, Ginsburg E, Couch F, Partridge AH, Wang L, Weinshilboum RM, Janni W, Vachon C, Fasching P. Genetic predictors of chemotherapy-related amenorrhea. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-07.

Objective: To establish evidence-based guidelines for the use of bedside cardiac ultrasound, echocardiography, in the ICU and equivalent care sites. Methods: Grading of Recommendations, Assessment, Development and Evaluation system was used to rank the “levels” of quality of evidence into high (A), moderate (B), or low (C) and to determine the “strength” of recommendations as either strong (strength class 1) or conditional/weak (strength class 2), thus generating six “grades” of recommendations (1A–1B–1C–2A–2B–2C). Grading of Recommendations, Assessment, Development and Evaluation was used for all questions with clinically relevant outcomes. RAND Appropriateness Method, incorporating the modified Delphi technique, was used in formulating recommendations related to terminology or definitions or in those based purely on expert consensus. The process was conducted by teleconference and electronic-based discussion, following clear rules for establishing consensus and agreement/disagreement. Individual panel members provided full disclosure and were judged to be free of any commercial bias. Results: Forty-five statements were considered. Among these statements, six did not achieve agreement based on RAND appropriateness method rules (majority of at least 70%). Fifteen statements were approved as conditional recommendations (strength class 2). The rest (24 statements) were approved as strong recommendations (strength class 1). Each recommendation was also linked to its level of quality of evidence and the required level of echo expertise of the intensivist. Key recommendations, listed by category, included the use of cardiac ultrasonography to assess preload responsiveness in mechanically ventilated (1B) patients, left ventricular (LV) systolic (1C) and diastolic (2C) function, acute cor pulmonale (ACP) (1C), pulmonary hypertension (1B), symptomatic pulmonary embolism (PE) (1C), right ventricular (RV) infarct (1C), the efficacy of fluid resuscitation (1C) and inotropic therapy (2C), presence of RV dysfunction (2C) in septic shock, the reason for cardiac arrest to assist in cardiopulmonary resuscitation (1B–2C depending on rhythm), status in acute coronary syndromes (ACS) (1C), the presence of pericardial effusion (1C), cardiac tamponade (1B), valvular dysfunction (1C), endocarditis in native (2C) or mechanical valves (1B), great vessel disease and injury (2C), penetrating chest trauma (1C) and for use of contrast (1B–2C depending on indication). Finally, several recommendations were made regarding the use of bedside cardiac ultrasound in pediatric patients ranging from 1B for preload responsiveness to no recommendation for RV dysfunction. Conclusions: There was strong agreement among a large cohort of international experts regarding several class 1 recommendations for the use of bedside cardiac ultrasound, echocardiography, in the ICU. Evidence-based recommendations regarding the appropriate use of this technology are a step toward improving patient outcomes in relevant patients and guiding appropriate integration of ultrasound into critical care practice.

Background: The objective of this study was to review the outcomes of patients who underwent one-bone forearm (OBF) reconstruction. Methods: A retrospective review of patients who underwent OBF surgery between 1994 and 2014 was undertaken. Patient demographics, etiology, associated injuries, number of surgeries prior to OBF surgery, surgical details, and postoperative information were collected. A telephone interview was conducted at final follow-up, including a Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire, a 10-point scoring system used by Peterson et al, and a series of questions concerning pain and patient satisfaction. Results: There were 6 males and 2 females with a mean age of 44 years (range, 20-66 years). All patients had traumatic etiology, with 6 having open wounds and 2 having closed wounds. All patients had union with a mean follow-up of 83.6 months (range, 16-218 months). The mean pain score was 3 (range, 0-8), of which 3 were painless (score 0). The mean QuickDASH score was 39 (range, 7-75), and 4 patients had good or excellent results according to the 10-point score system used by Peterson et al. All patients were satisfied with the result. Five of 8 had complications related to soft tissues that were residual from their prior injuries and surgeries. One patient had post healing fracture requiring revision fixation and 1 had a postoperative infection requiring parenteral antibiotics. Conclusions: OBF surgery is an effective salvage procedure for complicated forearm instability, particularly after trauma. While union rates are high, complications are typically related to pain and soft tissue secondary to the previous injury and reconstructive procedures.

Background: The purpose of this study is to evaluate long-term outcomes of ligamentous repair rather than reconstruction for chronic thumb ulnar collateral ligament (UCL) injuries. Methods: Patients at least 15-years status-post repair of a chronic (greater than 6 weeks) UCL tear were contacted for clinical evaluation, radiographs, and postoperative outcome questionnaires, including the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, visual analog scale (VAS) pain scale, and study-specific questions. Twelve of 21 (57%) living patients were available for long-term, greater than 15-year follow-up (average 24.5 years, range 16.9-35.6). Results: Eighty-eight percent of patients had some degree of osteoarthritis. Increased age at the time of injury and higher DASH scores were correlated with increased grades of the thumb metacarpophalangeal osteoarthritis. Delay to treatment and VAS pain scores had no correlation with radiographic findings. Conclusions: Repair of a chronic UCL injury with available local tissue appears to be a reasonable alternative to ligament reconstruction, resulting in durable long-term outcomes despite the majority of patients progressing to osteoarthritis.

