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In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates how different data sources can contribute to and assist phase I trial designs. Single-drug and drug combination toxicity and pharmacokinetic data were primarily reviewed from several databases. We focused on the MTD, dose-limiting toxicity (DLT), toxicity, and pharmacokinetic profiles. To demonstrate the feasibility and utility of these data sources in improving trial designs, phase I studies reported in ClincalTrials.gov from January 1, 2018 to December 31, 2018 were used as examples. We evaluated whether and how these studies could have been designed differently given toxicity and pharmacokinetic data. None of the existing pharmacokinetic and toxicity databases contain either MTD or DLT. Among 268 candidate trials, four drug combinations were studied in other phase I trials before 2018; 185 combinations had complete or partial information on drug interactions or overlapping toxicity, and 79 combinations did not have available information. Two drug combination trials were selected as case studies. The nivolumab-axitinib trial could have been designed as a dose deescalating study, and the vinorelbine-trastuzumab emtansine trial could have been designed with a lower dose of either drug. Public data sources contain significant knowledge of the drug combination phase I trial design. Some important data (MTD and DLT) are not available in existing databases but in the literature. Some phase I studies could have been designed more efficiently with additional preliminary data. Significance: Prior preclinical and clinical knowledge is critical for designing effective and efficient cancer drug combinatory trials. We reported results on the feasibility and utility of different informatics resources for contributing to and assisting phase I trial designs based on our designed classification approach. We also found that public data sources contained significant knowledge for drug combination phase I trial design, but some critical data elements (MTD and DLT) were missing.

Background Despite immunotherapy’s promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this study, we explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in advanced sarcoma outcomes. Methods Patients in The Ohio State University Sarcoma Clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single-agent ICI or ICI + combination) along with clinical covariates. ICI + combination was further categorized into ICI + medication, ICI + radiation, ICI + surgery, or ICI + multiple (more than 2 modalities). Statistical analysis included log-rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). Results Of the patients in the database, 135 met inclusion criteria. We demonstrated improved OS in patients treated with ICI + combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Patients with a documented immune-related adverse event (irAE) of dermatitis had improved OS, but only in the ICI + combination cohort (p = 0.021). Patients who received single-agent ICI and whose change in the neutrophil-to-lymphocyte ratio (NLR) was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI + combination therapy (p = 0.441). There were no differences in OS based on age, gender, histology, or subcategories of ICI + combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036) compared with their older counterparts in this dataset. Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048), or dermatitis (p = 0.003), had an improved PFS. There were no differences in PFS based on ICI regimen (or subcategories of ICI + combination), gender, histology, change in NLR, or grade of irAE. Conclusions This retrospective study demonstrates that ICI + combination therapy can improve OS in some patients with advanced sarcoma. This is consistent with our prior results of ICI in sarcoma.

Supporting Information S2 provides classification results offor cancer drug combination phase I clinical trials in clinicaltrials.gov (01 January through 31 December 2018)using the designed approach in the paper.

In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates how different data sources can contribute to and assist phase I trial designs. Single-drug and drug combination toxicity and pharmacokinetic data were primarily reviewed from several databases. We focused on the MTD, dose-limiting toxicity (DLT), toxicity, and pharmacokinetic profiles. To demonstrate the feasibility and utility of these data sources in improving trial designs, phase I studies reported in ClincalTrials.gov from January 1, 2018 to December 31, 2018 were used as examples. We evaluated whether and how these studies could have been designed differently given toxicity and pharmacokinetic data. None of the existing pharmacokinetic and toxicity databases contain either MTD or DLT. Among 268 candidate trials, four drug combinations were studied in other phase I trials before 2018; 185 combinations had complete or partial information on drug interactions or overlapping toxicity, and 79 combinations did not have available information. Two drug combination trials were selected as case studies. The nivolumab-axitinib trial could have been designed as a dose deescalating study, and the vinorelbine-trastuzumab emtansine trial could have been designed with a lower dose of either drug. Public data sources contain significant knowledge of the drug combination phase I trial design. Some important data (MTD and DLT) are not available in existing databases but in the literature. Some phase I studies could have been designed more efficiently with additional preliminary data.Significance:Prior preclinical and clinical knowledge is critical for designing effective and efficient cancer drug combinatory trials. We reported results on the feasibility and utility of different informatics resources for contributing to and assisting phase I trial designs based on our designed classification approach. We also found that public data sources contained significant knowledge for drug combination phase I trial design, but some critical data elements (MTD and DLT) were missing.

HEYA8 gene signature enrichment.

