Unadjusted HR Research Articles

NCOG-33. HEMATOLOGIC PREDICTORS OF OUTCOMES IN GLIOBLASTOMA TREATED WITH SURGERY AND CHEMORADIATION

Abstract BACKGROUND There are conflicting reports regarding the prognostic value of platelet and other blood counts in glioblastoma. However, few series have looked at all hematologic parameters simultaneously. METHODS We performed a retrospective chart review of patients diagnosed with supratentorial glioblastoma from 2014-2019 who started conventional chemoradiation following initial surgical biopsy and/or resection. Hematologic parameters were collected at baseline, in the preoperative and postoperative periods and at the initiation and completion of chemoradiation. This included platelet counts, hemoglobin levels, white blood cell counts (WBC), neutrophil and lymphocyte counts with neutrophil:lymphocyte (NLR) and platelet:lymphocyte ratios (PLR) calculated at each time point. Cox regression was performed to assess the association between each hematologic parameter and both overall survival (OS) and progression free survival (PFS). A multivariate Cox proportional hazards model adjusted for all hematologic parameters, age, sex, race and KPS was generated for each time point. All hematologic parameters were modeled as continuous variables. RESULTS A total of 58 patients met inclusion criteria. 18 were female and 40 male. The median age was 59.5 (range 43-82). Median follow up for all patients was 15.3 months. A total of 52 patients completed radiation therapy and 18 completed 6 cycles of adjuvant chemotherapy. Hemoglobin and neutrophil counts at the conclusion of chemoradiation were associated with OS and PFS on univariate and multivariate analyses. The HR for OS were 0.74 (95% CI 0.5807-0.9313) and 1.28 (1.143-1.441) respectively. The HR for PFS were 0.70 (0.5531-0.8881) and 1.16 (1.05-1.271) respectively. Postoperative lymphocyte and platelet counts at initiation of chemoradiation were both associated with OS with unadjusted HR of 3.2 (1.037-9.960) and HR of 0.99 (0.9898-0.9999) respectively, which remained significant on multivariate analysis. However, neither were associated with PFS. CONCLUSION Several hematologic parameters are associated with glioblastoma outcomes in these initial analyses. Further analyses with additional patients are ongoing.

Assessing Early Mortality in Intensively-Treated Acute Myeloid Leukemia in a Developing Country: Genetic, Laboratory Findings, and Comorbidities Add Prognostic Information

