Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving CAR-T Cell Therapy

Introduction: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas. Despite this improvement, a subset of patients do not respond to treatment or relapses afterwards. The purpose of this study is to determine patient clinical and radiographic variables that may be predictive of response to CAR-T therapy in order to improve patient selection for CAR-T therapy. Methods: We conducted a single-center retrospective review of all R/R B-cell non-Hodgkin lymphoma patients who received infusion of CAR T-cells from 2017-2020 and had one PET scan post-treatment for response evaluation. Clinicopathological and radiographic parameters were identified a-priori and collected through chart review. PET parameters included standardized uptake value (SUV), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG). For continuous parameters without established cutoffs, variables were dichotomized separately for time to progression and time to death using the Contal and O'Quigley method. Risk factors for progression free survival (PFS) and overall survival (OS) were identified by constructing a univariate Cox proportional hazards regression model. Variables meeting a p-value threshold of 0.10 for PFS or OS were included in stepwise selection to create a final multivariate model for PFS and OS at one year. Variables were retained with a p-value ≤0.05. The same process was also completed to create multivariate logistic regression models for progressive disease and death at one year. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). Results: 64 patients with R/R lymphoma (87% DLBCL) were included in the study. At a median follow up of 23.7 months (95% CI: 16.8 months, 28.8 months), 37 patients (57.8%) progressed and 33 patients (51.6%) remain alive. Median progression free survival (PFS) at 1 year was 9.0 months (95% CI: 3.1 months, not reached) and median overall survival (OS) at 1 year was not reached, though the lower bound of its 95% CI is 11.4 months. Investigating progression at 1 year, the following variables met a p-value threshold of 0.10 in univariate Cox regression models and were therefore included in stepwise selection of the multivariate model for progression: stage (III/IV vs I/II) (odds ratio (OR) 3.132, p=0.0824), extranodal involvement (OR 2.117, p=0.0314), IPI score (OR 1.467, p=0.0125) and tocilizumab administration (OR 0.555, p=0.0932). The final multivariate model identified IPI (OR 1.972, p=0.0022) and tocilizumab administration (OR 0.277, p=0.0095) as predictive variables for PFS at 1 year. Investigating OS at 1 year, the following variables met a p-value threshold of 0.10 in univariate Cox regression models and were therefore included in stepwise selection of the multivariate model for survival: ECOG 2 (OR 4.677, p=0.0757), LDH high (OR 2.401, p=0.0453), CNS involvement (OR 5.030, p=0.0105), IPI (OR 1.720, p=0.0075), Ferritin pre CAR T (continuous) (OR 1.001, p=0.0041), CRS (OR 0.437, p=0.0658), tocilizumab administration (OR 0.363, p=0.0363), TMTV >89 (OR 2.479, p=0.0442), TLG >229 (OR 2.188, p=0.0918), and SUV >18 (OR 2.116, p=0.0906). The final multivariate model identified IPI (OR 1.973, p=0.0082), ferritin (OR 1.001, p=0.0101), and tocilizumab administration (OR 0.216, p=0.0046) as predictive variables for OS at 1 year. The multivariate logistic regression model identified stage IV disease (OR 23.952, p=0.0029) and BMI >24 (OR 0.225, p=0.0472) as predictors for progression at 1 year and IPI (OR 2.607, p=0.0071) and tocilizumab administration (OR 0.108, p=0.0068) as predictors for survival at 1 year. The AUROC for progression and death were 0.815 (p<0.0001) and 0.833 (p<0.0001), respectively. Conclusions: Both clinical and radiographic variables identify R/R lymphoma patients who are at low or high risk for progression and/or poor overall survival after CAR T-cell therapy. IPI, ferritin, BMI, advanced stage, and tocilizumab administration may be predictors of response. These results need validation in larger prospective trials. Figure 1 Figure 1. Disclosures Kamdar: Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Genetech: Other; Kite: Consultancy; KaryoPharm: Consultancy; AbbVie: Consultancy; Genentech: Research Funding; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; Celgene: Other.