PURPOSE: Treatment-related adverse events associated with systemic anticancer therapy (SACT) can deter patients with sarcoma from completing treatment. With self-monitoring, patients may be better empowered to self-advocate for improved symptom management. We hypothesized that by incorporating journaling, a structured form of self-monitoring, care team communication, and symptom management would improve. We thus designed a prospective randomized trial exploring journaling as a therapeutic adjuvant for symptom management ( NCT03258892 ). METHODS: Participants with sarcoma initiating SACT were randomly assigned to receive either a symptom management journal at the start of SACT or after completing two cycles of SACT. Symptom journals were designed jointly by a cancer patient focus group and by education experts. Journals were reviewed with clinical staff at each visit. Participant responses were obtained through questionnaires. Patient call volume was obtained through the electronic health record. RESULTS: Of 64 participants consented for the trial, 53 were evaluable for analysis. Fifty-five percent of participants reported that the journal was at least moderately useful. These participants were more likely to report improved communication scores ( P = .027), symptom management ( P = .011), and quality of life (QOL) ( P = .019). Participants who received the journal early were less likely to report a decrease in QOL as compared with the late journal group ( P = .757 v P = .035). CONCLUSION: To our knowledge, this is the first prospective randomized trial evaluating the use of structured journaling as a low-cost means to improve treatment-related adverse event management and QOL in patients with sarcoma undergoing SACT. These promising results will need to be confirmed by additional studies.

PDF file, 315KB, Supplemental Figure 1: Validation of differential Meis1 and Meis2 expression between Prostate and Seminal Vesicle Epithelial Cells. Supplemental Figure 2: Gene expression profiles from 181 prostatectomy specimens of patients (Taylor dataset) using the PAM (Prediction Analysis for Microarrays) algorithm to stratify patients into two groups based on changes in expression of Meis1, Meis2, Pbx1, HoxA9, HoxB7. Supplemental Figure 3: Meis biomodule network analysis. Supplemental Methods: qPCR Analyses of Meis1 and Meis2. Supplemental Table 1: Historical datasets used in the analyses. Supplemental Table 2: Prostate epithelial cell (PrEC) versus seminal epithelial cell (SVEC) culture differentially expressed genes. Supplemental Table 3: Functional Annotation of the Prostate versus Seminal Vesicle Epithelium Signature. Supplementary Table 4: Univariate and Multivariate Cox Regression.

Purpose: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare.Experimental Design: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets.Results: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors.Conclusion: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. Clin Cancer Res; 18(16); 4291–302. ©2012 AACR.

Supplementary Table S1. Detailed information about patients (A) and control group (B)used in the discovery set; Supplementary Table S2. Detailed information about patients (A) and control group (B) used in the validation set; Supplementary Table S3. Detailed information about cancer tissue (A) and normal adjacent tissue (B) analyzed; Supplementary Table S4. Detailed information about additional patients whose tissues have been analyzed by immunohistochemistry (not previously reported); Supplementary Figure S1. Peripheral blood-derived EVs characterization (Nanosight); Supplementary Figure S2. LPS- secreted EVs characterization (Nanosight); Supplementary Figure S3. Expression levels of miR-25-3p and miR-92a-3p in EVs and LPS tissues; Supplementary Figure S4. Western blot analysis for phospho-p65; Supplementary Figure S5. miR-25-3p and miR-92a-3p stimulate the secretion of TNFα from macrophages

Despite the development of combined modality treatments against liposarcoma in recent years, a significant proportion of patients respond only modestly to such approaches, possibly contributing to local or distant recurrence. Early detection of recurrent or metastatic disease could improve patient prognosis by triggering earlier clinical intervention. However, useful biomarkers for such purposes are lacking. Using both patient plasma samples and cell lines, we demonstrate here that miR-25-3p and miR-92a-3p are secreted by liposarcoma cells through extracellular vesicles and may be useful as potential biomarkers of disease. Both miR-25-3p and miR-92a-3p stimulated secretion of proinflammatory cytokine IL6 from tumor-associated macrophages in a TLR7/8-dependent manner, which in turn promoted liposarcoma cell proliferation, invasion, and metastasis via this interaction with the surrounding microenvironment. Our findings provide novel and previously unreported insight into liposarcoma progression, identifying communication between liposarcoma cells and their microenvironment as a process critically involved in liposarcoma progression. This study establishes the possibility that the pattern of circulating miRNAs may identify recurrence prior to radiological detectability while providing insight into disease outcome and as a possible approach to monitor treatment efficacy. Cancer Res; 77(14); 3846–56. ©2017 AACR.