Background: Early death (ED) during first-line therapy for acute myeloid leukemia (AML) is acknowledged as a pending issue worldwide. Few pivotal studies from developed countries have identified baseline characteristics related to poor outcome. Retrospective reports from Brazil and Mexico indicate alarming ED rates from real-world data, raising the question of which factors contribute towards this finding in low-income centers. In this study, we aimed to identify risk factors for ED in AML to increase the prediction power of previously known tools such as Charlson's Comorbidity Index (CCI) as well as to examine the role of anti-infective prophylaxis in our cohort. Methods: This is a retrospective cohort study involving adult patients (pts) newly diagnosed with AML treated at Instituto do Cancer do Estado de Sao Paulo, Brazil between June 2011 and June 2020. Only pts receiving the classic "7+3" regimen were included. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). The primary endpoint was ED rate, calculated by the Kaplan-Meier method. A Cox regression model selected by a stepwise method was used to find risk factors. Post-chemotherapy events (secondary endpoints) constituted any documented infection, bleeding, thrombosis, and acute kidney injury (AKI) during the first 30 days. Results: Overall, 206 out of 337 pts (61%) entered in the analysis. The median age was 54 years (range,17-74) and 50.5% were male. The median time between symptoms' onset and hospital admission was 7 weeks (0-48). Thirteen pts (6.3%) presented with leukostasis, of which 9 proceeded leukapheresis. At the presentation, clinical tumor lysis syndrome was seen in 12% of patients (associated with extramedullary disease [p<0.001], among other factors). Other baselines clinical and laboratory findings are summarized in table 1. Pre-chemotherapy infection was found in 67% of patients (positive blood culture: 26.3%). 45-day mortality was 23.8% (95% CI 17.8-29.4) (Figure 1), being 39.8% in pts above 60y. Dose reductions for liver or kidney dysfunction were not, per si, associated with higher ED. Multivariable Cox regression models examined the utility of baseline markers in predicting ED in our cohort and the best-fitted model by Akaike information criteria (AIC) is outlined in a forestplot (Figure 2). Briefly, in a model controlled for age, adding phenotype, genetic risk, platelets and C-reactive protein (CRP) to CCI resulted in improved prediction in our cohort (AIC 479 vs 542). CRP, AGR, and CCI were independently associated with short-term survival in AML (figure 3, 4, and 5). Noticeably, 13/20 diabetic patients died during the first 45 days (unadjusted HR 4.29 [95% CI 2.33-7.92]). Only antibacterial prophylaxis with quinolone was associated with decreased ED (unadjusted HR 0.38 [95% CI 0.15-0.95]), while the use of fluconazole or anidulafungin did not affect survival. Colonization during hospitalization occurred in 71% (mainly vancomycin-resistant Enterococcus [77%] and carbapenemase-producing Enterobacteriaceae [44%]). Any sort of colonization was associated with ED (OR 4.41 [95% CI 1.89-12.08]). Thromboembolic events were registered in 11.9% (95% CI 7.9-17.4, mostly catheter-related) and were marginally associated with central nervous system disease (OR 4.31 [95% CI 0.84-18.25) and diabetes mellitus (DM) (OR 3.24 [95% CI 0.94-9.82) 20.8 vs 7.9%, p=0.097). Bleeding was observed in 17.6% and was associated with monocytic AML subtypes, tumor lysis, and DM. Complete response was attained in 50.5% (95% CI 43.4- 57.5). Presumed or confirmed invasive fungal infection was diagnosed during induction in 26.6%, but empirical amphotericin was prescribed in 60.2%. 66.5% of subjects developed any grade of AKI, with the need for hemodialysis in 10.3%. Conclusion: This is the first Brazilian study to evaluate risk factors for ED in newly diagnosed AML in the public setting, as well as to address which events explain such higher mortality in comparison to American and European reports. In line with the literature, age itself was not associated with mortality when adjusted for other variables such as CCI and genetic stratification. Interestingly, we found that the baseline CRP levels are significantly correlated with ED, highlighting the role of infection and inflammation at the AML diagnosis. Disclosures No relevant conflicts of interest to declare.

Frailty Is Associated with Increased One-Year Mortality in Patients with Newly Diagnosed Diffuse Large-B-Cell Lymphoma: A Population-Based Study

