Significant Independent Covariates Research Articles

Prognostic factors for esophageal squamous cell carcinoma without pathological lymph node metastasis after neoadjuvant therapy and surgery.

Pathological lymph node metastasis (LNM) following multimodal therapy is an important indicator of poor prognosis in patients with esophageal cancer. However, a significant number of patients without LNM are still at high risk for recurrence. We assessed prognostic factors in 143 patients without pathological LNM who were diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) and underwent neoadjuvant chemotherapy (NAC) or chemoradiotherapy (NACRT), followed by surgery. Using univariate and multivariate analyses of recurrence-free survival, carcinoembryonic antigen (CEA) levels (hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.12-4.23, and p=0.02) and neutrophil-to-lymphocyte ratio (NLR) (HR: 1.22, 95% CI: 1.04-1.43, and p=0.02) were significant independent covariates. Furthermore, pretherapeutic LNM (HR: 1.94, 95% CI: 1.003-3.76, and p=0.049), NACRT (HR: 3.29, 95% CI: 1.30-8.33, and p=0.01), poorly differentiated tumors (HR: 2.52, 95% CI: 1.28-4.98, and p=0.01), and lymphovascular invasion (LVI) (HR: 2.78, 95% CI: 1.27-6.09, and p=0.01) were also significant independent covariates. The recurrence rates among patients with 0/1, 2, 3, and 4/5 poor prognostic factors were significantly different (5.0%, 25.0%, 35.7%, and 53.8%, respectively; p=0.001); the survival rates were stratified among these prognostic groups. Pretherapeutic CEA and NLR levels, pretherapeutic LNM, NACRT, poorly differentiated tumors, and LVI were significantly correlated with survivals in patients without pathological LNM after neoadjuvant therapy and surgery. Postoperative therapy should be considered in patients with ESCC with several indicators of recurrence, even in those without pathological LNM who underwent surgery following neoadjuvant therapy.

Economic living standard and abdominal pain mediate the association between functional gastrointestinal disorders and depression or anxiety.

Functional gastrointestinal disorders (FGIDs) are common and cause significant morbidity. Psychiatric comorbidities associated with FGIDs include anxiety and depression. However, little is understood about the factors that modulate this association. The aim of this study was to examine the association between FGIDs and depression and anxiety, and to determine the covariates influencing this association in a New Zealand cohort. The Christchurch IBS cOhort to investigate Mechanisms FOr gut Relief and improved Transit (COMFORT) study is an observational case-control study that recruited FGID cases and healthy controls between 2016 and 2018. In addition to the collection of a wide range of biological samples, participants completed questionnaires concerning socioeconomic status, physical activity, smoking, alcohol intake, anxiety, and depression (the latter two measured using the Hospital Anxiety and Depression Score [HADS]). A multivariate analysis was performed using the significant covariates from the univariate analyses to test whether their effect was independently significant on anxiety and depression. A total of 315 participants (57 with diarrhea-predominant IBS (IBS-D), 30 with constipation-predominant IBS (IBS-C), 41 with mixed-IBS (IBS-M), 16 with functional diarrhea (FD), 42 with functional constipation (FC), and 129 controls); mean age 53 years (range 18-70 years), 221 (70%) female) completed the questionnaires. Anxiety (odds ratio [OR] 2.85 [95% confidence interval [CI] 1.64-4.94, p < 0.01) and depression (OR 3.40 [95% CI 1.35-8.55, p=0.01]) were strongly associated with FGID cases versus controls. Lower economic living status (p < 0.01) was an independent covariate associated with depression, while lower economic living status (p < 0.005) and abdominal pain (p=0.005) were both independently associated with anxiety. In addition to the established associations between FGIDs and anxiety and depression, we have shown that the economic standard of living, pain, and IBS phenotype are significant independent covariates. This study demonstrates the range of lifestyle and demographic factors that modulate morbidity associated with FGIDs and may provide targets for intervention.

