Citations

510 Background: Several studies have established the critical role of preexisting immune response in triple negative breast cancer (TNBC). Most studies evaluated the tumor infiltrating lymphocytes in stroma. However, limited data are available with regards to the importance of specific subtypes and spatial distribution of these immune infiltrates. Methods: NanoString IO360 gene expression analysis and Digital Spatial Profiling (DSP) were used. DSP was used to quantify 39 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 335 samples from the Mayo Clinic (MC) cohort of centrally reviewed TNBC (Leon-Ferre BCRT 2018). In FinXX trial, 22 patients with recurrence and 22 patients without recurrence were included. In MC cohort, 217/335 patients received adjuvant chemotherapy while 118 patients had surgery only without adjuvant chemotherapy. Regions were segmented based on pancytokeratin staining. The general linear model was used for statistical analysis of differential expression with recurrence free survival (RFS) as a categorical variable (recur yes or no). Kaplan-Meier estimates and Cox regression models were also used for analysis. Results: In the FinXX trial, using global gene expression analysis with IO360, there was no signature significantly associated with RFS. However, using DSP, high protein expression of CD56 in the tumor-enriched segments was associated with significant improvement in RFS (HR 0.26, 95%CI 0.09-0.78, p 0.01). Nevertheless, CD56 expression in the stroma (HR 0.66, 95%CI 0.29-1.53, p 0.33) and all segments (HR 0.53, 95%CI 0.23-1.25, p 0.14) was not significantly associated with improved outcome. We further validated these findings in the MC TNBC cohort where intratumoral CD56 expression was associated with a significant improvement in RFS (HR 0.23, p 0.002) but not stromal CD56 (p 0.79). Interestingly, when evaluating the MC TNBC cohort according to receipt of chemotherapy, intratumoral CD56 was associated with improved outcome only in patients who received chemotherapy (p 0.02 vs. 0.07). In both cohorts, higher expressions of intratumoral PD-L1, HLA-DR, and CD8 were associated with improved outcome. Conclusions: Using an in-depth analysis with spatially defined context, we identify that intratumoral CD56-positive NK cells are associated with improved outcome in TNBC. Our study highlights the potential role of NK cells in TNBC and future implications for biomarkers and therapeutic targets.Support: W81XWH-15-1-0292, P50CA116201-9, P50CA015083. Clinical trial information: NCT00114816 .

This study aimed to assess the one-year mortality risk based on discharge serum chloride among the hospital survivors. We analyzed a cohort of adult hospital survivors at a tertiary referral hospital from 2011 through 2013. We categorized discharge serum chloride; ≤96, 97–99, 100–102, 103–105, 106–108, and ≥109 mmoL/L. We performed Cox proportional hazard analysis to assess the association of discharge serum chloride with one-year mortality after hospital discharge, using discharge serum chloride of 103–105 mmoL/L as the reference group. Of 56,907 eligible patients, 9%, 14%, 26%, 28%, 16%, and 7% of patients had discharge serum chloride of ≤96, 97–99, 100–102, 103–105, 106–108, and ≥109 mmoL/L, respectively. We observed a U-shaped association of discharge serum chloride with one-year mortality, with nadir mortality associated with discharge serum chloride of 103–105 mmoL/L. When adjusting for potential confounders, including discharge serum sodium, discharge serum bicarbonate, and admission serum chloride, one-year mortality was significantly higher in both discharge serum chloride ≤99 hazard ratio (HR): 1.45 and 1.94 for discharge serum chloride of 97–99 and ≤96 mmoL/L, respectively; p < 0.001) and ≥109 mmoL/L (HR: 1.41; p < 0.001), compared with discharge serum chloride of 103–105 mmoL/L. The mortality risk did not differ when discharge serum chloride ranged from 100 to 108 mmoL/L. Of note, there was a significant interaction between admission and discharge serum chloride on one-year mortality. Serum chloride at hospital discharge in the optimal range of 100–108 mmoL/L predicted the favorable survival outcome. Both hypochloremia and hyperchloremia at discharge were associated with increased risk of one-year mortality, independent of admission serum chloride, discharge serum sodium, and serum bicarbonate.