Pathology of the long head of the biceps tendon is a known cause of anterior shoulder pain. Current surgical management options include tenotomy and tenodesis. Tenodesis can be performed arthroscopically or as an open procedure. Arthroscopic tenodesis typically uses a suprapectoral attachment, which may fail to address tendon pathology in the bicipital groove. Open tenodesis carries iatrogenic risk to neurovascular structures and a fracture risk while drilling, as well as the morbidity of an open procedure. This technique paper describes a mini-open subpectoral approach using a suture anchor and bone bridge backup for dual fixation. Use of a suture anchor instead of an interference screw reduces drill hole diameter reducing the risk of iatrogenic humeral fracture. Dual fixation provides a robust repair which may be of use for athletic patients desiring an accelerated recovery., Technique Video Video 1 Mini-open subpectoral biceps tenodesis using a suture anchor with a bone-bridge backup. The patient is positioned in a beach-chair position for the right shoulder for posterior portal visualization. The biceps anchor shows significant fraying at the superior labrum. The biceps tendon has avulsed from the anchor and is adhered to the anterior capsule of the glenohumeral joint. Through an anterior portal, a shaver is introduced to debride the superior labrum and any adhesions holding the biceps tendon to the anterior capsule. An incision is made at the anterior axillary space at the inferior border of the pectoralis major. While retracting the pectoralis major tendon superiorly, the long head of the biceps tendon (LHBT) can be palpated within the bicipital groove. After releasing the LHBT from the groove with electrocautery, the tendon is whipstitched with a FiberLink suture. The inferior bicipital groove is prepared with electrocautery and a Cobb elevator, and a 5.5-mm reamer is drilled unicortically at the approximated location of the tenodesis. Proximally, a 2.4-mm drill is used to create the bone bridge hole 5 mm superior to the tenodesis hole. The LHBT is sized using with a sizer on the 5.5-mm SwiveLock Anchor, the tails of the suture are loaded into the anchor. One tail is passed from the distal to proximal hole and the other tail is passed from the proximal to distal hole using a suture passing flag or nitinol micro suture lasso. With tension on the suture tails, the SwiveLock anchor is inserted and placed into tenodesis hole. Using a free needle, the suture tails are passed through the LHBT multiple times and are tied down, securing the tendon onto the tenodesis site.

Posterior shoulder instability occurs when the labrum detaches posteriorly from the glenoid owing to significant trauma and is a relatively uncommon type of shoulder dislocation. Although posterior instability has often been treated with open shoulder stabilization, modern arthroscopic procedures are being rapidly pursued by surgeons as an improved option because of decreased invasiveness and reduced operative times. Arthroscopic stabilization of the posterior glenoid labrum typically involves 2 working portals, but the procedure still yields successful results when performed with a single posterior portal and a suture passer. Our technique involves 1 less portal to reduce invasiveness, lower the risk of nerve damage, and decrease the operative time and postoperative pain. The purpose of this article is to describe an arthroscopic posterior stabilization technique with a single working portal., Technique Video Video 1 Single-portal arthroscopic posterior shoulder stabilization. The patient is in the lateral decubitus position for treatment of the left shoulder. A stab incision using a No. 11 blade creates a posterior portal for initial posterior visualization. Diagnostic arthroscopy looking from posterior to anterior shows a tear of the posterior labrum. The site for the anterior portal is located using a spinal needle. An 8.25-mm cannula is inserted posteriorly with the aid of a switching stick before the arthroscope is moved to the anterior portal for further visualization. A bite of the posterior capsule and healthy labral tissue is taken using a loaded suture passer. After unreeling of the No. 0 polydioxanone sulfate monofilament suture, No. 2 FiberWire is shuttled to create a racking-hitch suture knot. A pilot hole is drilled using an Arthrex drill guide, and a 2.9-mm PushLock suture anchor loaded with SutureTape is impacted into the pilot hole to stabilize the posterior labrum. A suture cutter is used to cut the residual suture. The process is repeated in another position to sufficiently reduce the posterior labrum.