Introduction: Previous studies have demonstrated that frailty is associated with mortality among patients with non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). However, no studies have examined frailty in an unselected population-based sample of patients with DLBCL, nor have data on health care utilization been considered as a potential mediator of this relationship. Objective: To determine whether frailty is associated with one-year survival in an unselected population of patients with DLBCL, and examine whether its impact is mediated by health care utilization during chemotherapy treatment. Methods: A retrospective cohort study was conducted using population-based health care data in Ontario, Canada. Patients >65 years diagnosed with DLBCL or transformed follicular lymphoma between January 2006 and December 2017 and receiving first-line chemo-immunotherapy were included. Frailty was defined by modifying a previously validated score developed for use with population-based data in Ontario, comprising 30 multidimensional variables (McIsaac, Ann Surg. 2019;270(1):102-108). Patients were categorized as "frail" (score >0.21) vs. "non-frail" (score ≤0.21). Covariates included age, number of comorbidities based on the Johns Hopkins Aggregated Diagnosis Groups (ADGs), and health care utilization during chemotherapy (defined as emergency department (ED) visit or inpatient hospitalization not resulting in death during treatment, and analysed as a time-varying covariate). Cox regression was performed to examine the association between frailty and one-year mortality (primary outcome). Secondary outcomes included health care utilization, chemo-immunotherapy exposure, and cause of death. Results: 5,527 patients were included in the study. 5,216 patients (94%) had de novo DLBCL, and 311 (6%) of patients had transformed follicular lymphoma. The median age was 75 years (IQR 70-80), and 48% (N=2672) were female (Table 1). 2,699 (49%) of patients were classified as frail (Table 2). Frail patients tended to be older (median age 76 (IQR 71-81) vs. 74 years (IQR 70-79)). The difference in mortality between frail and non-frail patients was most pronounced in the initial year following start of treatment (Figure 1a). Within 90 days of first-line rituximab, 14% (N=370) of frail vs. 7% (N=185) of non-frail patients had died (p<0.0001). Within one-year of first-line treatment, 32% (N=868) of frail patients had died compared to 20% (N=553) of non-frail patients (unadjusted HR 1.8, 95% CI 1.6-2.0, p<0.0001, Figure 1b). Among frail patients who died within 1 year (N=868), 34% (N=298) had only received 1 cycle of chemotherapy. In multivariable modelling controlling for age, number of ADG comorbidities, and health care utilization during chemotherapy, frailty (binary exposure) remained independently associated with one-year mortality (adjusted HR 1.6, 95% CI 1.5-1.8, p<0.0001). The relationship between frailty and survival remained consistent when measured in quartiles (HR 1.6 (95% CI 1.3-1.9) for Q2, 2.0 (95% CI 1.7-2.4) for Q3, 2.7 (95% CI 2.3-3.2) for Q4, p<0.0001, Figure 1b). Frail patients were significantly more likely to receive only 1 cycle of chemotherapy than non-frail patients (14% vs. 7%, p<0.0001). Frail patients also had higher health care utilization during chemotherapy (mean ED visits 0.75 + 1.47 vs. 0.59 + 1.17, p<0.001; mean hospitalizations 0.9 + 1.12 vs. 0.72 + 1.05, p<0.001). Frail patients were also more likely to die of DLBCL (38.3 vs. 29%, p<0.0001). Conclusion: Frailty is significantly associated with one-year mortality in patients with newly diagnosed DLBCL, even after adjusting for age, comorbidities, and health care utilization. Frailty appears to be associated with poor tolerability of chemotherapy and a higher likelihood for requiring acute hospital-based care, and future analyses will explore whether this is related to patients suffering increased treatment-related toxicity. Future analyses of these data will also address whether frail patients who die within one-year of first-line treatment have different clinical characteristics compared to frail patients who survive beyond one year. Future prospective studies may help clinicians understand whether any frailty-related variables are modifiable and the role of alternative treatment strategies for vulnerable patients. Disclosures Prica: astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria.

Incremental prognostic value of pericoronary adipose tissue attenuation on top of comprehensive CCTA assessment

