Citations

AbstractBackgroundOncologic outcomes of human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (SCC) requiring resection of major muscular or neurovascular tissue during neck dissection for invasive nodal disease remain uncertain.MethodsPatients with HPV‐related oropharyngeal SCC requiring resection of major muscular or neurovascular tissue during their neck dissections were retrospectively identified.ResultsSeventy‐two patients were included. Regional and distant recurrences occurred in 6% and 17% of patients. Advanced T classification, pathological node number of 5 or more, and omission of adjuvant therapy were associated with decreased disease‐free survival (DFS). The addition of adjuvant chemotherapy was not associated with improved survival.ConclusionPatients with invasive nodal disease from HPV‐related oropharyngeal SCC can be managed with up‐front surgery and adjuvant therapy, as indicated with good regional control. Although distant recurrence was the primary site of failure, adjuvant chemotherapy was not associated with improved outcomes. The T classification, node number, and adjuvant radiotherapy are independent prognostic factors in this patient population.

Patient-reported outcomes (PROs) provide information on how health care affects patient health and well-being and represent a patient-centered approach. Despite this potential, PROs are not widely used in clinical settings. Semi-structured focus groups were conducted with 3 stakeholder groups (patients, providers, and health care administrators) to determine the top 5 perceived barriers and benefits of PRO implementation. The Delphi technique was employed to obtain consensus and rank order responses. Patients perceived survey length to be important, whereas providers and administrators perceived time to collect data and patient health literacy, respectively, as the greatest barriers to PRO implementation. The greatest perceived benefits were the ability to track changes in clinical symptoms over time, improved quality of care, and better disease control among patients, providers, and administrators, respectively. These results may guide the development of novel frameworks for PRO implementation by addressing perceived barriers and building on the perceived benefits to encourage adoption of PROs.

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s; P =0.047) and during hypercapnia ( P =0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg; P =0.009). Globally, the association of the 7 identified principal components with preeclampsia ( P =0.107) and with baseline middle cerebral artery velocity ( P =0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR ( P =0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes ( P =0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.

This discussion panel will focus on solutions for mitigating the negative impact of interruptions in healthcare. Five human factors practitioners who work within healthcare systems will present solutions of mitigating the negative impact of interruptions on safety and quality with the acknowledgement that interruptions in and of themselves should not be viewed as purely negative (i.e. some interruptions are not only necessary but beneficial to patient care). Additionally, one panelist will focus on the difficulties in bridging the gap between research and practice in this arena. The session will lead to an interactive discussion about how human factors methods can be adapted and applied to identify and develop realistic, impactful solutions that improve safety by eliminating the negative impact of interruptions in applied healthcare settings.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising single-agent activity in ovarian cancers with BRCA1 and BRCA2 mutations (C. Scott, JCO 33:1397, 2015). Ongoing studies are testing the efficacy of PARP inhibitors in ovarian cancers with other genetic or epigenetic alterations that impair the homologous recombination (HR) pathway of DNA repair. It is less clear whether PARP inhibitor clinical activity can be enhanced in HR deficient cancers or even extended to HR proficient ovarian cancers through judicious combinations. Our preclinical studies have demonstrated that PARP inhibitors enhance the cytotoxic effects of selected therapeutic agents through a variety of mechanisms: By trapping PARP at sites of DNA damage, PARP inhibitors enhance the cytotoxicity of topotecan (A. Patel, J. Biol. Chem. 287: 4198, 2012).By inhibiting base excision repair, PARP inhibitors enhance the cytotoxicity of floxuridine (A. Huehls, Cancer Res. 71: 4944, 2011), an agent previously shown to have clinical activity in ovarian cancer. Building on the first of these observations, we conducted a phase 1 clinical trial of topotecan weekly x 3 in combination with veliparib (NCT01012817). Using a standard 3+3 design, patients were treated with veliparib PO twice daily on days 1-3, 8-10 and 15-17 and topotecan IV on days 2, 9 and 16 every 28 days. The dose-limiting toxicity was neutropenia. The MTD was veliparib 300 mg PO twice daily and topotecan 3 mg/m2/dose. Among 52 evaluable patients, objective responses (1 CR, 3 PRs) and stable disease (22 patients, 6 lasting ≥ 8 cycles) were observed. While there was no clear correlation between germline BRCA1 or BRCA2 mutations and clinical benefit, a patient with a germline RAD51D mutation had stable disease for 14 cycles. A phase 2 cohort in platinum-resistant ovarian cancer has just opened. Building on the second set of preclinical observations, we are also conducting a phase 1 trial of veliparib and IP floxuridine in patients with recurrent ovarian cancer confined to the peritoneal cavity (NCT01749397). Using a rolling 6 design, patients are treated with veliparib PO twice daily on days 1-10 and floxuridine IP on days 3-5 every 21 days. The trial is currently enrolling at dose level 5 (veliparib 300 mg PO twice daily on days 1-10 and floxuridine 3 gm/dose IP on days 3-5). Grade 3 toxicities in any cycle have included nausea (1), fatigue (1) and neutropenia (3). Among 20 evaluable patients, treatment duration has ranged from 2-33 cycles. These studies, which build on two different aspects of PARP1 function, illustrate two different approaches to potentially enhancing the activity of PARP inhibitors in relapsed ovarian cancer. These studies were funded in part by NIH grants P50 CA136393, R01 CA190423, and UM1 CA186686 as well as SU2C-AACR DT16-15. Citation Format: Scott H. Kaufmann, Andrea E. Wahner Hendrickson, Maria I Harrell, Michael E. Menefee, Edward J. Tanner, David G, Mutch, Elizabeth M. Swisher, and Larry M. Karnitz. PARP INHIBITOR COMBINATIONS FOR THE TREATMENT OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr IS04.

SummaryBackgroundThe impact of combination therapy on disease‐related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well‐defined.AimTo examine the effect of combination therapy on disease outcomes in CD and UC.MethodsUsing a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti‐TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD‐related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders.ResultsWe included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63‐1.22) or UC (OR: 1.45, 95% CI: 0.63‐3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37‐0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14‐0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45‐1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti‐TNF biologics.ConclusionThe benefit of combination immunomodulator‐biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.