Citations

2562 Background: Empiric chemotherapy (taxane/platinum) is standard for CUP. Because prognosis is poor, novel approaches are needed. The PI3K/mTOR pathway is frequently dysregulated in cancer. Everolimus (E), an mTOR inhibitor, is approved for multiple malignancies. We performed a phase II study of Pac + Carb + E as first-line therapy in metastatic CUP patients (pts). We additionally determined if a gene expression profiling (GEP) test that identifies tissue of origin (Pathwork Tissue of Origin) could identify responsive pts. (NCT00936702) Methods: Newly diagnosed, untreated CUP pts were eligible. Central pathology review confirmed CUP prior to registration; GEP was performed on formalin fixed tumor tissue. Pac (200 mg/m2), Carb (AUC=6) and E (30 mg once weekly) were delivered every 3 wks until progression or intolerable adverse events (AEs). The primary endpoint was confirmed response, with ≥11 of 50 responses (22%) needed for trial success. Secondary endpoints were OS, progression-free survival (PFS) and AEs. Results: 46 pts (median age 61) received a median 4 cycles (range: 1-33). 39 (85%), 21 (46%) and 1 (2%) experienced ≥1 grade (gr) 3+, 4+, or 5 (sepsis) AE, with gr 3+ hematologic AE most common (74%). Of 44 evaluable pts, 15 had a confirmed response (RR 34%, 95% CI: 21-50%), with a median PFS and OS of 4.1 and 10.1 mos, respectively. Adequate tissue for GEP was available in 36 pts and predicted 10 different sites of origin. In pts with a predicted tissue of origin in which taxane/platinum is standardly used, higher RR and significantly longer PFS and OS were observed compared with pts whose GEP identified a malignancy where taxane/platinum is not standard (Table). Conclusions: In pts with untreated CUP, Carb +Pac +E demonstrated promising antitumor activity. The GEP test identified patients clinically responsive to Carb/Pac/E therapy, and may be useful to select CUP pts for specific antitumor regimens. Clinical trial information: NCT00936702. [Table: see text]

6571 Background: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the natural history of these cancers once they occur. Methods: All patients with breast (n=583,838), colon (n=412,932), prostate (n=632,922), lung (n=489,290), kidney (n=95,902), pancreas (n=82,121) and ovarian (n=61,958) cancer reported to the Surveillance, Epidemiology, and End Results (SEER) Program from 1990 to 2007 were identified. Overall survival (OS; death due to any cause) and cancer-specific survival (death due to cancer site of interest) were examined, comparing patients with or without pre-existing CLL. Age- and sex-adjusted hazard ratios (HRs) were calculated. Results: OS for patients with pre-existing CLL was inferior for patients with breast (HR=1.61; p<0.001), colon (HR=1.65; p<0.001), kidney (HR=1.41; p<0.001), prostate (HR=1.75; p<0.001), and lung (HR=1.22; p<0.001) cancer after adjusting for age and sex. After excluding CLL-related deaths, OS remained shorter among patients with breast (p<0.001), colon (p<0.001), kidney (p=0.03), prostate (p<0.001), and lung (p<0.001) cancer. Cancer-specific survival was inferior for patients with breast (HR=1.29; p=0.03), colon (HR=1.75; p<0.001), and lung cancer (HR=1.17; p<0.001) who had pre-existing CLL after adjusting for age and sex. Conclusions: Several common cancers, including breast, colon, and lung, have inferior overall and cancer-specific survival when there is coexistent CLL. [Table: see text]