The osteochondral autograft transfer system (OATS) procedure is at the forefront of cartilage restoration surgeries of the knee, offering superior return to sport rates and long-term functionality. This technique reports an arthroscopic OATS procedure of the lateral femoral condyle with donor-site backfill using an osteochondral allograft plug. Potential complications from unfilled donor site sockets are eliminated through donor site backfill with an allograft plug., Technique Video Video 1 Arthroscopic osteochondral autograft transfer system (OATS) procedure of the lateral femoral condyle using allograft donor site backfill. The Arthrex Single-Use 2.0 OATS set for articular cartilage transfer and graft harvest of 10 mm osteochondral defects is our primary surgical instrument. The anterolateral portal of the operative knee is needle localized with an 18 gauge spinal needle perpendicular to the osteochondral defect of the lateral femoral condyle. A 10 × 15 mm autograft plug is then harvested from the medial trochlear edge of the medial femoral condyle donor site under direct arthroscopic visualization. Two 90˚ turns, clockwise and counterclockwise, are performed with the harvester before disengagement and autograft harvest withdrawal. The hollowed donor site of the medial femoral condyle is then backfilled with a precut osteochondral allograft plug and flushed adequately into the articular surface. After backfill insertion with the allograft plug, a guide pin is drilled perpendicular into the osteochondral defect of the lateral femoral condyle. A cannulated reamer, perpendicular and in line with the guide pin, is used to advance to the appropriate depth within the subchondral bone of the osteochondral defect. The harvested autograft plug from the medial femoral condyle donor site is then impacted into the hollowed recipient site with a clear cannula and implanted within 1 to 1.5 mm of the articular surface. Last, a soft tamp is used to firmly advance the donor plug until a flush chondral surface is observed.

Revision anterior cruciate ligament reconstruction (R-ACLR) has become more common as the number of failed primary ACLRs increase. Although increasingly common, R-ACLR has a greater failure rate than a primary reconstruction. Technical errors, particularly in tunnel placement, account for a large proportion of graft failure in R-ACLR as well as re-revision cases. Tunnel placement and trajectory is particularly important in R-ACLR and becomes more challenging with each additional revision attempt. This is in part because any tunnels created for revision may converge with formerly drilled tunnels or face interference hardware creating, complicating proper graft fixation. While there are many approaches to revision ACL surgery, our technique describes a simple, tibial tunnel-first graft-sizing method initially reaming tunnels with very small diameters and sequentially working your way up to more anatomic diameters., Technique Video Video 1 Revision anterior cruciate ligament (ACL) reconstruction using the tibial tunnel sizing technique. Diagnostic arthroscopy showing few fibers of the remnant ACL. An electrocautery wand is used to clean the back wall. The lateral femoral condyle notch is clear. The tibial tunnel sizing technique is accomplished by firing a guide pin using a tip aiming guide to confirm a good guide pin trajectory for the new tibial tunnel. Once the position and trajectory of the pin is satisfactory, the smallest reamer available, size 6-mm reamer, is used to ream the new tibial tunnel. An arthroscope is then used to confirm a sufficient bony wall throughout the tibial tunnel before proceeding. The next size up reamer, a size 7-mm reamer, is reinserted into the same tibial tunnel that is created using the size 6-mm reamer and is positioned using a straight clamp from the anteromedial portal. This process is repeated until the size 10-mm reamer is inserted while each time looking up the tibial tunnel to confirm a sufficient bony circumferential wall. At the graft preparation station, the Achilles tendon is cut down to a size 10, loaded on the TightRope (Arthrex), and confirmed with a sizing block. The TightRope button with Achilles allograft is passed up the femoral socket and flipped in the cortex. The Achilles allograft is cinched up, the FastThread Biocomposite Interference Screw (Arthrex) is used, and graft is probed to check for proper tension. The graft is retensioned and then a final check is completed.

Numerous techniques exist for arthroscopic subscapularis repair with varying degrees of complexity based on tear morphology, all of which have established satisfactory outcomes in function and patient satisfaction. Arthroscopic subscapularis repair can require several working portals and suture anchors, increasing both technical complexity and operative time. This Technical Note describes an arthroscopic repair of a superior one-third subscapularis tear using a self-punching knotless soft suture anchor through a single anterior working portal. Thus, we offer a unique approach to arthroscopic repair of superior one-third subscapularis tears that is time-saving, reproducible, and highly efficient while minimizing iatrogenic damage and postoperative complications., Technique Video Video 1 Arthroscopic single-portal and single-anchor superior third subscapularis repair. Patient is positioned in the right lateral decubitus position, and the left shoulder is visualized through the posterior portal. A superior third subscapularis tear is visualized, and the subscapularis is properly debrided prior to repair. Through a single anterior portal, a knotless 2.6-mm Fibertak Soft anchor with a self-punching mechanism from Arthrex is used to pierce the subscapularis tendon 1 cm proximal to the lateral edge of the tear. The anchor is malletted into the lesser tuberosity of the humerus to the laser line, while maintaining proper length-tension relationship of the subscapularis. The self-punching mechanism is removed, leaving three suture tails (1 blue and 2 black) through the cannula. The self-bunching mechanism of the anchor is deployed by pulling firmly on the blue suture anchor. A grasper is used to retrieve the blue no. 5 FiberWire suture around the subscapularis and through the anterior cannula. The surgeon then passes the tail of the blue no. 5 FiberWire suture through the shuttling loop of black suture. The nonlooped end of the black shuttling suture is gently pulled, guiding the blue no. 5 FiberWire suture through the subscapularis tendon and the soft suture anchor and back out of the anterior cannula. Through direct visualization, the surgeon is able to apply tension to the repair suture as necessary. Once the surgeon has applied appropriate tension to the repair, excess suture is removed with a suture cutter.

Sarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

Anterior shoulder pathology involving the subscapularis is often associated with the biceps tendon because both anatomic structures intersect the lesser tuberosity. Standard procedures for such pathology often involve simultaneous subscapularis repairs and biceps tenodesis. Single anterior portal subscapularis repairs have been emerging in the past 5 years because of cost-effectiveness and efficiency. Biceps tenodesis is a common procedure performed both open and arthroscopically. This technique takes advantage of the close relation between the long head of the biceps tendon and subscapularis tendon to restore the functional length-tension relation and preserve function through fixation using a single portal and a single knotless suture anchor., Technique Video Video 1 Arthroscopic single portal and single anchor subscapularis repair and biceps tenodesis. Patient is in the lateral position for the left shoulder with posterior portal visualization. Biceps has a lipstick sign and shows inflammation. Through a single anterior portal, a grasper is used to create a hitch knot, and the BirdBeak grasper is used to pierce the long head of the biceps tendon and retrieve the No. 2 FiberWire. The construct is now a luggage tag racking suture around the biceps tendon to create the Loop ‘N’ Tack. A wand is used to anatomize the biceps off of the biceps-labral junction. For the upper one-third subscapularis tear, a Scorpion is used to fire in a FiberWire and create a luggage tag racking hitch suture. The first suture is used to pull traction to allow for a larger bite of the upper one-third subscapularis. Then a second luggage tag is made using the Scorpion. A 4.75-mm SwiveLock punch was used to punch a hole at the lesser tuberosity footprint. All 3 pairs of the FiberWire tails are loaded onto the SwiveLock suture anchor. The SwiveLock is gently malleted in until it engages the bone, after which the anchor is advanced by turning the inserter in a clockwise direction. After making sure that the anchor is flush to the cortex, a suture cutter is used to cut the excess suture.

Several factors affect the success of an anterior cruciate ligament reconstruction, including graft origin, type, and morphology. Hamstring and bone–patellar tendon–bone autografts are the most widely used, and there are many different techniques of graft preparation with each. In this Technical Note and accompanying video, a 4-strand hamstring autograft technique is described that uses a simple diamond-type braid to produce a more ovoid morphology with increased cross-sectional area. Increased graft diameters have been associated with higher success rates and more positive long-term outcomes. Therefore, this braiding construct may provide additional tensile strength with increased resistance to failure than grafts that are otherwise undersized using conventional techniques., Technique Video Video 1 Right 4-strand diamond braiding technique for hamstring autograft in anterior cruciate ligament reconstruction. Autograft hamstring gracilis and semitendinosus tendons were harvested. At the graft preparation station, the muscles were removed from the tendons. Both ends of the tendons were whipstitched, and then both strands of the hamstring were loaded onto the tightrope. The final length was measured to be 100 mm, and the diameter was sized to be 6.5 mm. A 0-Vicryl suture (Arthrex) was used to secure one end so the strands did not move or shift. Strand 1 was passed under strands 2 and 3 and then passed back over strand 3. After each braid, the strands were pulled taut. The steps were repeated for strand 4 by passing it under strands 1 and 3 and then back over strand 1. An additional suture was put halfway down the graft to keep the braid tensioned. The braid was continued to the end of the graft, and then a suture was put at the end. The length was measured to be 90 mm, and the diameter was measured to be 8 mm. Then the graft was passed arthroscopically and the button flipped in the cortex. The graft was then dunked into the socket and the tension was checked with the probe. The graft was retensioned and then a final check was done.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Background and objectives Caval leiomyosarcomas (cLMS) are rare soft tissue sarcomas historically associated with high recurrence rates and poor prognosis. While radical resection remains the mainstay of therapy for cLMS, new systemic therapies have presented opportunities for multimodality treatment. We examined the clinical outcomes of patients with cLMS treated with modern, multimodality approaches, and compared their outcomes to those of patients with noncaval retroperitoneal LMS (ncLMS). Methods A retrospective, single-institution review identified all patients diagnosed with primary retroperitoneal LMS from 2012 to 2018. Radiographic and pathologic review distinguished patients with cLMS and ncLMS. Standard clinicopathologic variables and response to chemotherapy (when applicable) were analyzed. Primary endpoints were overall (OS) and progression-free survival (PFS). Results Eleven patients with cLMS were identified. Median tumor size was 7.5 cm (IQR, 5.0-14.3 cm); all patients had Stage II/III disease. Seven patients received neoadjuvant chemotherapy. Nine cLMS patients underwent R0/R1 resection; two did not complete resection. Six patients received adjuvant systemic therapy. Twenty patients with ncLMS were treated during the same period. No statistical intergroup differences were noted in tumor size, pathologic grade, stage, or resection margin status. Patients with ncLMS were less likely to receive neoadjuvant (10% vs. 64%) and adjuvant chemotherapy (30% vs. 55%). Two-year OS (81% vs. 78%; p = NS) and PFS (55% vs. 46%; p = NS) were comparable between cLMS and ncLMS patients. Conclusions Multimodality treatment with systemic therapy and aggressive surgical resection may achieve equivalent survival outcomes for patients with cLMS versus similar ncLMS. We recommend that all patients with cLMS be evaluated for multidisciplinary treatment. Genomic and proteomic expression profiling may identify novel or targetable mutations.

