Citations

Abstract Purpose: Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention. Experimental Designs: APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages. Results: One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues. Conclusions: These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly. OBJECTIVE To improve understanding of clinical and dosimetric factors predicting biochemical remission. METHODS A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission—defined as normalization of insulin-like growth factor-1 index (IGF-1 i ) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1 i were assessed via systematic literature review and meta-analysis using random-effect modeling. RESULTS A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1 i was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1 i ≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1 i , only BED remained significant—and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1 i was 2.25 (95% CI = 1.33-3.16, P < .0001). CONCLUSION IGF-1 i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.

Background: Loss of upper and lower extremity range of motion (ROM) is a significant risk factor for injuries in professional baseball players. Purpose/Hypothesis: The purpose was to determine changes in ROM in professional baseball players over the course of a single season and their careers. We hypothesized that pitchers and position players would lose ROM, specifically total shoulder motion (total ROM [TROM]) and hip internal rotation (IR), over the course of a season and their careers. Study Design: Case series; Level of evidence, 4. Methods: Upper and lower extremity ROM measurements were recorded during pre-, mid-, and postseason on all professional baseball players for a single organization between 2011 and 2018. ROM measurements were compared for pitchers and position players over the course of the season and their careers. Also, ROM measurements over the pre-, mid-, and postseason were compared between pitchers and position players. Results: A total of 166 professional baseball players (98 pitchers, 68 position players) were included. Pitcher hip external rotation (ER; P < .001), IR ( P = .010), and TROM ( P < .001) for lead and trail legs decreased over the course of the season. Pitcher shoulder ER ( P = .005), TROM ( P = .042), and horizontal adduction ( P < .001) significantly increased over the course of the season. Position player shoulder flexion ( P = .046), hip ER ( P < .001, lead leg; P < .001, trail leg), and hip TROM ( P = .001; P = .002) decreased over the course of the season. Position player shoulder ER ( P = .031) and humeral adduction ( P < .001) significantly increased over the course of the season. Over the course of pitchers’ careers, there was decreased shoulder IR ( P = .014), increased shoulder horizontal adduction ( P < .001), and hip IR ( P = .042) and hip TROM ( P = .027) for the lead leg. Position players experienced loss of hip TROM ( P = .010, lead leg; P = .018, trail leg) over the course of their careers. Pitchers started with and maintained more shoulder ER and gained more shoulder TROM over a season as compared with position players. Conclusion: Pitchers and position players saw overall decreases in hip ROM but increases in shoulder ROM over the course of the season and career.

Background: The aim of this study was to assess the relationship between admission serum potassium and one-year mortality in all adult hospitalized patients. Methods: All adult hospitalized patients who had an admission serum potassium level between the years 2011 and 2013 at a tertiary referral hospital were enrolled. End-stage kidney disease patients were excluded. Admission serum potassium was categorized into levels of ≤2.9, 3.0–3.4, 3.5–3.9, 4.0–4.4, 4.5–4.9, 5.0–5.4, and ≥5.5 mEq/L. Cox proportional hazard analysis was performed to assess the independent association between admission serum potassium and one-year mortality after hospital admission, using an admission potassium level of 4.0–4.4 mEq/L as the reference group. Results: A total of 73,983 patients with mean admission potassium of 4.2 ± 0.5 mEq/L were studied. Of these, 12.6% died within a year after hospital admission, with the lowest one-year mortality associated with an admission serum potassium of 4.0–4.4 mEq/L. After adjustment for age, sex, race, estimated glomerular filtration rate (eGFR), principal diagnosis, comorbidities, medications, acute kidney injury, mechanical ventilation, and other electrolytes at hospital admission, both a low admission serum potassium ≤3.9 mEq/L and elevated admission potassium ≥5.0 mEq/L were significantly associated with an increased risk of one-year mortality, when compared with an admission serum potassium of 4.0–4.4 mEq/L. Subgroup analysis of chronic kidney disease and cardiovascular disease patients showed similar results. Conclusion: This study demonstrated that hypokalemia ≤3.9 mEq/L and hyperkalemia ≥5.0 mEq/L at the time of hospital admission were associated with higher one-year mortality.

Objectives:With the introduction of novel immune therapeutics for the treatment of disseminated malignancies, we sought to evaluate whether deliberate sequencing of immunotherapy before/after conventional cytotoxic chemotherapy would have an impact on clinical outcomes in patients with previously treated metastatic melanoma. We sought to evaluate whether or not ipilimumab immunotherapy administered before or after cytotoxic chemotherapy (nab-paclitaxel+bevacizumab, AB) would impact clinical outcomes.Methods:We conducted a randomized phase 2 clinical trial of patients with BRAF wild-type metastatic melanoma (up to 2 prior therapies) who received either: (A) AB followed by ipilimumab therapy at progression; or (B) ipilimumab followed by AB treatment at progression. The primary goal of the study was a comparison of AB versus ipilimumab progression-free survival, with secondary clinical and laboratory endpoints.Results:This study did not reach full accrual due to concurrent Food and Drug Administration approval of anti-programmed cell death 1 agents. Nevertheless, the available data suggests a cumulative therapeutic advantage to the sequential use of ipilimumab followed by AB. Correlative laboratory data revealed a favorable effect on systemic immune homeostasis in patients receiving AB therapy, of potential interest in further investigations, especially in the context of chemotherapy/immunotherapy combinations.Conclusion:Albeit limited in scope, our data suggest that cytotoxic therapy with nab-paclitaxel and bevacizumab appear to favorably alter systemic parameters of immune function of potential benefit in combination T-cell directed immune checkpoint inhibitor therapy.