Abstract Background Coronary computed tomography angiography (CCTA) derived parameters linked to severity and extent of atherosclerosis are associated with prognosis in patients with coronary artery disease (CAD). Furthermore, coronary inflammation, by determining pericoronary adipose tissue CT-attenuation (PCATa), can be assessed on CCTA as well and has been proposed as promising prognostic marker. Objective To assess the prognostic value of PCATa on top of traditional CCTA derived atherosclerotic parameters. Methods A total of 543 patients who underwent CCTA because of suspected CAD and in whom follow-up was obtained were included. CCTA assessment comprised; coronary artery calcium score (CACS), presence of obstructive CAD (≥50% stenosis) and high-risk plaques (HRP), total plaque volume (TPV), non-calcified plaque volume (NCPV), and PCATa. The endpoint was a composite of death and non-fatal myocardial infarction (MI). Optimal prognostic thresholds were determined for quantitative CCTA variables. Univariable Cox regression analyses were performed to determine clinical characteristics and CCTA variables associated with the endpoint, a subsequent multivariable Cox regression analysis that included variables associated with the endpoint was used to determine independent predictors of the endpoint. An additional Cox regression analysis was performed to test the incremental prognostic value of CCTA variables over clinical characteristics, significance of each sequentially added variable was tested using the likelihood ratio test. Results During a median follow-up time of 6.6 [interquartile range: 4.7–7.8] years, a total of 42 (20 MI/22 death) (8%) patients suffered an endpoint. CACS >83.2, obstructive CAD, HRP, TPV >269mm3, and NCPV >83mm3 were all associated with occurrence of the endpoint with unadujsted hazard ratio's (HR) of; 5.37, 5.70, 3.31, 7.76, and 6.77, respectively (p<0.001 for all). PCATa of the RCA above −74.4 Hounsfield units (HU) had a detrimental effect on prognosis (unadjusted HR: 1.99, p=0.037), while PCATa of the LAD nor Cx was associated with outcome (Log-rank p-value 0.255 and 0.218, respectively). PCATa of the RCA remained an independent predictor of death and MI when incorporated in a multivariable analysis inlcuding all CCTA variables and clincal chacteristics associated with the endpoint (adjusted HR: 2.11, p=0.024). Furthermore, adding PCATa of the RCA to a model that included clinical characteristics and all CCTA parameters led to an improvement of the prognostic value of the model (change in Chi-square = 4.45, p=0.035) (figure). Conclusion Coronary inflammation of the RCA determined by PCATa provides incremental prognostic value on top of traditional CCTA parameters linked to extent and severity of CAD. Figure 1. Cox regression analysis demonstrating the incremental prognostic value of sequentially added CCTA variables over clinical characteristics tested for significance using the likelihood ratio test. Funding Acknowledgement Type of funding source: None

Sex differences in ventricular remodeling and long-term heart failure outcomes following acute coronary syndrome

Abstract Background Compared with men, women are at increased risk of heart failure hospitalization following acute coronary syndrome (ACS). Purpose We sought to determine whether this increased hazard was associated with differing patterns in left ventricular (LV) remodeling over the first 12 months after ACS. Methods In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event. Heart failure hospitalisation events were captured over a median 4.8 (IQR 3.4–6.5) years and relative risk compared between women and men using a multivariable Cox model adjusted for baseline demographics (age and systolic blood pressure) and echocardiographic variables (LV end diastolic and end systolic volumes, LV ejection fraction, interventricular septal wall thickness, and E/e') captured at baseline and 12 months. Results The 609 (28.5%) women were older (mean [SD] age 70 [12] versus 65 [12] years), had higher systolic blood pressure, demonstrated smaller increases in peak myocardial biomarkers, and were less likely to undergo coronary revascularization during the index admission (41.9% versus 62.0%; p<0.001 for all). After indexing for body surface area, women had smaller LV end diastolic and end systolic volumes, greater LV ejection fractions, and greater septal wall thickness and diastolic filling pressure estimates (E/e' 14 versus 11; p<0.001 for all). Diastolic volumes further diverged at 12 months (p=0.05) and septal wall thickness increased compared with men (p=0.016). In unadjusted and adjusted analyses women were at increased risk of future heart failure hospitalization (unadjusted HR 1.5, 95% CI 1.2–1.9, adjusted HR 1.6, 95% CI 1.1–2.4). Conclusions Women experience a more concentric remodeling pattern over the 12 months following ACS. Women remain at increased risk of long-term heart failure hospitalization after accounting for clinical and echocardiographic characteristics. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation of New Zealand, New Zealand Health Research Council

Hypertension attenuates the prognostic value of coronary artery calcification scoring in low-risk patients

ObjectivesIn outpatients with suspected ischaemic symptoms, we investigated the impact of risk factor profile on the prognostic value of coronary artery calcium scoring (CACS) and CT coronary angiography (CTCA).Methods772 consecutive...

The association of living donor source with patient and graft survival among kidney transplant recipients in the ERA-EDTA Registry - a retrospective study.