P755: HYPERFERRITINEMIA IS A PREDICTIVE BIOMARKER OF POOR CLINICAL OUTCOMES IN CMML

Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Aims: We aimed to identify whether hyperferritinemia correlated with worse outcomes in CMML and to characterize relevant baseline clinical and molecular features associated with this clinical phenotype. Methods: Retrospective data was collected from a database of pts with CMML treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels (<1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin >1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n=168) developed hyperferritinemia vs 71% (n=403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p=0.001) and harbor a proliferative phenotype (p=0.01). They presented with higher marrow cellularity (mean 83%, p =0.08), PLT (mean 177k, p= 0.038), and lower Hb (mean 9.5, p<0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p=0.007), cytopenias (p<0.05), % peripheral blasts (p<0.05), RBC and PLT transfusion dependence (p<0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p<0.05); and had higher rates of AML transformation (p<0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p<0.05). ASXL1 (p=0.002), EZH2 (p=0.003), and SETBP1 (p=0.019) mutations were more common among pts who developed hyperferritinemia. Conversely, TET2 (p=0.001), CBL (p=0.028) and SRSF2 (p=0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin <1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p<0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR= 0.69; 95%CI 0.53-0.89; p=0.005). Summary/Conclusion: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.

Hyperferritinemia as predictive biomarker of poor clinical outcomes in CMML.

7055 Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Methods: Retrospective data was collected from a database of CMML pts treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels ( &lt; 1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin &gt; 1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n = 168) developed hyperferritinemia vs 71% (n = 403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p = 0.001) and harbor a proliferative phenotype (p = 0.01). They presented with higher marrow cellularity (mean 83%, p = 0.08), PLT (mean 177k, p = 0.038), and lower Hb (mean 9.5, p &lt; 0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p = 0.007), cytopenias (p &lt; 0.05), % peripheral blasts (p &lt; 0.05), RBC and PLT transfusion dependence (p &lt; 0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p &lt; 0.05); and had higher rates of AML transformation (p &lt; 0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p &lt; 0.05). ASXL1 (p = 0.002), EZH2 (p = 0.003), and SETBP1 (p = 0.019) mutations were more common among pts with hyperferritinemia. Conversely, TET2 (p = 0.001), CBL (p = 0.028) and SRSF2 (p = 0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin &lt; 1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p &lt; 0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR = 0.69; 95%CI 0.53-0.89; p = 0.005). Conclusions: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and higher rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.

Contemporary Experience with Paravisceral Aortic Aneurysm (PVAAA) Repair in a Tertiary Center

To describe contemporary outcomes from a single center capable of both complex open and endovascular aortic repair for paravisceral aortic aneurysms (PVAAA). Data on all patients receiving open or endovascular (endo) treatment for aortic aneurysms with proximal extent at or above the renal arteries and distal to the inferior pulmonary ligament (IPL) were reviewed. Coarsened exact matching (CEM) on age, aneurysm type, gender, coronary artery disease (CAD), previous aortic surgery and symptomatic status created balanced cohorts for outcomes comparisons. Between October, 2006 and February, 2018, 194 patients were treated for juxtarenal (40%), pararenal (21%), paravisceral (6%) and Type 4 thoracoabdominal (34%) aortic aneurysms with open (81, 42%) or endo (113, 58%) at a single tertiary center. Endo repairs included renal coverage with a bifurcated graft (2%), unilateral (13%) or bilateral (4%) renal snorkels, Z-fen (15%), multi-branched graft (IDE protocol; 62%) and unique complex configurations (4%). On multivariable analysis, patients selected for open surgery were more likely to be symptomatic, whereas older patients, female patients and those with Type 4 TAAA extent were more often selected for endovascular treatment. Matching based on the significant independent covariates reduced the open and endovascular groups by one-third. Survival at 30 days was 97% for endo and 94% for open repair, 98% for both subgroups when excluding symptomatic cases, and was not different between the matched groups (98% vs 89%; P=0.23). Hospital and ICU stays were longer in open patients (8 vs. 10 days, 2 vs. 4, both P≤0.001). Post-op CVA, MI, lower extremity ischemia, surgical site infections and reoperation were not different between matched groups (all p>0.05), while pulmonary and intestinal complications, as well as grade 1/2 renal dysfunction by RIFLE criteria, were more common after open repair (all P<0.05). Spinal cord ischemia was significantly more frequent in the unmatched Endo group (11% vs. 1%, P=0.02), but this difference was not significant after matching. Composite major aortic complications was no different between treatment groups (unmatched P=0.91, matched P=0.87). Endo treatment resulted in patients more frequently discharged to home (84% vs. 66%, P=0.02). Reintervention after 30 days occurred more frequently in the endo group (P=0.002). Estimated survivals at 1 and 5 years for endo and open are 96% vs. 81% and 69% vs. 81% respectively (Log-rank P=0.57). Contemporary repair of PVAAA demonstrates safe outcomes with durable survival benefit when patients are well-selected for open or complex endovascular repair. We believe these data have implications for off-label device use in the treatment of PVAAA, and that open repair remains an essential option for younger, good risk patients in experienced centers.