Background and Objectives: The optimal range of serum potassium at hospital discharge is unclear. The aim of this study was to assess the relationship between discharge serum potassium levels and one-year mortality in hospitalized patients. Materials and Methods: All adult hospital survivors between 2011 and 2013 at a tertiary referral hospital, who had available admission and discharge serum potassium data, were enrolled. End-stage kidney disease patients were excluded. Discharge serum potassium was defined as the last serum potassium level measured within 48 h prior to hospital discharge and categorized into ≤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. A Cox proportional hazards analysis was performed to assess the independent association between discharge serum potassium and one-year mortality after hospital discharge, using the discharge potassium range of 4.0–4.4 mEq/L as the reference group. Results: Of 57,874 eligible patients, with a mean discharge serum potassium of 4.1 ± 0.4 mEq/L, the estimated one-year mortality rate after discharge was 13.2%. A U-shaped association was observed between discharge serum potassium and one-year mortality, with the nadir mortality in the discharge serum potassium range of 4.0–4.4 mEq/L. After adjusting for clinical characteristics, including admission serum potassium, both discharge serum potassium ≤3.9 mEq/L and ≥4.5 mEq/L were significantly associated with increased one-year mortality, compared with the discharge serum potassium of 4.0–4.4 mEq/L. Stratified analysis based on admission serum potassium showed similar results, except that there was no increased risk of one-year mortality when discharge serum potassium was ≤3.9 mEq/L in patients with an admission serum potassium of ≥5.0 mEq/L. Conclusion: The association between discharge serum potassium and one-year mortality after hospital discharge had a U-shaped distribution and was independent of admission serum potassium. Favorable survival outcomes occurred when discharge serum potassium was strictly within the range of 4.0–4.4 mEq/L.

Background: This study aimed to assess the risk factors and impact of acute myocardial infarction on in-hospital treatments, complications, outcomes, and resource utilization in hospitalized patients for heat stroke in the United States. Methods: Hospitalized patients with a principal diagnosis of heat stroke were identified in the National Inpatient Sample dataset from the years 2003 to 2014. Acute myocardial infarction was identified using the hospital International Classification of Diseases, Ninth Revision (ICD-9), diagnosis of 410.xx. Clinical characteristics, in-hospital treatment, complications, outcomes, and resource utilization between patients with and without acute myocardial infarction were compared. Results: A total of 3372 heat stroke patients were included in the analysis. Of these, acute myocardial infarction occurred in 225 (7%) admissions. Acute myocardial infarction occurred more commonly in obese female patients with a history of chronic kidney disease, but less often in male patients aged <20 years with a history of hypothyroidism. The need for mechanical ventilation, blood transfusion, and renal replacement therapy were higher in patients with acute myocardial infarction. Acute myocardial infarction was associated with rhabdomyolysis, metabolic acidosis, sepsis, gastrointestinal bleeding, ventricular arrhythmia or cardiac arrest, renal failure, respiratory failure, circulatory failure, liver failure, neurological failure, and hematologic failure. Patients with acute myocardial infarction had 5.2-times greater odds of in-hospital mortality than those without myocardial infarction. The length of hospital stay and hospitalization cost were also higher when an acute myocardial infarction occurred while hospitalized. Conclusion: Acute myocardial infarction was associated with worse outcomes and higher economic burden among patients hospitalized for heat stroke. Obesity and chronic kidney disease were associated with increased risk of acute myocardial infarction, while young male patients and hypothyroidism were associated with decreased risk.

Cervical vagal nerve stimulation (VNS) is an FDA approved treatment for epilepsy and depression and is currently being evaluated for treatment of numerous other disorders including pain, anxiety, and inflammation. VNS also received European market approval for heart failure, bronchoconstriction, and diabetes; however, approval for these indications was based on studies in animals, such as dogs and rats, whose vagal nerve size may not have been representative of humans. When subjected to double‐blinded, randomized, sham controlled studies for subsequent U.S. approval, many of these CE‐marked VNS indications failed to meet their primary efficacy endpoints. More than 100,000 patients have undergone VNS, but despite the efficacy of vagal nerve stimulation in a subset of patients, many fail to reach stimulation levels that result in alleviation of symptoms without triggering unwanted side effects. Post hoc studies of the patient population suggested that VNS may not engage the intended fiber pathways in humans, despite engagement in preclinical studies in mouse, rat, or dog. Stimulation parameters were limited in these studies as higher parameters caused side effects such as cough, voice alteration, and dyspnea. Discrepancies between stimulation amplitude needed for intended effect versus unwanted side effect could be directly related to the relative size of the vagus nerve across animal models, variations in fascicle organization, or variations in branching patterns. To address translating improvements in VNS from the lab to the clinic, we evaluated the swine as a potential model for approximating the clinical environment. The size and fascicular organization of the swine vagus nerve is more representative of the human nerve than previously used models. We used a combination of histology, microdissection, and ultrasound to establish a distinct bimodal organization of groups of fascicles stemming from one large fascicle at the inferior (nodose) ganglion, an organization we have termed ‘vagotopy’. We demonstrated that with the use of ultrasound we can visualize the fascicular organization in vivo , an approach that could be used clinically to target stimulation of either sensory fibers or parasympathetic efferents, depending on therapeutic intent. These advances in a clinically relevant model not only inform electrode placement for target engagement, but provide an approach for reduction of side effects. Support or Funding Information Acknowledgements Funded by TL1TR002380 andThe Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO) Targeted Neuroplasticity Training Program under the auspices of Doug Weber and Tristan McClure‐Begley through the Space and Naval Warfare Systems Command (SPAWAR) Systems Center with (SSC) Pacific grants no. N66001‐17‐2‐4010, and the NIH SPARC Program Award OT2 OD025340.