TPS10594 Background: Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Despite primary surgery many patients develop recurrent disease. Response rates to chemotherapy are low and new agents are needed. Gene array studies have shown Aurora Kinase A (AURKA) commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel and oral, ATP-competitive, selective small-molecule inhibitor of AURKA. We hypothesize that alisertib will be an effective treatment for advanced/metastatic sarcoma. Methods: This CTEP-sponsored, investigator-initiated, multi-center phase II study uses alisertib in patients with advanced/metastatic sarcoma and is conducted through the Alliance for Clinical Trials in Oncology (Alliance A091102). Patients must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are enrolled in one of five cohorts, depending on histology: 1) liposarcoma, 2) leiomyosarcoma, 3) undifferentiated sarcoma, 4) malignant peripheral nerve sheath tumor, or 5) other. Patients are treated with alisertib 50mg PO BID d1-d7 every 21 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with baseline and post-treatment markers of AURKA inhibition in tumor biopsies and baseline and post-treatment [F-18] FLT-PET scans. A Simon two-stage design is used for each of the 5 cohorts and one confirmed response in the first 9 patients expands enrollment in that cohort to 24. Enrollment began in December 2012. As of January 2013, 14 pts have been enrolled. Funded by the Alliance for Clinical Trials in Oncology. Clinical trial information: NCT01653028.

9514 Background: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy. Methods: Entry criteria included non-GIST STS diagnosis, age > 10, measurable disease, ≤ 3 prior regimens, normal organ function, and Grade (Gr) ≤ 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m2 (over 120 min, d1+d8) or G 900 mg/m2 (over 90 min, d1+d8) and docetaxel (100 mg/m2 d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ∼120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05. Results: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1–26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ∼6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6–8.8) vs. 2.6 m (G, 95%CI 2.0–3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7–24.1) vs. 11.2 m (G, 95%CI 6.8–15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p<0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy. [Table: see text]

Papillary fibroelastoma (PFE) is an increasingly recognized cardiac tumor. Despite its prevalence, controversy exists as to whether it represents a reactive or neoplastic process due to histopathologic similarities with Lambl excrescences (LEs), an accepted reactive phenomenon. Recently, KRAS mutations were reported in a small collection of PFEs, but the incidence of mutations and conditions in which they arise in are unknown. Furthermore, the relationship between PFE and LE has yet to be investigated. Institutional archives were queried for cases of PFE (2001-2017). Paraffin-embedded tissue was microdissected for tumor isolation. Prospectively identified LEs (2018) were collected and wholly isolated. Extracted DNA underwent droplet digital polymerase chain reaction analysis of the most common KRAS mutations (codons 12/13 and 61). Relevant clinical information was abstracted from the medical record. Fifty-two PFEs were tested from 50 patients (32 women). The median patient age was 67 years. Seventeen (33%) PFEs harbored pathogenic variants in tested KRAS codons (12 in codons 12/13; 5 in codon 61). Mutations were mutually exclusive. No clinical or pathologic correlates differed significantly from cases without detectable pathogenic variants. No pathogenic mutation were detected in LEs (n=20; P=0.002). Herein, we report on the largest series of PFE tested for KRAS mutations and present the largest cohort of KRAS-mutant PFEs to date, providing evidence in support of the notion that at least a subset of PFEs represents neoplasia. Moreover, the lack of KRAS mutations in LEs provides evidence as to the separate etiology of this accepted reactive lesion.