DNR Code Status Is Not Associated with Under-Utilization of Inpatient Transthoracic Echocardiograms

In the strictest sense, do-not-resuscitate (DNR) status means that cardiopulmonary resuscitation should not be performed after death has occurred; all other medical interventions in line with a patient’s goals of care should be implemented. The use of transthoracic echocardiography (TTE) in patients with DNR status is unknown. Therefore, we aim to evaluate the utilization of TTE among patients with DNR status using this retrospective data analysis. A total of 16,546 patient admissions were included in the final study. A total of 4370 (26.4%) of the patients had a TTE during hospitalization; among full code patients, 3976 (25.7%) underwent TTE, whereas TTEs were performed in 394 (37.4%) of DNR patients. On univariate logistic regression analysis, full code status had OR (95% confidence interval, CI) 0.57 (0.51–0.66), p < 0.01 compared with DNR status for the performance of inpatient TTE. In the final multivariate model adjusted for age, sex, race, and clinical comorbidities, the full code patients had OR (95% CI) 0.91 (0.79–1.05), p = 0.22 compared with DNR patients for the performance of inpatient TTE. DNR status is not associated with a decrease in inpatient transthoracic echocardiography performance.

Prevalence of skin tears in hospitalized adults and older adults

ABSTRACT Objective: To identify the prevalence, related factors and to classify Skin Tears in hospitalized adults and older adults. Method: Prevalence study with adults and older adults in inpatient and intensive care units of a hospital in the South Region of Brazil. The STAR Skin Tear Classification System was used to analyze the lesions. Data were collected by physical examination and consultation of medical records. The Poisson Regression Prevalence Ratio with robust variance was calculated. Results: The participants were 148 patients. There were 29 Skin Tears (mean 1.6 ± 0.7) in 18 individuals (prevalence of 12.2%). The variables age, friable skin, enteral feeding catheter, degree of dependence, use of antihypertensives, micronutrients, diuretics, antidepressants, and antifungals were associated with lesions in the bivariate analysis. In the final multivariate model, antihypertensives PR 2.42 (95%CI 1.01-5.77), antidepressants PR 2.72 (95%CI 1.1-6.33) and micronutrients PR 4.93 (95%CI 1.64-14.80) maintained a relationship. Conclusion: The prevalence of injuries was 12.2%, showing they are present in the health care setting, especially in nursing care. Care protocols need to be developed for the prevention, identification and early treatment of ST.

Investigating the Impact of Indemnity Waivers on the Length of Stay of Cats at an Australian Shelter

Due to resource limitations, animal shelters in Australia historically have focused on rehoming animals considered ‘highly adoptable’. Increasingly, animal shelters in Australia are rehoming animals with pre-existing medical and/or behavioural issues. These animals are often rehomed with an ‘indemnity waiver’ to transfer the responsibility of ongoing financial costs associated with these conditions from the shelter to the new owner. However, it is unknown what effect these indemnity waivers have on the length of stay (LOS) of animals prior to adoption. The current study used data collected from the Royal Society for the Prevention of Cruelty to Animals (RSPCA) Weston shelter located in the Australian Capital Territory (ACT), Australia in 2017 to investigate the effect of indemnity waivers on the LOS of cats. A restricted maximum likelihood model (REML) was used to determine the effect of breed, age, coat colour, presence of a waiver, waiver type (categorised into seven groups) and waiver number (no waiver, single waiver or multiple waivers) on LOS. In the final multivariate model, age, breed and waiver number were found to influence LOS. Young cats, purebred cats and cats adopted without a waiver were adopted fastest. This study is the first to report the effect of indemnity waivers on the adoptability of cats from shelters.

A simple prognostic model for overall survival in metastatic renal cell carcinoma

<p><strong>Introduction:</strong> The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival.</p><p><strong>Methods:</strong> We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first-line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had.</p><p><strong>Results:</strong> There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate-risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months.</p><p><strong>Conclusions:</strong> In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis.</p>

A preoperative clinical staging and metabolic imaging model to predict prognosis in early-stage esophageal adenocarcinoma.