Epidemiological and clinical characteristics of 161 discharged cases with coronavirus disease 2019 in Shanghai, China

BackgroundIn December 2019, the outbreak of coronavirus disease 2019 (COVID-19) began in Wuhan, China, and rapidly spread to other regions. We aimed to further describe the epidemiological and clinical characteristics of discharged COVID-19 cases and evaluate the public health interventions.MethodsWe collected epidemiological and clinical data of all discharged COVID-19 cases as of 17 February 2020 in Shanghai. The key epidemiological distributions were estimated and outcomes were also compared between patients whose illness were before 24 January and those whose illness were after 24 January.ResultsOf 161 discharged COVID-19 cases, the median age was 45 years, and 80 (49.7%) cases were male. All of the cases were categorized as clinical moderate type. The most common initial symptoms were fever (85.7%), cough (41.0%), fatigue (19.3%), muscle ache (17.4%), sputum production (14.9%), and there were six asymptomatic cases. 39 (24.2%) cases got infected in Shanghai, and three of them were second-generation cases of Shanghai native cases. The estimated median of the time from onset to first medical visit, admission, disease confirmation, and discharge for 161 cases was 1.0 day (95% CI, 0.6–1.2), 2.0 days (95% CI, 1.5–2.6), 5.2 days (95% CI, 4.6–5.7), 18.1 days (95% CI, 17.4–18.8), respectively. The estimated median of the time from admission to discharge was 14.0 days (95% CI, 13.3–14.6). The time from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai’s first-level public health emergency response. In Cox regression model, the significant independent covariates for the duration of hospitalization were age, the time from onset to admission and the first-level public health emergency response.ConclusionsLocal transmission had occurred in Shanghai in late January 2020. The estimated median of the time from onset to discharge of moderate COVID-19 was 18.1 days in Shanghai. Time intervals from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai’s first-level public health emergency response. Age, the first-level public health emergency response and the time from onset to admission were the impact factors for the duration of hospitalization.

Higher serum PD-L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial.

The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P=.04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P=.37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P=.001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P=.0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