Total shoulder arthroplasty (TSA) has evolved over the years and is used for a variety of indications, with arthritis being the most common. Stemless TSA is a unique bone-preserving design that can eliminate rotational malalignment. Additionally, recent literature has found utility in the use of biological mesh and a platelet-rich plasma injection to improve healing. The purpose of this article is to outline the process of TSA using a stemless system and how to incorporate the use of amnion matrix and platelet-rich plasma into the surgical technique., Technique Video Video 1 Surgical technique for stemless total shoulder replacement using Arthrex Eclipse system. A radiograph shows that the patient has glenohumeral arthritis, with small inferior osteophytes and bone spurring (bone-on-bone arthritis). Magnetic resonance imaging shows complete cartilage loss, cystic changes in the glenoid, and deformation of the humeral head. The patient is placed in the beach-chair position; a standard deltopectoral incision is made; and blunt dissection is performed through the deltopectoral interval, with care taken to avoid the cephalic vein. Once the interval is achieved, a deep Kolbel retractor is used. The biceps tendon and subscapularis are palpated. Tagging sutures are placed through the subscapularis, and the subscapularis is taken down with Bovie cautery (Bovie Medical, Clearwater, FL). The joint is then entered; the large inferior osteophytes can be seen, with complete loss of cartilage on the humeral head. A rongeur is used to excise the osteophytes so that the native contour of the ball can be achieved. Once this is achieved, the surgeon performs a freehand cut of the anatomic head to remove the ball. The cut is made anatomically without the use of a jig because the articular margin can be seen. The sliced humeral head is then taken to the back table. The next step is preparation of the trunnion. A trunnion coring template of the appropriate size is used; the coring guide is then impacted, which creates the exact spot where the trunnion will be implanted later. The coring guide and coring template are removed, and the circle can be observed. A protective cap is then placed on the head, turn my attention to the glenoid. Standard glenoid preparation is performed in which a pin is fired through a guide. A semicircular reamer is used to denude the cartilage. A central reamed hole is then created, followed by reaming of the keel. Cementation and impaction are performed in the glenoid. The humeral head is then sized; as shown, an exact match is desired. The surgeon returns to the humeral head and puts down the coring template; a pin is used to measure the depth of the trunnion. The trunnion is impacted and screwed in. Now that the trunnion is down, impaction is performed in the humeral head. Copious irrigation is administered, the rotator cuff interval is closed, and the subscapularis is repaired in a side-to-side fashion with FiberWire sutures. An amnion matrix is then sewn in; this helps with the closure and healing of the subscapularis. The weakest point of this surgical procedure is taking down the subscapularis; therefore, a robust repair with FiberWire plus an orthobiologic (i.e., amnion matrix) to augment healing is useful. The amnion orthobiologic is shown. Platelet-rich plasma is then injected into the joint. The deltopectoral interval is reapproximated, and the subcutaneous tissue and skin are closed. The final radiograph shows anatomic placement of a stemless shoulder replacement using the Eclipse system.