63 Background: Accurate prediction of outcome for neo-adjuvant therapy in early stage esophageal adenocarcinoma (EAC) is essential for clinical trial design, patient counseling and treatment decisions. The use of 18F-fluorodeoxyglucose positron emission tomography (PET) has improved the staging of EAC and can predict pathological response and survival. Our aim was to develop a pre-operative prognostic model based on metabolic imaging and clinical parameters. Methods: Between April 2004 and December 2010, 118 patients with early stage adenocarcinoma of the distal esophagus or gastro-esophageal junction were treated with platinum and fluorouracil-based combination chemotherapy prior to surgical resection. Patients were staged by endoscopic ultrasound and PET/CT was performed prior to, and upon completion of, chemotherapy. A metabolic response was defined as a >35% reduction in the maximum standard uptake variable (SUVmax). The final prognostic model was selected by multivariate Cox regression analyses and the concordance-index (c-index) was used to assess the fit of the final multivariate model. Results: In both the univariate and multivariate analysis of patient prognosis post-surgery, five pre-surgery factors were included: clinical T and N staging, PET response, neutrophil-lymphocyte ratio and albumin levels. The majority of the patients were T3 (82.1%) and N1 (73.7%) and 69.8% of patients demonstrated a PET response. In the univariate analysis PET response was the only significant prognostic factor with a median overall survival (OS) of 60.4 months for responders compared to 23.3 months for non-responders (p=0.0241). The final multivariate model of T staging and PET response had a c-index of 0.624 with T3/PET non-response resulting in a poorer prognosis compared to T3/PET response and T2/PET responder or non-responder (median OS 11.5 vs 44.5 vs undefined months; p=0.0284). We seek to validate our model in an independent patient dataset to assess its predictive capability. Conclusions: Metabolic imaging and clinical staging can be combined in a prognostic model in early stage EAC. Our model can inform patient counseling and the development of clinical trial strategies.

Sexuality Challenges, Intimacy, and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG)

Background We have previously reported on the high prevalence and severity of challenges with intimacy and sexuality amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between issues of intimacy (sexual desire and function), their relationships to MPN disease features, individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF sexuality item asked about “problems with sexual desire or function”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF sexuality item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the sexuality item with the final multivariate model selected using forward regression. Results Demographics A total of 1908 MPN patients (essential thrombocythemia=799, polycythemia vera=671, myelofibrosis=432, missing=6) completed the sexuality item. Participants were of typical age (median=60, range 15-94) and gender (female=53%). Overall, 1218 subjects described sexuality related complaints (score >0) with an overall mean symptom score of 3.5 (median=2.0, SD=3.7, range 0-10); 725/1908 (38%) patients had severe sexuality related complaints (score >4). Univariate Analysis Among the QLQ-C30 functioning scales, all domains had similar statistically significant correlations (r=-.26 to -.32, all p<0.001). Among QLQ-C30 symptom scales, all QLQ-C30 symptoms displayed correlations ranging between .08 and .29 (all p<0.001). Among MPN-SAF items, the MPN-SAF sexuality item correlated most significantly with the TSS (r=.41, p<0.001), along with MPN-SAF symptoms (r=.16 to .39; all p<0.001). MPN-SAF sexuality measure significantly differed by anemia (means: absent 3.3, present 4.5; p<0.001), leukopenia (means: absent 3.4, present 4.4; p=0.01), thrombocytopenia (means: absent 3.3, present 4.5; p<0.001), red cell transfusion (means: no 3.5, yes 5.0; p<0.001), MPN subtype (ET mean 3.1, PV mean=3.6, MF mean=4.4; p<0.001) and language (means ranged from 2.4 [Swedish] to 4.6 [Chinese]; p<0.001). MPN-SAF sexuality did not significantly differ by age, gender, prior thrombosis or prior hemorrhage. Multivariate Analysis In a multivariate model of MPN-SAF sexuality containing all QLQ-C30 functioning scales, physical (p=0.001), emotional (p=0.01), cognitive (p=0.005) and social (p=0.002) functioning were all statistically significant. Numerous symptoms were also significant in a multivariate model of MPN-SAF sexuality containing all other MPN-SAF symptoms (all p<0.05; abdominal pain, inactivity, dizziness/vertigo/lightheadedness, insomnia, depression/sad mood, cough, night sweats and overall QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, language, QLQ-C30 role functioning and MPN-SAF items (insomnia, depression/sad mood, night sweats and QOL) to be significant (p<0.05). Conclusions Sexuality related complaints have been linked to both physiologic and psychologic origins and are highly prevalent within the MPN population. The results of this study congruently identified close associations between sexuality and function within emotional, cognitive and social domains. Additionally, the correlations of sexuality issues with MPN symptoms and disease features further suggest this item is a key correlate of overall functionality and quality of life. Future investigations into the causative factors and biological correlates of this complaint may assist in addressing this ongoing challenge. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding.