P1149PERITONEAL MEMBRANE CHARACTERISTICS OVER TIME: A LONGITUDINAL STUDY

Abstract Background and Aims Modified PET (use of 3.86% glucose dialysate instead of 2.27%) and temporal drainage at one hour allows a more complete study of peritoneal membrane transport, as it provides information about sodium sieving, free water transport (FWT) and ultrafiltration failure (UFF). Longitudinal data using this PET are sporadic. Aims of our study were a) longitudinal follow-up of the membrane function using modified PET b) evaluation of UFF and association with clinical and membrane characteristics. Method We analyzed all modified PET tests performed in our unit during the last 9 years. Patients who underwent the first test during the first year of treatment and then once a year were included. We estimated classic peritoneal transport parameters like D/P creatinine, D/D0 glucose and ultrafiltration (UF) at 4 hours. Moreover we calculated sodium seiving expressed as Dip/DPNa= (Dialysate sodium time 0/plasma sodium)-(Dialysate sodium time 1 hour/plasma sodium)], sodium removal (in one hour) and FWT. We collected clinical and lab data of the patients too. Results A total of 219 PETs were performed in 85 PD patients, (median age 64 years (range 18-45). The baseline membrane characteristics of the patients were: DP creatinine=0.74±0.11, D/D0glucose=0.28±0.08, DipDPNa=0.05±0.04, sodium removal=29,804 ±26,894 (mmol/L), FWT=214.9±194.7 ml and UF =655.1±265.5 ml. On multivariate regression analysis D/P creatinine, FWT and sodium removal were significant independent covariates accounting for 50% of the variability of ultrafiltration . The patients were followed-up for a median of 36 months (range 2.4-143).For the repeated measurements, the analysis showed that the observed values of D/Pcre,D/D0, Dip/DPNa, FWT and UF remained rather stable across the different time measurements. During the study, 23 out of 85 pts developed peritoneal UF failure (UFF). Analysis was performed using univariate random effects logistic time-series models and only D/D0 (OR=0.84, P=0.001), D/P Cre (OR=1.15, p&amp;lt;0.001), urine volume (OR=1.26, p=0.027) and sodium removal (OR=0.99, p=0.003) were significantly associated with relative risk of UFF development. Conclusion Surprisingly, our patients present a stable membrane function over time. Possible explanations could be the low peritonitis rate and strict use of hypertonic glucose dialysates. Ultrafiltration failure was correlated with higher D/P creatinine and lower D/D0 glucose values, higher baseline urine volume and lower sodium sieving.

Elevated serum activin A and PD-L1 and survival in the CCTG MA.31 phase III trial (trastuzumab vs. lapatinib) in first-line HER2+ metastatic breast cancer.

1031 Background: In MA.31 the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2+ metastatic breast cancer (MBC). In MA.31 we previously reported the prognostic/predictive utility of pretreatment serum PD-L1 (SABCS 2018, PD3-10) and serum activin A (SABCS 2016, P6-07-06) separately; here we evaluate them combined. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients, and pretreatment serum was available for 382 patients (184 in trastuzumab arm, 198 in lapatinib arm). The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1, and ELISA for activin A (R&amp;D Systems, Minneapolis, MN). Results: In correlation analysis, pretreatment serum PD-L1 was moderately correlated with serum activin A (r = 0.21, p = 0.004). In univariate analysis for OS, the combination of higher serum PD-L1 and higher serum activin A (median cutpoints) (vs. both low) was significant for shorter OS in the trastuzumab arm (HR 6.62, p=0.0005) and in the lapatinib arm (HR 3.25, p=0.0003)(table). In multivariate analysis for OS (17 covariates included), elevated serum activin A/PD-L1 combination remained the most significant independent covariate in the trastuzumab arm (HR 12.40, p=0.001), and in the lapatinib arm (HR 5.2, p=0.0001). Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum activin A (TGF-B superfamily) and PD-L1 was associated with a shorter OS to HER2-targeted treatment. Multiple mechanisms, including immune evasion, may decrease the effectiveness of HER2-targeted therapy. Elevated serum activin A and PD-L1 may identify HER2-positive MBC patients who would benefit from inhibitors of the HER2, PD-1, and activin A pathways. [Table: see text]

Abstract PD3-10: Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial

Abstract Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015). Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab. Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (&amp;gt;median vs &amp;lt;median)0.0012.271.403.68EGFR Status (continuous IHC score)0.0031.0121.0041.019Other Chemotherapy (yes vs no)0.0081.911.193.07Treatment Arm (trastuzumab vs. lapatinib)0.0100.530.330.86ECOG Performance Status (0 vs 1 or 2)0.0250.590.370.94Ki67 (log)0.0461.451.0062.081 Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-10.