SummaryIn this study we aimed to compare patient and graft survival of kidney transplant recipients who received a kidney from a living‐related donor (LRD) or living‐unrelated donor (LUD). Adult patients in the ERA‐EDTA Registry who received their first kidney transplant in 1998–2017 were included. Ten‐year patient and graft survival were compared between LRD and LUD transplants using Cox regression analysis. In total, 14 370 patients received a kidney from a living donor. Of those, 9212 (64.1%) grafts were from a LRD, 5063 (35.2%) from a LUD and for 95 (0.7%), the donor type was unknown. Unadjusted five‐year risks of death and graft failure (including death as event) were lower for LRD transplants than for LUD grafts: 4.2% (95% confidence interval [CI]: 3.7–4.6) and 10.8% (95% CI: 10.1–11.5) versus 6.5% (95% CI: 5.7–7.4) and 12.2% (95% CI: 11.2–13.3), respectively. However, after adjusting for potential confounders, associations disappeared with hazard ratios of 0.99 (95% CI: 0.87–1.13) for patient survival and 1.03 (95% CI: 0.94–1.14) for graft survival. Unadjusted risk of death‐censored graft failure was similar, but after adjustment, it was higher for LUD transplants (1.19; 95% CI: 1.04–1.35). In conclusion, patient and graft survival of LRD and LUD kidney transplant recipients was similar, whereas death‐censored graft failure was higher in LUD. These findings confirm the importance of both living kidney donor types.

Disease-free and overall survival after neoadjuvant chemotherapy in breast cancer: breast-conserving surgery compared to mastectomy in a large single-centre cohort study

PurposeThe extended role of breast-conserving surgery (BCS) in the neoadjuvant setting may raise concerns on the oncologic safety of BCS compared to mastectomy. This study compared long-term outcomes after neoadjuvant chemotherapy (NAC) between patients treated with BCS and mastectomy.MethodsAll breast cancer patients treated with NAC from 2008 until 2017 at the Amphia Hospital (the Netherlands) were included. Disease-free and overall survival were compared between BCS and mastectomy with survival functions. Multivariable Cox proportional hazard regression was performed to determine prognostic variables for disease-free survival.Results561 of 612 patients treated with NAC were eligible: 362 (64.5%) with BCS and 199 (35.5%) with mastectomy. Median follow-up was 6.8 years (0.9–11.9). Mastectomy patients had larger tumours and more frequently node-positive or lobular cancer. Unadjusted five-year disease-free survival was 90.9% for BCS versus 82.9% for mastectomy (p = .004). Unadjusted five-year overall survival was 95.3% and 85.9% (p < .001), respectively. In multivariable analysis, clinical T4 (cT4) (HR 3.336, 95% CI 1.214–9.165, p = .019) and triple negative disease (HR 5.946, 95% CI 2.703–13.081, p < .001) were negative predictors and pathologic complete response of the breast (HR 0.467, 95% CI 0.238–0.918, p = .027) and axilla (HR 0.332, 95% CI 0.193–0.572, p = .001) were positive predictors for disease-free survival. Mastectomy versus BCS was not a significant predictor for disease-free survival when adjusted for the former variables (unadjusted HR 2.13 (95%CI: 1.4–3.24), adjusted HR 1.31 (95%CI: 0.81–2.13)). In the BCS group, disease-free and overall survival did not differ significantly between cT1, cT2 or cT3 tumours.ConclusionBCS does not impair disease-free and overall survival in patients treated with NAC. Tumour biology and treatment response are significant prognostic indicators.

Peri-transplant glycaemic control as a predictor of pancreas transplant survival.