Vagus nerve stimulation (VNS) is FDA‐approved and CE‐marked for a diverse set of conditions including epilepsy, depression, heart failure, and others. Despite widespread adoption and perceived efficacy, a post‐hoc analysis of patients treated for heart failure using VNS revealed that only 12% of patients showed stimulation evoked heart rate changes one‐year post‐implant. This finding is not unexpected given that A‐type nerve fibers have the lowest activation thresholds, and they innervate neck muscles, causing contractions that patients will not tolerate. Therefore, muscle responses at lower amplitudes may have prevented application of higher amplitudes required to achieve cardiac effects in clinical trials of VNS for heart failure. Understanding therapy‐limiting side effects to VNS and finding ways to mitigate them are critical for optimizing VNS for clinical therapies. We developed a swine model of VNS which closely approximates the size and fascicular organization of the cervical vagus nerve observed in humans. The clinical LivaNova stimulation electrode was used as advised by a practicing neurosurgeon. We hypothesized that neck muscle responses are mediated by somatic branches of the vagus nerve as opposed to direct electrical activation of the muscle fibers. Further, we hypothesized that stimulation evoked responses depend on the location of the stimulation electrode on the vagus nerve. We measured compound nerve action potentials using intrafascicular electrodes placed within the vagus to identify activation of different nerve fiber types by conduction velocity. The downstream effects of nerve fiber activation, i.e. changes in heart rate and neck muscle responses (EMG), were measured using an arterial catheter and intramuscular electrodes, respectively. We then used a neuromuscular junction blocking agent, as well as systematic transection of somatic vagus nerve branches, to specifically identify the pathways causing neck muscle contractions. Two pathways contributed to VNS‐evoked neck muscle responses: activation of nerve fibers in the recurrent laryngeal branch of the cervical vagus nerve at low amplitudes and in the superior laryngeal branch at higher amplitudes. Lesser activation of the superior laryngeal branch could be achieved by moving the stimulation electrode caudally down the length of the vagus. This work represents a step towards mitigating intolerable side effects of VNS, thereby allowing maximization of intended target engagement and therapeutic benefit. Support or Funding Information The Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO) Targeted Neuroplasticity Training Program under the auspices of Doug Weber and Tristan McClure‐Begley through the Space and Naval Warfare Systems Command (SPAWAR) Systems Center with (SSC) Pacific grants no. N66001‐17‐2‐4010, and the NIH SPARC Program Award OT2 OD025340.

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of the mTOR inhibitor RAD001 in low- grade lymphomas. Our preclinical studies demonstrated activity of mTOR inhibitors in Waldenstrom Macroglobulinemia (WM) cell lines and patient samples. This phase II study aimed to determine safety and activity of the oral mTOR inhibitor RAD001 (Novartis Pharmaceutical, MA) in patients with relapsed or refractory WM. METHODS: Patients who had at least one previous therapy for WM, and who had symptomatic relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received daily RAD001 at 10 mg. A cycle was considered 28 days. Patients were allowed to stay on therapy until progression of disease or excessive toxicity. This study was conducted in a collaborative effort between Dana Farber Cancer Institute (DFCI) and Mayo Clinic College of Medicine. Here, we report the data on the patients accrued at DFCI. RESULTS: 19 pts (15 men and 4 women) have been treated to date. All patients had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including included rituximab, nucleoside analogues (fludarabine or 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3330 mg/dL (range 1010– 7410). The median follow on RAD001 was 8 months (range 3 – 22 months). Eighteen pts are currently evaluable for response. Best responses to RAD001 after 2 cycles using IgM monoclonal protein were as follows: partial remission in 8 (44%), minimal response in 5 (28%). Progressive disease occurred in 4 (22%) and stable disease occurred in 1 (6%). The overall response rate (PR+MR) was 72%. The median duration of response has not been reached (3–22+ months). Patients tolerated therapy well without significant toxicities. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 1 patient, grade 3 pneumonia in 1 patient, grade 3 hyperglycemia in 1 patient and grade 3 mucositis in 1 patient. Other adverse events of grade 2 or lower included nail cracking, mucositis, diarrhea, and fatigue. Attributable toxicities otherwise proved manageable with appropriate supportive care, and RAD001 was generally well tolerated. One patient enrolled on the study withdrew consent and changed to hospice care within 3 weeks of therapy, and passed away due to disease progression. CONCLUSIONS: The use of the oral RAD001 single agent RAD001 in patients with relapsed or refractory WM was welltolerated and demonstrated significant activity achieving an overall response rate in 72% of patients. Future studies of combination of this agent with rituximab and bortezomib are currently being planned.