Clinical, Angiographic, and Procedural Correlates of Acute, Subacute, and Late Absorb Scaffold Thrombosis

ObjectivesThe authors sought to identify and verify independent correlates of device thrombosis from an analysis of multicenter trials and registries. BackgroundRecent analyses suggest an increased risk of device thrombosis with Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, California) implantation compared with metallic drug-eluting stents, and data from moderate size studies suggest a risk relationship to vessel size and technique. MethodsFrom 8,771 consecutively treated patients, 105 patients (1.2%) were identified with scaffold thrombosis within 1 year of implantation. They were matched 2:1 with controls selected randomly from nonthrombosis patients. Data-restricted multiple logistic analysis was used to identify significant independent covariates of the outcome. ResultsEarly (within 1 month) scaffold thrombosis occurred in 69 patients and late (1 to 12 months) thrombosis occurred in 36 patients. Modelling found significant correlations of thrombosis to be final minimal lumen diameter <1.85 mm (odds ratio [OR]: 3.1; p = 0.004), off dual antiplatelet therapy (DAPT) status (OR: 3.1 to 3.5; p = 0.006 to 0.053), no post-dilatation with >1.1:1 balloon/scaffold ratio (OR: 2.3; p = 0.022), and reference vessel diameter <2.40 mm (OR: 2.1; p = 0.036). ConclusionsSuboptimal vessel sizing, procedural technique, angiographic outcomes, and dual antiplatelet therapy discontinuation appear to be the principal determinants of Absorb scaffold thrombosis risk through 12 months after implantation.

Is Preoperative Duration of Symptoms a Significant Predictor of Functional Status and Quality of Life Outcomes in Patients Undergoing Surgery for the Treatment of Degenerative Cervical Myelopathy?

Introduction Longstanding compression of the spinal cord in patients with degenerative cervical myelopathy (DCM) may result in irreversible neural tissue damage. This study aims to analyze whether a longer duration of symptoms is associated with poor surgical outcomes and to determine the optimal timing for decompressive surgery. Material and Methods Three hundred and fifty patients with symptomatic DCM were prospectively enrolled in either the CSM-North America or International study at 12 sites in North America. For each patient, extensive demographic information was collected, including age, co-morbidities, and a self-reported estimate of preoperative duration of symptoms. Postoperative functional status and quality of life were evaluated at 6-, 12- and 24-months using the modified Japanese Orthopaedic Association (mJOA), Nurick grade, Neck Disability Index (NDI) and Short-Form-36 (SF-36) Physical (PCS) and Mental (MCS) Component Scores. Change scores between baseline and 12-month follow-up were computed for each outcome measure. Duration of symptoms was dichotomized into a “short” and “long” group at several cut-offs. An iterative mixed model analytic approach procedure was used to evaluate differences in change scores on the mJOA, Nurick, SF-36 MCS and PCS and NDI between duration groups in 1-month increments. Two models were constructed: 1) an unadjusted model between duration of symptoms and surgical outcome and 2) a model adjusting for significant independent covariates identified through stepwise regression analysis. Results Our cohort consisted of 201 (57.43%) men and 149 (42.57%) women, with a mean age of 57.49 ± 11.77 years (range: 29–87 years). The mean duration of symptoms was 25.71 ± 36.68 months (range: 1–240 months). In unadjusted analysis, patients with a duration of symptoms shorter than 4 months had significantly better functional outcomes based on the mJOA ( p = 0.04) than patients with a longer duration of symptoms (&gt;4 months). On average, patients with a shorter duration of symptom improved by 3.71 on the mJOA, whereas those with a duration 4 months or longer only exhibited a 2.96 mean gain. Twelve months was identified as the next important cut-off beyond which patients had a significantly worse outcomes on the mJOA; however, this difference was smaller. Following adjusted analysis, cut-offs of 4 and 12 months remained significant. Duration of symptoms was not associated with Nurick or SF-36 PCS or MCS in either the unadjusted or adjusted models. Conclusion Patients who are operated on within 4 months of symptom presentation have better mJOA outcomes. It is recommended that patients with DCM are diagnosed in a timely fashion and referred early for surgical consultation. Our study does not support the traditional conservative “watchful waiting” approach to symptomatic patients with DCM.