The relationship between peri-transplant glycaemic control and outcomes following pancreas transplantation is unknown. We aimed to relate peri-transplant glycaemic control to pancreas graft survival and to develop a framework for defining early graft dysfunction. Peri-transplant glycaemic control profiles over the first 5 days postoperatively were determined by an area under the curve [AUC; average daily glucose level (mmol/L) × time (days)] and the coefficient of variation of mean daily glucose levels. Peri-transplant hyperglycaemia was defined as an AUC ≥35 mmol/day/L (daily mean blood glucose ≥7 mmol/L). Risks of graft failure associated with glycaemic control and variability and peri-transplant hyperglycaemia were determined using covariate-adjusted Cox regression. We collected 7606 glucose readings over 5 days postoperatively from 123 pancreas transplant recipients. Glucose AUC was a significant predictor of graft failure during 3.6 years of follow-up (unadjusted HR [95% confidence interval] 1.17 [1.06-1.30], P = .002). Death censored non-technical graft failure occurred in eight (10%) recipients with peri-transplant normoglycaemia, and eight (25%) recipients with peri-transplant hyperglycaemia such that hyperglycaemia predicted a 3-fold higher risk of graft failure [HR (95% confidence interval): 3.0 (1.1-8.0); P = .028]. Peri-transplant hyperglycaemia is strongly associated with graft loss and could be a valuable tool guiding individualized graft monitoring and treatment. The 5-day peri-transplant glucose AUC provides a robust and responsive framework for comparing graft function.

S0133 Incidence and Predictors of New Onset Diabetes Mellitus Following Surgical Resection of Pancreatic Cystic Lesions

INTRODUCTION: There is a risk of new onset diabetes mellitus (NODM) following pancreatic resection. Compared with patients who undergo surgery for other indications, including acute and chronic pancreatitis and pancreatic adenocarcinoma, patients with pancreatic cystic lesions (PCLs) generally have normal adjacent pancreatic parenchyma. However, the risk of post-operative diabetes mellitus (DM) among patients with PCLs is poorly defined. Therefore, the objective of the current study was to characterize the incidence and risk factors associated with NODM following pancreatectomy for PCLs. METHODS: The Truven MarketScan Research Database (2012–2018) was utilized to identify all adult subjects with PCLs and without prevalent DM who underwent a pancreatic resection. Stringent exclusion criteria (Figure 1) were utilized to isolate only those patients without other diseases of the exocrine pancreas. A time to event analysis using Kaplan-Meier curves and multivariable Cox proportional hazards analysis was conducted to identify incidence and risk factors associated with post-operative NODM. RESULTS: Among 311 subjects with PCLs who underwent partial pancreatectomy, the overall risk of post-operative DM was 9.1% (95% CI 6.3%–12.9%) at 6 months, 15.1% (95% CI 11.3%–20.2%) at 1 year, and 20.2% (95% CI 15.3%–26.4%) at 2 years. In a multivariable Cox proportional hazards model, older age (55–64 years, adjusted Hazard Ratio (aHR) 1.97, 95% CI 1.04–3.72 vs. 18–54 years), obesity (aHR 2.63, 95% CI 1.35–5.12), hypertension (aHR 1.79, 95% CI 1.01–3.17) and cardiovascular disease/heart failure (aHR 2.54, 95% CI 1.02–6.28) were independent predictors of post-operative NODM. Moreover, there was no significant difference in risk of NODM after distal pancreatectomy versus pancreaticoduodenectomy (unadjusted HR 1.41, 95% CI 0.69–2.88) in this population. CONCLUSION: In a large population-based cohort, the risk of NODM following pancreatectomy for PCL was not excessive, and was relatively higher in older patients with features of metabolic syndrome and/or cardiovascular disease. Individuals with these clinical characteristics may benefit from peri- and post-operative monitoring, education, and treatment strategies for DM.Figure 1

Arterial calcification and long-term outcome in chronic limb-threatening ischemia patients