Acromioclavicular joint separations are common shoulder injuries, yet standard treatment practices vary. Popular surgical techniques include reconstruction using allografts or neighboring ligaments as well as repair using screws and sutures. This Technical Note and accompanying video describe both an acromioclavicular and coracoclavicular joint reconstruction using an allograft to replace native acromioclavicular ligament along with an AC joint reduction using a Suture Cerclage System to precisely control reduction and restore anatomic alignment., Technique Video Video 1 Right combined acromioclavicular and coracoclavicular joint reconstruction with allograft using a cerclage tensioning system. Preoperative radiographs of the right shoulder in the anteroposterior view confirm a type V acromioclavicular joint separation. A curved AC Joint Graft Passing Instrument (Arthrex) shuttles a nitinol wire around the coracoid. The nitinol wire is then used to pass a #2 FiberWire suture around the coracoid. Electrocautery is used to mark the anatomic positions of the conoid and trapezoid coracoclavicular ligaments. A drill is used to create bone tunnels at these anatomic positions on the right clavicle. Nitinol wires are used to shuttle one #2 FiberWire suture tail through each bone tunnel whilst it remains passed under the coracoid. The Suture Cerclage System is opened on the back table and the FiberTape Cerclage Suture is unwound. The FiberTape Cerclage Suture is then passed through the conoid drill hole, under the coracoid, and out of the trapezoid drill hole. This suture tail is passed through the FiberTape Cerclage System Card (Arthrex) and the card is discarded. A guide pen is drilled into the right distal clavicle and acromion and reamed with a 4-mm reamer to create bone tunnels. The allograft is passed through the bone tunnels. The ends of the FiberTape Cerclage Suture are trimmed and then placed through the roller adjacent to the handle of the FiberTape Cerclage Tensioner. The FiberTape Cerclage Tensioner is then dialed in to 80 lbs of tension on the coracoclavicular joint reconstruction construct to reduce the acromioclavicular joint. The allograft is tied down over the acromioclavicular joint and #2 FiberWire Sutures are passed to secure the tied graft. Final fluoroscopic imaging confirms the anatomic reduction of the right acromioclavicular and coracoclavicular joint reconstruction.

PURPOSE Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP. METHODS A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure. RESULTS CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; P = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival. CONCLUSION To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.

Background Sarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear. Methods Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study. Results Partial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS. Conclusions This study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

PURPOSE The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) requires eligible clinicians to report clinical quality measures (CQMs) in the Merit-Based Incentive Payment System (MIPS) to maximize reimbursement. To determine whether structured data in electronic health records (EHRs) were adequate to report MIPS CQMs, EHR data aggregated by ASCO's CancerLinQ platform were analyzed. MATERIALS AND METHODS Using the CancerLinQ health technology platform, 19 Oncology MIPS (oMIPS) CQMs were evaluated to determine the presence of data elements (DEs) necessary to satisfy each CQM and the DE percent population with patient data (fill rates). At the time of this analysis, the CancerLinQ network comprised 63 active practices, representing eight different EHR vendors and containing records for more than 1.63 million unique patients with one or more malignant neoplasms (1.73 million cancer cases). RESULTS Fill rates for the 63 oMIPS-associated DEs varied widely among the practices. The average site had at least one filled DE for 52% of the DEs. Only 35% of the DEs were populated for at least one patient record in 95% of the practices. However, the average DE fill rate of all practices was 23%. No data were found at any practice for 22% of the DEs. Since any oMIPS CQM with an unpopulated DE component resulted in an inability to compute the measure, only two (10.5%) of the 19 oMIPS CQMs were computable for more than 1% of the patients. CONCLUSION Although EHR systems had relatively high DE fill rates for some DEs, underfilling and inconsistency of DEs in EHRs render automated oncology MIPS CQM calculations impractical.

Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.

Combined anterior cruciate ligament and posterior cruciate ligament tibial avulsion fractures are rare knee injuries that are primarily seen in adults. Prompt surgical intervention is indicated for displaced fractures to restore knee stability. Arthroscopic techniques are now the preferred method for treating anterior tibial spine avulsion fractures with posterior cruciate ligament tibial avulsion fractures being treated arthroscopically or with open reduction and internal fixation methods. This Technical Note and accompanying video demonstrate an arthroscopically assisted repair of bicruciate tibial avulsion fractures using an arthroscopic lever push technique. Two sutures are passed through the anterior cruciate ligament and pulled down through two bone tunnels placed within the tibial fracture bed, and one suture is passed around the posterior cruciate ligament and pulled down through one bone tunnel passing from the anterior tibia to the tibial fracture bed. Our technique is simple and effective in reducing bicruciate tibial avulsion fractures to anatomic position.

