Citations

Abstract Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908–16. ©2018 AACR.

125 Background: Men with lymph node involvement (LNI) at prostatectomy (RP) are at high risk of dying from prostate cancer. However, survival following RP is highly variable, with some men apparently cured. Nomograms developed for men with LNI have been based on series where all or the vast majority of men received adjuvant treatment. Because administration of adjuvant treatment is not universal, even for LNI, we evaluated whether the Decipher genomic classifier (GC) can improve upon clinical models to predict metastasis within 5 years (MET5) and prostate cancer specific mortality within 10 years (PCSM10) in a cohort of LNI patients, the majority of whom did not receive adjuvant treatment. Methods: 141 patients from 4 institutions (Johns Hopkins, Mayo Clinic, Leuven, MD Anderson) had LNI at RP, had adequate tissue and clinical data for analysis of MET5, and 86 were analyzed for PCSM10. 43% of men received adjuvant therapy. RP tumor tissue was analyzed by Affymetrix Human Exon 1.0 ST GeneChip; the GC was calculated based on 22 genes in the previously trained and validated algorithm. Logistic regression evaluated whether the GC, dichotomized as high risk (GC score > 0.6) vs low-intermediate risk (≤0.6), improved prediction of MET5 and PCSM10 beyond that achieved with established clinical prognostic factors. Results: 62 men (43%) developed MET5, and 35 (41%) developed PCSM10. For both MET5 and PCSM10 CAPRA-S, number of positive lymph nodes, and age were significant; adjuvant therapy was not significant. GC was a significant independent strong prognostic factor when added to the clinical model for prediction of MET5, odds ratio = 4.04 (95% CI: 1.48, 11.02), p = 0.006, and prediction of PCSM10, odds ratio = 6.71 (95% CI: 2.01, 22.38), p = 0.002. Addition of GC to the clinical model improved the AUC from 0.77 to 0.79 for MET5, and from 0.65 to 0.74 for PCSM10. Conclusions: The Decipher GC significantly improves upon clinical variables to predict metastasis and prostate cancer specific mortality in men at high risk due to LNI. This is the first study to show a genomic classifier predicts outcomes in men with LNI; validation is needed to determine if Decipher can improve treatment decisions in men with LNI.

The PROSTALAC functional spacer is made of antibiotic-loaded acrylic cement but has a small metal-on-polythene articular surface. We have used it as an interim spacer in two-stage exchange arthroplasty for infected total knee replacement. PROSTALAC allows continuous rehabilitation between stages as it maintains good alignment and stability of the knee and a reasonable range of movement. It also helps to maintain the soft-tissue planes, which facilitates the second-stage procedure. We reviewed 45 consecutive patients, treated over a period of nine years. The mean follow-up was for 48 months (20 to 112). At final review, there was no evidence of infection in 41 patients (91%); only one had a recurrent infection with the same organism. There was improvement in the Hospital for Special Surgery knee score between stages and at final review. The range of movement was maintained between stages. Complications were primarily related to the extensor mechanism and stability of the knee between stages. Both of these problems decreased with refinement of the design of the implant. The rate of cure of the infection in our patients was similar to that using other methods. Movement of the knee does not appear to hinder control of infection.

Abstract Background: Stage III triple negative(TN) inflammatory breast cancer(IBC) is associated with a poor prognosis evidenced by a 15 month(mo) median disease free survival(DFS) and overall survival(OS) of 34 mo. The substantial incidence of developing distant metastasis may be due to the prevalence of cancer cells with stem cell-like features (e.g. CD44+/CD24-) in TNIBC. The transcriptional pathway JAK2/STAT3 is associated with the survival of CD44+/CD24- cells, and preclinical data demonstrates overexpression of activated STAT3(pSTAT3) in > 95% of TNIBC. Preclinical studies have shown that ruxolitinib (Incyte®Corporation), an approved JAK1/JAK2 inhibitor, suppresses pSTAT3 in IBC patient derived xenograft models, and when combined with paclitaxel, results in a synergistic reduction in tumor weight. Given the lack of a known therapeutic target in TNIBC, this preoperative proof of principle study exploits the survival mechanism of CD44+/CD24- stem cells prevalent in this disease, by combining ruxolitinib(Rux) with paclitaxel(T) followed by doxorubicin/cyclophosphamide(AC). Methods: Up to 64 pts with newly diagnosed stage III TNIBC (cT4d, any N, M0) are eligible if they have adequate organ function and are willing to undergo 2 research biopsies(rbx) of the affected breast. Following baseline rbx, pts are randomized to a 7 day(d) run-in phase of Rux vs Rux(15 mg bid) + T(80mg/m2/wkx1). A 2nd rbx is obtained after the run-in phase. Pts randomized to RuxT continue to receive a total of Tx12 wks+Rux. Pts randomized to Rux alone, are re-randomized to receive Tx12 wks+Rux vs Tx12wks alone. Following T, all pts receive AC (A-60mg/m2,C-600mg/m2) every 14d x 4. Pts proceed to modified radical mastectomy (MRM) followed by chest wall/regional lymph nodes radiation therapy. Correlatives: To assess the effect of JAK inhibition with Rux on pSTAT3 and STAT3 related gene expression, molecular and genomic markers (e.g. RNA-seq, ChIPseq, FISH) will be determined in each rbx and residual tumor at MRM. The relative frequency and topology of CD44+/CD24- cell population and pSTAT3 expression by IHC will also be assessed in these tumor specimens. IL-6 and CRP plasma concentrations will be measured at baseline, prior to T and AC and prior to MRM. Statistics: The primary endpoint is change in markers of JAK/STAT inhibition. If the proportion of rbx exhibit a biologic response to Rux alone (i.e. change from pSTAT3 expression to pSTAT3 negative) is <10%, then Rux alone is minimally effective on JAK inhibition vs alternative hypothesis that Rux inhibits JAK if the proportion of biologic response is ≥33%. If ≥5/25 rbx treated with Rux alone have a biologic response then the hypothesis that biologic response is ≤10% is rejected with an error rate of 0.098 (target 0.10). If ≤4/25 rbx have a biologic response then the hypothesis that biologic response is ≥33% is rejected with an error rate of 0.05 (target 0.10). Biologic response of rbx with Rux alone will also be compared with the proportion of biologic response to RuxT (33% vs. 66% based upon presumed synergy with RuxT). Secondary endpoints are clinical: pathologic complete response in breast/lymph nodes, Residual Cancer Burden, DFS and OS. Clinical Trial Information: NCT02876302. Citation Format: Overmoyer B, Regan M, Polyak K, Brock J, Van Poznak C, King T, Haddad T, Stearns V, Hwang S, Winer E. TBCRC 039: Phase II study of combination ruxolitinib (INCB018424) with preoperative chemotherapy for triple negative inflammatory breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-01.