Gender and Race As Prognostic Factors In Patients Treated With Rituximab For B-Cell Non-Hodgkin Lymphoma

Introduction The International Prognostic Index (IPI) and the age-adjusted IPI (aaIPI) are the most commonly used tools to predict outcomes in patients with Non-Hodgkin Lymphoma (NHL). The IPI does not take into account sex or race. In the pre-rituximab era, sex was found to be a strong predictor of poor prognosis in low-grade lymphomas. While there is emerging evidence that female sex is associated with better survival in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, much less is known about the prognostic impact of race. We retrospectively assessed the impact of sex and race on overall survival in patients with indolent and aggressive NHL treated at any stage with rituximab at our institution. Methods We retrospectively identified all patients >/=18 years who were diagnosed with B-cell NHL (except SLL/CLL and Burkitt lymphoma) between 1/1/2000 and 12/31/2010 and received rituximab at any stage as part of their therapy at the Montefiore Medical Center. We collected data on histology, age (<60 vs. >/=60), date of diagnosis, date and status at last follow-up, and stage from the MECCC Cancer registry, and we obtained data on the Charlson Comorbidity Index (CCI) from Clinical Looking Glass® (CLG), an interactive software application developed at Montefiore Medical Center which integrates clinical and administrative datasets. The histological subtypes DLBCL and grade 3 follicular lymphoma (FL) were classified as “high-grade lymphoma” (HGL), while other types of lymphoma were termed “low-grade lymphoma” (LGL; these included marginal zone lymphoma, mantle cell lymphoma, grade 1 & 2 FL, and malignant lymphoma NOS). Self-reported race was classified as White, Black, Hispanic or “Other”. Only <2% of the patients were of “Other” racial background and therefore excluded from this analysis. The primary outcome was overall survival (OS) calculated as time from diagnosis to time of death. We used the Kaplan-Meier (KM) method to describe OS for race and sex and the log-rank test to test for significance (p<0.05). We used a Cox proportional hazard (CPH) model to assess the association of variables with OS. Except for age, race and sex, variables that were not significantly associated with OS (i.e. p-value>0.10 in the multivariate model) were excluded from the final model (backward elimination). Results 353 patients were included in the analysis. Median follow-up for all patients was 37.3 months (range 0.03-202.40). Baseline characteristics between male and females were similar with the exception of age at diagnosis and histology (see Table 1). On univariate analysis there was no OS difference between male and female patients (p=0.13), while race was associated with significant differences in OS (p=0.04; see Fig. 1). In the multivariate model, only stage >/=3 was associated with worse survival (Hazard Ratio [HR] 2.78, 95% CI 1.62-4.77; p<0.0001), but there was no significant association with OS for type of lymphoma (HGL vs. LGL) or the CCI (low vs. high score) and these 2 variables were therefore eliminated from the final multivariate model. In the final multivariate model, female sex was associated with a 37% reduction in the risk of death (HR 0.63; 95%CI 0.40-0.98; p=0.04), while race was no longer associated with OS (Hispanic vs. White: HR 0.76, 95%CI 0.41-1.40, p=0.38; Black vs. White: HR 0.66, 95%CI 0.40-1.10; p=0.11; Black vs. Hispanic: HR 1.15; 95% CI 0.63-2.08, p=0.65). Conclusions Female patients treated at any stage with rituximab for high-grade and low-grade B-cell NHL at our institution experienced longer OS. However, we observed no racial disparity in survival in our analysis. Disclosures: No relevant conflicts of interest to declare.