PURPOSESoft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma.MATERIALS AND METHODSThis review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data.RESULTSDespite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A.CONCLUSIONCDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma.

Acromioclavicular joint separation is a common shoulder injury. Grade I and II separation may be treated nonoperatively, whereas higher grades tend to require surgical intervention. Various repair techniques have been described in the literature, with no consensus on the gold standard. This Technical Note describes our use of a graft-passing instrument to pass suture under the coracoid during an anatomic reconstruction of both the acromioclavicular and coracoclavicular ligaments. Although this approach is technically challenging, it avoids coracoid drilling and requires smaller-diameter clavicle and acromion drilling. Furthermore, using suture instead of graft material increases the cost-effectiveness of the procedure., Technique Video Video 1 Anchorless acromioclavicular (AC) and coracoclavicular ligament repair using graft-passing instrument to pass suture under coracoid. The radiographic image shows a type V AC joint separation. The patient is positioned in the beach-chair position, and the superior border of the clavicle and AC joint is exposed with careful dissection. Electrocautery is used to mark the approximate locations of the conoid and trapezoid ligaments, which are 4.5 cm and 3 cm proximal to the distal end of the clavicle, respectively. A No. 2 FiberWire is fed into the AC joint Coracoid Graft Passing Instrument (GPI), and knots are tied to prevent the FiberWire from retracting back through the GPI. The FiberWire is passed under the coracoid with the GPI, and the FiberWire acts as a shuttling suture. Four strands of No. 5 FiberTape are shuttled under the coracoid with the No. 2 FiberWire. After marking of the native attachment points of the conoid and trapezoid ligaments with electrocautery, a 2.4-mm pin is used to drill in a bicortical manner through these locations. A No. 2 FiberWire is fed through the trapezoid drill hole and is used to shuttle 2 tails of the No. 5 FiberTape through the clavicle. These steps are repeated for the opposite 2 ends of the No. 5 FiberTape through the conoid drill hole. With the application of a strong downward force on the clavicle with a bone tamp, the 4 suture tails passing through the clavicle are tied down to secure the reduction. A 2.4-mm pin is used to drill in a bicortical manner through the acromion and the distal clavicle, and the remaining 2 strands of No. 5 FiberTape currently under the coracoid are shuttled through the drill holes. Anterior-posterior stability is restored once the FiberTape is tied down, completing the AC joint repair.

Objectives Electronic health records (EHRs) contain a large quantity of machine-readable data. However, institutions choose different EHR vendors, and the same product may be implemented differently at different sites. Our goal was to quantify the interoperability of real-world EHR implementations with respect to clinically relevant structured data. Materials and Methods We analyzed de-identified and aggregated data from 68 oncology sites that implemented 1 of 5 EHR vendor products. Using 6 medications and 6 laboratory tests for which well-accepted standards exist, we calculated inter- and intra-EHR vendor interoperability scores. Results The mean intra-EHR vendor interoperability score was 0.68 as compared to a mean of 0.22 for inter-system interoperability, when weighted by number of systems of each type, and 0.57 and 0.20 when not weighting by number of systems of each type. Discussion In contrast to data elements required for successful billing, clinically relevant data elements are rarely standardized, even though applicable standards exist. We chose a representative sample of laboratory tests and medications for oncology practices, but our set of data elements should be seen as an example, rather than a definitive list. Conclusions We defined and demonstrated a quantitative measure of interoperability between site EHR systems and within/between implemented vendor systems. Two sites that share the same vendor are, on average, more interoperable. However, even for implementation of the same EHR product, interoperability is not guaranteed. Our results can inform institutional EHR selection, analysis, and optimization for interoperability.

Arthroscopic-assisted internal fixation is an ideal technique for visualizing chondral reduction during tibial open reduction–internal fixation. Typically, open reduction–internal fixation is performed using radiographic and Fluoroscan imaging (Hologic, Bedford, MA) for reduction of subchondral bone. However, reduction without visualization does not ensure chondral surface reduction. This Technical Note and supplemental video describe an arthroscopic-assisted technique involving the tibial plateau that gives complete visualization as tamping occurs to restore the cartilage surface of the subchondral bone and elevate the fracture.

Meniscus tears are among the most common knee injuries in the general population and often are treated arthroscopically with a meniscus repair. Of the various meniscus repair techniques available, the inside-out meniscus tear is considered the gold standard due to its versatility and good clinical outcomes. The purpose of this Technical Note and accompanying video is to describe an inside-out bucket-handle meniscus repair using a single handed, self-advancing meniscus repair device with an interchangeable zone-specific multicannula system to decrease the technical difficulty and operative time of the repair.