Purpose To investigate the alteration of passive stiffness in the supraspinatus muscle after double‐row (DR) and knotless transosseous‐equivalent (KL‐TOE) repair techniques, using shear wave elastography (SWE) in cadavers with rotator cuff tears. We also aimed to compare altered muscular stiffness after these repairs to that obtained from shoulders with intact rotator cuff tendon. Methods Twelve fresh‐frozen cadaveric shoulders with rotator cuff tear (tear size: small [6], medium‐large [6]) were used. Passive stiffness of 4 anatomic regions in the supraspinatus muscle was measured based on an established SWE method. Each specimen underwent DR and KL‐TOE footprint repairs at 30° glenohumeral abduction. SWE values, obtained at 0°, 10°, 20°, 30°, 60°, and 90° abduction, were assessed in 3 different conditions: preoperative (torn) and postoperative conditions with the 2 techniques. The increased ratio of SWE values after repair was compared among the 4 regions to assess stiffness distribution. In addition, SWE values were obtained on 12 shoulders with intact rotator cuff tendons as control. Results In shoulders with medium‐large‐sized tears, supraspinatus muscles showed an increased passive stiffness after rotator cuff repairs, and this was significantly observed at adducted positions. KL‐TOE repair showed uniform stiffness changes among the 4 regions of the supraspinatus muscle (mean, 189% to 218% increase after repair), whereas DR repair caused a significantly heterogeneous stiffness distribution within the muscle (mean, 187% to 319% after repair, P = .002). Although a repair‐induced increase in muscle stiffness was observed also in small‐sized tears, there were no significant differences in repaired stiffness changes between DR and KL‐TOE (mean, 127% to 138% and 127% to 130% after repairs, respectively). Shoulders with intact rotator cuff tendon showed uniform SWE values among the 4 regions of the supraspinatus muscle (mean, 38.2 to 43.0 kPa). Conclusions Passive stiffness of the supraspinatus muscle increases after rotator cuff repairs for medium‐large‐sized tears. KL‐TOE technique for the medium‐large‐sized tear provided a more uniform stiffness distribution across the repaired supraspinatus muscles compared with the DR technique. Clinical Relevance Based on this insight, investigating rotator cuff muscle stiffness changes, further studies using SWE may determine the optimal repair technique for various sizes of rotator cuff tears.

Most distal radius fractures are the result of low-energy mechanisms that can be successfully treated either non-operatively or with a variety of operative techniques if indicated. Complex distal radius fractures occur most commonly in high-energy injuries with extensive comminution or bone loss and associated soft tissue or vascular injuries. These high-energy fractures can present many challenges in reconstructing the distal radius. Effective restoration of the bony architecture requires a thorough knowledge of distal radius anatomy, understanding of the goals of treatment, versatility in surgical approaches, and familiarity with multiple fixation options.

Purpose To determine whether the amount of pain relief after preoperative intra‐articular (IA) anesthetic injection predicts clinical and functional outcomes after hip arthroscopy, especially when controlling for the presence of chondral degeneration. Methods We identified patients who underwent IA injection and subsequent hip arthroscopy for labral pathology between 2007 and 2013 performed by a single surgeon. Inclusion criteria were ultrasound‐ or fluoroscopic‐guided IA anesthetic injection performed at our institution, prospectively documented pre‐ and postinjection numerical rating scale pain scores, and minimum 1‐year follow‐up postoperatively. Patients were divided into 2 groups, those who received >50% pain relief from preoperative IA anesthetic injection and those who received ≤50% relief. Preoperative radiographs were reviewed, and degree of osteoarthritis was determined using the Tonnis classification system. Outcomes were assessed with Modified Harris Hip Score and Hip Outcome Score (HOS). Univariate and multivariate models were performed to assess whether percent pain relief correlated with outcome. Results Of the 319 arthroscopic hip surgeries performed between 2007 and 2013, 115 (37%) patients were lost to follow‐up, 16 (5%) patients did not receive an IA injection, 16 (5%) patients had an injection containing gadolinium, and 40 (13%) patients completed injections at an outside institution. Five (2%) patients were excluded for a history of ipsilateral hip surgery, and 3 (1%) for a history of contralateral hip surgery, leaving 96 hips in 96 patients. There were 71 females (74%) and 25 males (26%) with a mean age of 37.6 ± 14.0 years. Tonnis was grade 0, 1, and 2 for 26 (27%), 55 (56%), and 16 (17%) patients, respectively. Fifty‐one (53%) of the injections contained a corticosteroid. The mean pain relief after IA injection was 73% ± 36% (range, 0% to 100%). Twenty‐six hips (26%) had ≤50% pain relief, whereas 70 (73%) had >50% pain relief, and the median time interval from injection to surgery was 3 (range, <1 to 20) months. Outcome scores were obtained at a mean 14.8 (range, 11 to 30) months after arthroscopic surgery. Postoperative mean Modified Harris Hip Score, HOS activities of daily living, and HOS‐Sport scores were 79.2 ± 17.3, 82.6 ± 17.3, and 67.4 ± 28.2, respectively. There was no statistical correlation between percent pain relief and outcome. There was no significant difference in outcome scores between those with ≤50% and >50% pain relief. Multivariate regression analysis showed no significant predictors of outcome, including age, gender, Tonnis grade, percent relief with IA injection, or type of surgery. Conclusions In this study of patients undergoing hip arthroscopy for labral pathology, our data indicate that the amount of pain relief from IA injection may be a poor predictor of short‐term outcome, even when adjusting for chondral degeneration. Although anesthetic injections can be an important diagnostic tool in select patients, a combination of the clinical history, physical examination, and imaging findings is fundamental. Level of Evidence Level IV, therapeutic case series.

Most vertebrates, including cartilaginous fishes, maintain their plasma SO42−concentration ([SO42−]) within a narrow range of 0.2–1 mM. As seawater has a [SO42−] about 40 times higher than that of the plasma, SO42−excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO42−via the kidney. However, little is known about the underlying mechanisms for SO42−transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish ( Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO42−transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO42−transporter, while cmSlc26a6 is an apically located, electrogenic Cl−/SO42−exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO42−was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO42−by the kidney of elephant fish. Possible mechanisms for SO42−secretion in the PII segment are discussed.