AbstractBackgroundCoagulopathy can delay or complicate surgical diseases that require emergent surgical treatment. Prothrombin complex concentrates (PCC) provide concentrated coagulation factors which may reverse coagulopathy more quickly than plasma (FFP) alone. We aimed to determine the time to operative intervention in coagulopathic emergency general surgery patients receiving either PCC or FFP. We hypothesize that PCC administration more rapidly normalizes coagulopathy and that the time to operation is diminished compared to FFP alone.MethodsSingle institution retrospective review was performed for coagulopathic EGS patients during 2/1/2008 to 8/1/2016. Patients were divided into three groups (1) PCC alone (2) FFP alone and (3) PCC and FFP. The primary outcome was the duration from clinical decision to operate to the time of incision. Summary and univariate analyses were performed.ResultsCoagulopathic EGS patients (n = 183) received the following blood products: PCC (n = 20, 11%), FFP alone (n = 119, 65%) and PCC/FFP (n = 44, 24%). The mean (± SD) patient age was 71 ± 13 years; 60% were male. The median (IQR) Charlson comorbidity index was similar in all three groups (PCC = 5(4–6), FFP = 5(4–7), PCC/FFP = 5(4–6), p = 0.33). The mean (± SD) dose of PCC administered was similar in the PCC/FFP group and the PCC alone group (2539 ± 1454 units vs. 3232 ± 1684, p =. 09). The mean (±SD) time to incision in the PCC alone group was significantly lower than the FFP alone group (6.0 ± 3.6 vs. 8.8 ± 5.0 h, p = 0.01). The mean time to incision in the PCC + FFP group was also significantly lower than the FFP alone group (7.1 ± 3.6 vs. 8.8 ± 5.0, p = 0.03). The incidence of thromboembolic complications was similar in all three groups.ConclusionsPCC, alone or in combination with FFP, reduced INR and time to surgery effectively and safely in coagulopathic EGS patients without an apparent increased risk of thromboembolic events, when compared to FFP use alone.Level of evidenceIV single institutional retrospective review.

Abstract Background Axillary web syndrome (AWS) can develop following breast cancer surgery and presents as a tight band of tissue in the axilla with shoulder abduction. Objective The objectives were to determine the prevalence and natural history of AWS and the association between AWS and function, range of motion, pain, lymphedema, and body mass index (BMI). Design This study was a longitudinal prospective cohort study utilizing a repeated measures design. Methods Axillary web syndrome, function, shoulder range of motion, pain, and lymphedema (using circumference, bioimpedance spectroscopy, tissue dielectric constant) were assessed in women at 2, 4, and 12 weeks and 18 months following breast cancer surgery. Prevalence of AWS and the association with the measured outcomes were analyzed. Results Thirty-six women agreed to participate in the study. The cumulative prevalence of AWS was 50% (18/36) at 18 months following breast cancer surgery. AWS was identified as a risk factor for reduced function. Women with AWS had statistically reduced range of motion, lower BMI, and higher number of lymph nodes removed compared to the non-AWS group. Forty-one percent (13/32) of women had AWS at 18 months. AWS reoccurred in 6 women following resolution, and a new case developed beyond the early postoperative period. The overall prevalence of physical impairments ranged from 66% to 97% within the first 18 months following surgery regardless of AWS. Limitations Limitations include a small sample size and potential treatment effect. Conclusion AWS occurs in approximately 50% of women following breast cancer surgery. It can persist for 18 months and potentially longer, develop beyond the early postoperative time period, and reoccur after resolution. Clinicians need to be aware of the chronicity of AWS and its association with reduced range of motion and function.

Our hypothesis was that the canine ileocolonic sphincter (ICS), per se, would have little regulatory effect on the transit of chyme from ileum to colon. We argued, from earlier observations, that the ileocolonic junction was influenced more by functional motor integration of the ileum, ICS, and proximal colon. In five dogs, the ileocolonic sphincter was ablated by extramucosal sphincterotomy; the operation significantly lowered tonic pressures at the ICS. Animals were then studied in the fasting state and postprandially. Ileal flow was estimated by marker dilution, and ileocolonic flow was estimated by total recovery of chyme from a colonic cannula. Transit times were measured after the bolus infusion of nonabsorbable markers. Ileocolonic sphincterotomy did not significantly alter flow rates or transit times of chyme across the ICS, although ileal motor patterns were changed after sphincterotomy. We concluded that the ICS probably has only a small effect on transit and flow at the ileocolonic junction. These findings argue for the importance of integrated motility of the ileum, ICS, and proximal colon in controlling the flow of chyme in this region.