PurposeWithin five years after presentation 50–60% of patients with chronic limb-threatening ischemia (CLI) have died or had an amputation. We assessed the predictive value of lower extremity arterial calcification on computed tomography (CT) characteristics on both 7-years amputation-free survival and 10-years all-cause mortality in patients with CLI. MethodIncluded were 89 CLI patients (mean age 73.1 ± 11.6 years) who underwent a CT angiography of the lower extremities. In the femoropopliteal and crural arteries based on a CT score the following calcification characteristics were assessed: severity, annularity, thickness and continuity. The predictive value of different arterial calcification characteristics was analysed by age- and sex-adjusted multivariate Cox regression analysis. ResultsComplete annular calcifications were common (femoropopliteal 43.7%, n = 38; crural, 63.2%, n = 55). Mean survival was 278.4 weeks (95% CI 238.77–318.0 weeks). Patients with complete annular calcifications had a higher all-cause 10-year mortality (femoropopliteal unadjusted HR 1.64, p = 0.04 and adjusted for age and sex HR 1.68, p = 0.04; crural unadjusted HR 1.92, p = 0.02, adjusted for age and sex HR 2.29, p = 0.006) than patients with other calcification characteristics. ConclusionsAnnularity of calcification of both femoropopliteal and crural arteries is a predictor for 10-year all-cause survival, its hazard being even higher than the traditional prognostic risk factors for CLI and therefore could be involved in the poor survival of these patients.

Association between right atrial area measured by echocardiography and prognosis among pulmonary arterial hypertension: a systematic review and meta-analysis

ObjectiveThe purpose of this meta-analysis was to evaluate the association between enlarged right atrial area (RAA), as measured by echocardiography, and prognosis of patients with pulmonary arterial hypertension (PAH).DesignSystematic review...

Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial

Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings. We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed. Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01). Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible. Tata Memorial Center Research Administration Council. For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.

Childhood asthma increases respiratory morbidity, but not all-cause mortality in adulthood: The Busselton Health Study

BackgroundLong-term childhood asthma studies that investigate adult outcomes other than lung function are lacking. This study examines the associations of childhood asthma and the occurrence of respiratory events and all-cause mortality in adulthood. MethodsA cohort of 4430 school children (aged to 17 years) who attended the Busselton Health Study between 1967 and 1983 were analysed. Self-reported history of asthma was determined using questionnaires. Participants were followed until 2014 for respiratory disease-related events (hospital admissions or death) and all-cause mortality using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on respiratory events and all-cause mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analysed. ResultsA total of 462 (10%) of the cohort had childhood asthma. During follow-up 791 participants experienced a respiratory event and 140 participants died. Childhood asthma was associated with an increased risk of respiratory events in adulthood (unadjusted HR 1.84, 95% CI 1.52 to 2.23; P < 0.0001). The result remained significant after adjusting for adult-onset asthma, FEV1, body mass index, smoking, dusty job, hay fever, and respiratory symptoms (adjusted HR 1.68, 95% CI 1.07 to 2.64; P = 0.0247). Childhood asthma was not associated with all-cause mortality in adulthood (unadjusted HR 1.08, 95% CI 0.63 to 1.84; P = 0.7821). ConclusionChildhood asthma is associated with increased risk of respiratory disease-related hospital admissions and death but not all-cause mortality in adulthood.

Clozapine treatment and risk of COVID-19 infection: retrospective cohort study.

Clozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia. To investigate associations between clozapine treatment and increased risk of COVID-19 infection in patients with schizophrenia-spectrum disorders who are receiving antipsychotic medications in a geographically defined population in London, UK. Using information from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 6309 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders and were taking antipsychotics at the time of the COVID-19 pandemic onset in the UK. People who were on clozapine treatment were compared with those on any other antipsychotic treatment for risk of contracting COVID-19 between 1 March and 18 May 2020. We tested associations between clozapine treatment and COVID-19 infection, adjusting for gender, age, ethnicity, body mass index (BMI), smoking status and SLAM service use. Of 6309 participants, 102 tested positive for COVID-19. Individuals who were on clozapine had increased risk of COVID-19 infection compared with those who were on other antipsychotic medication (unadjusted hazard ratio HR = 2.62, 95% CI 1.73-3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR = 1.76, 95% CI 1.14-2.72). These findings provide support for the hypothesis that clozapine treatment is associated with an increased risk of COVID-19 infection. Further research will be needed in other samples to confirm this association. Potential clinical implications are discussed.