Efficacy of an Online Education Program for Ultrasound Diagnosis of Pneumothorax

BACKGROUND Experienced ultrasonographers can rule out pneumothorax reliably. The authors hypothesized that with basic training, anesthesia residents and faculty can also reliably rule out pneumothorax when presented with an optimal ultrasound image of the chest. METHODS The study investigators created a library of 99 ultrasound video images of the chest with or without pneumothorax obtained from 53 patients undergoing elective thoracic surgery. After a 5-min tutorial, the physicians were invited to take a quiz based on 20 ultrasound videos randomly selected from the library. Sensitivity and specificity were calculated for overall performance, and a generalized estimating equations model was created to identify significant independent covariates affecting performance. To detect the retention rate for this skill, participants were asked to take the quiz again 6 months later. RESULTS Seventy-nine anesthesia residents and faculty took part in the study. The sensitivity and specificity for ruling out pneumothorax was 86.6% and 85.6% respectively. On generalized estimating equation model, participants were significantly less likely to identify ultrasound features of pneumothorax if there was probe movement (P value = 0.002; OR 2.69; 95% CI 1.61-4.5) or heartbeat (P < 0.001; OR 3.54; 95% CI 2.27-5.51) on the ultrasound video. The median and interquartile ranges for scores (90%, and 80-95% respectively) did not change from the first to the second quiz. CONCLUSION After viewing a 5-min online training video, physicians can reliably rule out pneumothorax on an optimal ultrasound image. They are also able to retain this skill for up to 6 months.

Elevated pretreatment serum biomarkers and correlation with progression-free (PFS) and overall survival (OS) in first-line trastuzumab-treated metastatic breast cancer.

622 Background: Approximately one-half of HER2-positive breast cancer patients will respond tofirst-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a recurring clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Seven serum biomarkers (carbonic anhydrase 9 (CA9), endoglin, HER2, IGF-1R, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), and VEGF-A (isoform 165) were measured using ELISA assays in 81 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The endoglin and IGF-IR ELISAs were from R&amp;D Systems; others were from WILEX/Oncogene Science, Cambridge, MA. PFS and OS were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: For univariate PFS analysis, higher pretreatment serum biomarkers (except IGF-1R and VEGF-A) predicted reduced PFS (p&lt;0.05) to first-line trastuzumab-containing therapy. In multivariate PFS analysis, only serum CA9 (p= 0.038) remained a significant independent covariate. In univariate OS analysis, higher pretreatment serum biomarkers (except IGF-1R and VEGF-A) were prognostic for reduced OS (p&lt;0.05). In multivariate analysis for OS, TIMP-1 (p=0.001) and CA9 (p=0.04) remained significant independent prognostic factors, as well as line of chemotherapy (3 vs. 2 or 1 line)(p=0.005), and hormone receptor status (ER and/or PR positive vs. negative)(p=0.013). Conclusions: Higher pretreatment serum CA9 (a marker of hypoxia) predicted reduced PFS, and higher serum CA9 and TIMP-1 predicted reduced OS in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure.

High adiponectin levels fail to protect against the risk of hypertension and, in women, against coronary disease: involvement in autoimmunity?

To investigate whether serum adiponectin protects against cardiometabolic risk in a population sample with prevailing metabolic syndrome. Middle-aged adults representative of a general population with baseline circulating adiponectin measurements (n = 1224) were analyzed prospectively at a mean of 3.8 years' follow-up, using continuous values or sex-specific tertiles. Total adiponectin was assayed by an ELISA kit. Type-2 diabetes was identified by criteria of the American Diabetes Association. Hypertension was defined as a blood pressure ≥ 140 mmHg and/or ≥ 90 mmHg and/or use of antihypertensive medication. Outcomes were predicted using Cox proportional hazards regression analysis in models that were controlled for potential confounders. In models of multiple linear regression, sex hormone-binding globulin, fasting insulin (inverse) and, in men, age were significant independent covariates of serum adiponectin which further tended in women to be positively associated with serum creatinine. Cox regression analyses for incident coronary heart disease (CHD), adjusted for sex, age, non-HDL cholesterol, waist circumference and C-reactive protein, revealed significant inverse association with adiponectin tertiles in men but not women (HR = 0.66; 95%CI: 0.32-1.38 for highest tertile). Cox regression for type-2 diabetes in a similar model (wherein glucose replaced non-HDL cholesterol), adiponectin tertiles appeared to protect in each gender. HR for incident hypertension roughly displayed unity in each of the adiponectin tertiles (P-trend = 0.67). High adiponectin levels failed to protect against the development of hypertension and, in women, against CHD, presumably paralleling impairment in renal function as well. Involvement of adiponectin in autoimmune complex with loss of antioxidative-antiatherogenic properties may be underlying.

Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes

We hypothesized that hypoalbuminemia is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). We analyzed records of 767 patients treated at Moffitt Cancer Center between January 2001 and December 2009 to evaluate the relationship between serum albumin (SA) at the time of presentation and overall survival (OS). Patients (median age of 69 years) were stratified into three groups based on SA concentration (≤3.5, 3.6-4.0, and >4.0 g/dL). Two-thirds of the patients had low or intermediate-1 International Prognostic Scoring System (IPSS)-based risk for MDS. Median OS by SA concentration of ≤3.5, 3.6-4.0, and >4.0 g/dL was 11, 23, and 34 months, respectively (P < 0.005), whereas rate of acute myeloid leukemia progression was highest in patients with low SA (≤3.5 g/dL). The SA level offered prognostic discrimination for outcomes within the lower and higher IPSS risk groups, as well as with the MD Anderson risk model. In multivariable analysis, SA was a significant independent co-variate for OS after adjustment for IPSS, age, serum ferritin, and transfusion dependence (hazard ratio = 0.8; 95% CI 0.6-0.9; P = 0.004). Our findings indicate that hypoalbuminemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology or comorbidities in patients with MDS.

Epidemiologic trends in chronic renal replacement therapy over forty years: a Swiss dialysis experience.

BackgroundLong term longitudinal data are scarce on epidemiological characteristics and patient outcomes in patients on maintenance dialysis, especially in Switzerland. We examined changes in epidemiology of patients undergoing renal replacement therapy by either hemodialysis or peritoneal dialysis over four decades.MethodsSingle center retrospective study including all patients which initiated dialysis treatment for ESRD between 1970 and 2008. Analyses were performed for subgroups according to dialysis vintage, based on stratification into quartiles of date of first treatment. A multivariate model predicting death and survival time, using time-dependent Cox regression, was developed.Results964 patients were investigated. Incident mean age progressively increased from 48 ± 14 to 64 ± 15 years from 1st to 4th quartile (p < 0.001), with a concomitant decrease in 3- and 5-year survival from 72.2 to 67.7%, and 64.1 to 54.8%, respectively. Nevertheless, live span continuously increased from 57 ± 13 to 74 ± 11 years (p < 0.001). Patients transplanted at least once were significantly younger at dialysis initiation, with significantly better survival, however, shortened live span vs. individuals remaining on dialysis. Among age at time of initiating dialysis therapy, sex, dialysis modality and transplant status, only transplant status is a significant independent covariate predicting death (HR: 0.10 for transplanted vs. non-transplanted patients, p = 0.001). Dialysis vintage was associated with better survival during the second vs. the first quartile (p = 0.026).DiscussionWe document an increase of a predominantly elderly incident and prevalent dialysis population, with progressively shortened survival after initiation of renal replacement over four decades, and, nevertheless, a prolonged lifespan. Analysis of the data is limited by lack of information on comorbidity in the study population.ConclusionsSurvival in patients on renal replacement therapy seems to be affected not only by medical and technical advances in dialysis therapy, but may mostly reflect progressively lower mortality of individuals with cardiovascular and metabolic complications, as well as a policy of accepting older and polymorbid patients for dialysis in more recent times. This is relevant to make demographic predictions in face of the ESRD epidemic nephrologists and policy makers are facing in industrialized countries.