Insomnia, Quality Of Life and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG)

Background We have previously reported on the high prevalence and severity of insomnia amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between insomnia and the MPN disease features (in particular splenomegaly, status of blood counts), individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF insomnia item asked about “difficulty sleeping”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF insomnia item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the insomnia item with the final multivariate model selected using forward regression. Results Demographics A total of 1992 MPN patients (essential thrombocythemia=834, polycythemia vera=703, myelofibrosis=449, unknown=6) completed the insomnia item. Participants were of typical age (median=61, range-15-94) and gender (female=54%). Overall, 1307 subjects endorsed the MPN insomnia item (score >0) with an overall mean symptom score of 3.0 (median=2.0, SD=3.1. range=0-10); 603/1992 (30%) of patients had severe insomnia related complaints (score >4). Univariate Analysis Among QLQ-C30 functioning scales, emotional functioning most highly correlated with the MPN-SAF insomnia item (r=-.47, p<0.001) with all other domains also having statistically significant but slightly weaker correlation (all p<0.001). Among QLQ-C30 symptom scales, insomnia (r=.79, p<0.001) and fatigue (r=.45, p<0.001) most highly correlated with the MPN-SAF insomnia item with all other QLQ-C30 symptoms having correlations between .13 and .37 (all p<.001). Among MPN-SAF items, the MPN-SAF insomnia item correlated with all MPN-SAF items (all p<0.001) including the TSS (r=0.55, p<0.001) and most highly with depression (r=.52, p<0.001), concentration problems (r=.43, p<0.001), overall QOL (r=.41, p<0.001), night sweats (r=.41, p<0.001), and extremity tingling (r=.40, p<0.001). MPN-SAF insomnia significantly differed by gender (means: M 2.4, F 3.4; p<0.001), language (means ranged from 2.6 [Italian] to 3.6 [German]; p=0.01), anemia (means: absent 2.8, present 3.5; p<0.001), prior hemorrhage (means: no 2.9, yes 3.7; p=0.01), and requiring red blood cell transfusion (means: no 2.9, yes 3.6; p=0.03), with a trend for a difference by MPN type (ET mean=2.7, PV mean=3.0, MF mean=3.2; p=0.06). Multivariate Analysis In a multivariate model of MPN-SAF insomnia containing all QLQ-C30 functioning scales, physical, emotional, and cognitive functioning along with global health status/QOL were all significant (all p<0.001). Numerous symptoms were also significant in a multivariate model of MPN-SAF insomnia containing all other MPN-SAF symptoms (all p<0.05: headaches, extremity tingling, depression, sexual problems, night sweats, pruritus, fever, and QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, gender, QLQ-C30 emotional functioning and MPN-SAF items to be significant. Conclusions Insomnia is highly prevalent and severe in MPN patients and closely correlates with most other MPN-related symptoms and functional domains bearing a multi-faceted impact on overall quality of life. Correlations between insomnia and emotional, cognitive, and physical complaints including depression/sad mood, concentration problems, night sweats, and numbness/tingling in the extremities suggest that the cause of MPN-related sleep complaints is likely complex. Future studies should evaluate the impact of interventions on MPN associated insomnia as well as its biological underpinnings. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.