Citations

88 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

AbstractAlthough autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup.Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HRadj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HRadj = 8.34 (CI, 3.01‐23.1) and HRadj = 3.83 (CI, 1.20‐12.3), respectively.Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.

Abstract BACKGROUND: Arm morbidity, the most reported comorbidity following axillary surgery for breast cancer, is of particular importance in young patients given the longer survivorship period and detrimental effects of arm-morbidity on body image and social-, home- and personal care functions. We assessed the incidence of arm-morbidity stratified by local therapy strategies in young women enrolled in the Young Women's Breast Cancer Study (YWS). PATIENTS AND METHODS: The YWS, a multicenter prospective cohort study, established to explore biological, medical and psychosocial issues in young breast cancer patients, enrolled 1302 women with stage 0-4 breast cancer ≤40 years of age from October 2006 to June 2016. For this analysis, we examined incidence of patient reported arm-swelling or decreased range of motion (ROM) 1-year after diagnosis using relevant items of the CARES-SF. Patients with stage 4 disease (n = 60), those for whom no information on arm-morbidity was available (n=198) and those with bilateral cancer with different local therapy strategies on each side (n=7), were excluded. We performed logistic regression analyses to identify risk factors for arm morbidity. RESULTS: Among 1037 patients (median age 37 years), 13% and 40% reported arm-swelling or decreased ROM, respectively, in the ipsilateral arm at 1-year. 52% (n=539) of patients underwent SLNB and 39% (n=407) ALND. The incidence of arm-swelling was 4% (11/280) in patients who underwent SLNB without RT, 8% (21/252) in patients who underwent SLNB with RT, 20% (13/66) in patients who underwent ALND without RT and 24% (84/337) in patients who received ALND with RT. The incidence of decreased ROM was 21% (59) in patients who underwent SLNB without RT, 34% (86) in patients who underwent SLNB with RT, 33% (22) in patients who underwent ALND without RT and 44% (148) in patients who received ALND with RT. Being overweight, uncomfortable financial status, T4 tumors, ALND and RT were independently associated with an increased risk of arm-swelling. Overweight, mastectomy and RT were independently associated with an increased risk of a decreased ROM Table 1). Results of the logistic regression analyses. Arm swelling at 1 year (n=137)Decreased ROM at 1 year (n=335) ORpORpBMI <18.50.70.620.70.4018.5-24.9ref ref 25-29.91.70.031.50.05≥301.10.791.10.70Financial comfort Comfortableref ref Uncomfortable0.60.020.90.67pT stage pT1ref ref pT21.20.621.50.13pT31.20.701.30.63pT44.40.032.20.29pN stage pN0ref ref pN11.10.851.70.08pN23.00.111.90.27pN33.20.112.70.16Surgery BCSref ref Mastectomy1.20.611.80.02Bilateral mastectomy1.10.841.60.06Axillary surgery SLNBref ref SLNB + ALND3<0.011.30.33ALND3.6<0.011.00.90RT Noref ref Yes1.80.052.4<0.01Note. In these analysis we also corrected for age, incidence year, employment status, stage of disease, reconstructive surgery, and chemotherapy treatment. . CONCLUSION: Patient reported outcomes reveal high rates of arm-swelling and decreased ROM 1 year after breast cancer diagnosis in a large prospective cohort of young breast cancer survivors. These findings suggest an opportunity for pre-operative education and early intervention for arm impairment in this population. Citation Format: Kuijer A, Dominici LS, Rosenberg SM, Hu J, Gelber S, Di Lascio S, Ruddy KJ, Wong J, Tamimi RM, Schapira L, Borges VF, Come SE, Sprunck-Harrild K, Partridge AH, King TA. Risk of arm morbidity after local therapy in young breast cancer survivors [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 GS5-03.

Objective A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. Design Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. Results We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. Conclusion Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

Objective Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Methods Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. Results We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; −44 ± 25 vs −21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one‐third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy ( p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. Interpretation A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522–531

Abstract BACKGROUND Neck remnants are not uncommon after endovascular treatment of cerebral aneurysms. Critics of endovascular treatments for cerebral aneurysms cite neck remnants as evidence in favor of microsurgical clipping. However, studies have failed to evaluate the true clinical significance of aneurysm neck remnants following endovascular therapies. OBJECTIVE To assess the clinical significance of residual aneurysm necks and to determine the rate of subsequent rupture following coiling or stent-assisted coiling of cerebral aneurysms. METHODS We retrospectively reviewed the records of 1292 aneurysm cases that underwent endovascular treatment at 4 institutions. Aneurysms treated by primary coiling or stent-assisted coiling were included in the study; those treated by flow diversion were excluded Aneurysms with residual filling (i.e., Raymond–Roy Occlusion Classification II, neck remnant; or III, residual aneurysm filling) were assessed for their risk of subsequent rupture. RESULTS A total of 626 aneurysms were identified as having residual filling immediately posttreatment. Of these, 13 aneurysms (2.1%) ruptured during the follow-up period (mean 7.3 mo; range 1-84 mo). Eleven of the 13 (84.6%) were ruptured at presentation. Rupture at presentation, the size of the aneurysm, and the increasing age of the patient were predictive of posttreatment rupture. CONCLUSION We found that unruptured aneurysms with residual necks following endovascular treatment posed a very low risk of rupture (0.6%). However, patients presenting with ruptured aneurysms had a higher risk of rerupture from a neck remnant (3.4%). These results highlight the importance of achieving complete angiographic occlusion of ruptured aneurysms.