Abstract Aims To assess functional tricuspid regurgitation (FTR) determinants, consequences, and independent impact on outcome in degenerative mitral regurgitation (DMR). Methods and results All patients diagnosed with isolated DMR 2003–2011, with structurally normal tricuspid leaflets, prospective FTR grading and systolic pulmonary artery pressure (sPAP) estimation by Doppler echocardiography at diagnosis were identified and long-term outcome analysed. The 5083 DMR eligible patients [63 ± 16 years, 47% female, ejection fraction (EF) 63 ± 7%, and sPAP 35 ± 13 mmHg] presented with FTR graded trivial in 45%, mild in 37%, moderate in 15%, and severe in 3%. While pulmonary hypertension (PHTN-sPAP ≥ 50 mmHg) was the most powerful FTR severity determinant, other strong FTR determinants were older age, female sex, lower left ventricle EF, DMR, and particularly atrial fibrillation (AFib) (all P ≤ 0.002). Functional tricuspid regurgitation moderate/severe was independently linked to more severe clinical presentation, more oedema, lower stroke volume, and impaired renal function (P ≤ 0.01). Survival (95% confidence interval) throughout follow-up [70% (69–72%) at 10 years] was strongly associated with FTR severity [82% (80–84%) for trivial, 69% (66–71%) for mild, 51% (47–57%) for moderate, and 26% (19–35%) for severe, P &lt; 0.0001]. Excess mortality persisted after comprehensive adjustment [adjusted hazard ratio 1.40 (1.18–1.67) for moderate FTR and 2.10 (1.63–2.70) for severe FTR, P ≤ 0.01]. Excess mortality persisted adjusting for sPAP/right ventricular function (P &lt; 0.0001), by matching [adjusted hazard ratios 2.08 (1.50–2.89), P &lt; 0.0001] and vs. expected survival [risk ratio 1.79 (1.48–2.16), P &lt; 0.0001]. Within 5-year of diagnosis valve surgery was performed in 73% (70–75%) and 15% (13–17%) of severe and moderate DMR and in only 26% (19–34%) and 6% (4–8%) of severe and moderate FTR. Valvular surgery improved outcome without alleviating completely higher mortality associated with FTR (P &lt; 0.0001). Conclusion In this large DMR cohort, FTR was frequent and causally, not only linked to PHTN but also to other factors, particularly AFib. Higher FTR severity is associated at diagnosis with more severe clinical presentation. Long term, FTR is independently of all confounders, associated with considerably worse mortality. Functional tricuspid regurgitation moderate and even severe is profoundly undertreated. Thus careful assessment, consideration for tricuspid surgery, and testing of new transcatheter therapy is warranted.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

Background: Autologous fat grafting is a dynamic modality used in plastic surgery as an adjunct to improve functional and aesthetic form. However, current practices in fat grafting for soft-tissue augmentation are plagued by tremendous variability in long-term graft retention, resulting in suboptimal outcomes and repetitive procedures. This systematic review identifies and critically appraises the evidence for various enrichment strategies that can be used to augment and improve the viability of fat grafts. Methods: A comprehensive literature search of the Medline and PubMed databases was conducted for animal and human studies published through October of 2017 with multiple search terms related to adipose graft enrichment agents encompassing growth factors, platelet-rich plasma, adipose-derived and bone marrow stem cells, gene therapy, tissue engineering, and other strategies. Data on level of evidence, techniques, complications, and outcomes were collected. Results: A total of 1382 articles were identified, of which 147 met inclusion criteria. The majority of enrichment strategies demonstrated positive benefit for fat graft survival, particularly with growth factors and adipose-derived stem cell enrichment. Platelet-rich plasma and adipose-derived stem cells had the strongest evidence to support efficacy in human studies and may demonstrate a dose-dependent effect. Conclusions: Improved understanding of enrichment strategies contributing to fat graft survival can help to optimize safety and outcomes. Controlled clinical studies are lacking, and future studies should examine factors influencing graft survival through controlled clinical trials in order to establish safety and to obtain consistent outcomes.

Study Design. Review. Objective. To provide practicing spine surgeons a primer with key insights for reading, interpreting, and clinically integrating systematic reviews and meta-analyses. Summary of Background Data. Evidence-based medicine (EBM) refers to a family of standardized techniques for critical appraisal of clinical research. Within the contemporary spine literature, EBM is most commonly encountered in the form of systematic reviews and meta-analyses. Although these analytic techniques are potentially useful when appropriately applied to well-formulated questions with adequate primary data in the literature, the rapid and somewhat indiscriminate increase in volume of systematic reviews and meta-analyses published may be associated with an overall dilution in their quality, as well as misperceptions regarding the applicability of particular EBM studies to spine surgery in general. Methods. The collective experience of spine specialists with vested interests in advancing EBM and its utility was summarized into a primer. Results. We emphasize components that are pertinent methodologically (search strategy, study number, meta-analysis, bias, and certainty), and pertinent clinically (outcomes) to interpreting, and clinically integrating systematic reviews and meta-analyses into spine surgery practice. Conclusions. Armed with these insights into these five perspectives, we anticipate that practicing spine surgeons will be better equipped to interpret systematic reviews and meta-analyses in a fashion that will meaningfully impact their patient care. Level of Evidence: 2

Abstract Background Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.