Behavioral problems in children with epilepsy in rural Kenya

The aims of this study were to record behavioral problems in children with epilepsy (CWE), compare the prevalence with that reported among healthy children without epilepsy, and investigate the risk factors. A child behavioral questionnaire for parents comprising 15 items was administered to the main caregiver of 108 CWE and 108 controls matched for age in Kilifi, Kenya. CWE had a higher mean score for reported behavioral problems than controls (6.9 vs 4.9, t=4.7, P<0.001). CWE with active epilepsy also recorded more behavioral problems than those with inactive epilepsy (8.2 vs 6.2, t=−2.9, P=0.005). A significantly greater proportion of CWE (49% vs 26% of controls) were reported to have behavioral problems. Active epilepsy, cognitive impairment, and focal seizures were the most significant independent covariates of behavioral problems. Behavioral problems in African CWE are common and need to be taken into consideration in planning comprehensive clinical services in this region.

Temporal increase in organic mercury in an endangered pelagic seabird assessed by century-old museum specimens

Methylmercury cycling in the Pacific Ocean has garnered significant attention in recent years, especially with regard to rising mercury emissions from Asia. Uncertainty exists concerning whether increases in anthropogenic emissions over time may have caused increased mercury bioaccumulation in the biota. To address this, we measured total mercury and, for a subset of samples, methylmercury (the bioaccumulated form of mercury) in museum feathers from an endangered seabird, the black-footed albatross (Phoebastria nigripes), spanning a 120-y period. We analyzed stable isotopes of nitrogen (δ(15)N) and carbon (δ(13)C) to control for temporal changes in trophic structure and diet. In post-1940 and -1990 feathers, we detected significantly higher mean methylmercury concentrations and higher proportions of samples exhibiting above deleterious threshold levels (∼ 40,000 ng · g(-1)) of methylmercury relative to prior time points, suggesting that mercury toxicity may undermine reproductive effort in the species. We also found higher levels of (presumably curator-mediated) inorganic mercury in older specimens of albatross as well as two nonpelagic species lacking historical exposure to bioavailable mercury, patterns suggesting that studies on bioaccumulation should measure methylmercury rather than total mercury when using museum collections. δ(15)N contributed substantially to models explaining the observed methylmercury variation. After simultaneously controlling for significant trends in δ(13)C over time and δ(15)N with methylmercury exposure, year remained a significant independent covariate with feather methylmercury levels among the albatrosses. These data show that remote seabird colonies in the Pacific basin exhibit temporal changes in methylmercury levels consistent with historical global and recent regional increases in anthropogenic emissions.

Prognostic implication of metastatic lymph node ratio in node-positive rectal cancer

PurposeThe aim of this study was to evaluate the prognostic significance of the ratio between metastatic and examined lymph nodes (LNs) in patients with stage III rectal cancer.MethodsA review was made of 175 (male, 98) patients with stage III rectal cancer of R0 resection. LN disease was stratified both by the American Joint Committee on Cancer/International Union Against Cancer nodal classification (pN) and by quartiles of the lymph node ratio (LNR). Disease-free survivals (DFS) were made using Kaplan-Meier curves and assessed by the log rank test and multivariate analysis was performed using the Cox proportional hazards model.ResultsPatients ranged in age from 29 to 83 (median, 60) years with median follow-up of 47 months (range, 13 to 181 months). months. There was a significant correlation between the number of metastatic LNs and the LNR (r = 0.8681, P < 0.0001). Cut-off points of LNR quartiles best to separate patients with regard to 5-year DFS were between quartile 2 and 3, and between 3 and 4 (LNR1, 2, and 3); the 5-year DFS according to such stratification was 89.6%, 55.8%, and 18.2% in LNR1, 2, and 3, respectively (P < 0.0001). Cox model identified the LNR as the most significant independent prognostic covariate; LNR2 showed 3.6 times (95% confidence interval [CI], 1.682 to 7.584; P = 0.0009) and LNR3, 18.7 times (95% CI, 6.872 to 50.664; P < 0.0001) more risky than LNR1.ConclusionThis study suggests that ratio-based LN staging, which reflects the number of LNs examined and the quality of LN dissection, is a simple and reliable system for prognostic LN stratification in patients with stage III rectal cancer.