Midlife susceptibility to the effects of poor diet on diabetes risk.

Type 2 diabetes mellitus (T2D) prevalence continues to increase, and age of incidence continues to decrease. More information is needed to target interventions to the ages where they can be most effective. The objective of this study was to explore the degree to which the association between diet and T2D incidence changes through adulthood. Participants were a large number (N = 2818) of community living adults in Canberra and Queanbeyan, Australia across three cohorts; young (20-24 followed to 32-36), mid-life (40-44 followed to 52-56) and late-life (60-64 followed to 72-76). Self-report dietary pattern scores at baseline and diabetes incidence across 12 years follow-up were measured, alongside confounders of caloric intake, sex, smoking status, years of education, hypertension, BMI and physical activity. Cox proportional hazards indicated that neither Western nor Prudent dietary pattern scores were significantly associated with T2D incidence when confounders were included in the model. Unadjusted estimates suggested a positive association between Western dietary pattern scores and subsequent diabetes incidence (HR = 1.40, 95% CI [1.18, 1.64]). Compared with the mid-life cohort, a higher Western dietary pattern score posed a lower risk for incident T2D in the young cohort (unadjusted HR = 0.46, 95% CI [0.22, 0.96]), who also had significantly lower BMI and higher physical activity. No such significant effects were found for the late-life cohort. Our findings indicate that mid-life may be a period of heightened vulnerability to the effects of an unhealthy diet on diabetes risk, but this effect is attenuated when risk factors related to diet, such as adiposity, are taken into account.

Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial

BackgroundLuminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes. MethodsPatients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%. ResultsOut of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]). ConclusionsNo significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.

Low Protein Intake Irrespective of Source is Associated with Higher Mortality Among Older Community-dwelling Men.

Our aim was to determine the association between protein intake (overall and by source) and all-cause and cause-specific mortality among older men. Prospective cohort study. 5790 ambulatory community-dwelling older men from multicenter Osteoporotic Fractures in Men (MrOS) study. Total energy and protein intake, and protein intake by source (dairy, non-dairy animal, plant) were assessed using a 69-item food frequency questionnaire. We included up to 10-year follow-up with adjudicated cardiovascular, cancer and other mortality outcomes. We used time-to-event analysis with protein exposures, mortality outcome, and adjusted for possible confounders including age, center, education, race, smoking, alcohol use, physical activity, weight, total energy intake (TEI), and comorbidities. Hazard ratios were expressed per each unit=2.9% TEI decrement for all protein intake variables. The mean (SD) baseline age of 5790 men was 73.6 (5.8) y. There were 1611 deaths and 211 drop-outs prior to 10 years, and 3868 men who were alive at the 10-year follow-up. The mean (SD) total protein intake was 64.7 (25.8) g/d, while the mean (SD) intake expressed as percent of total energy intake (%TEI) was 16.1 (2.9) %TEI. Lower protein intake was associated with an increased risk of death, with unadjusted HR=1.11 (95% CI: 1.06, 1.17) and adjusted HR=1.09 (95% CI: 1.04, 1.14) and the associations for protein intake by source were similar. The adjusted HR for cancer mortality was HR=1.13 (95% CI: 1.03, 1.25) while the association for CVD mortality was HR=1.08 (95% CI: 0.99, 1.18). Low protein intake, irrespective of source, was associated with a modest increase in risk of all-cause and cause-specific mortality among older men. Special consideration should be given to level of protein intake among older adults.

1604-P: Glucose Intolerance Modifies the Association between Diastolic Blood Pressure Variability and All-Cause Mortality

Purpose: There is growing literature on the association between blood pressure variability (BPV) and mortality. We sought to determine whether the association between BPV and all-cause mortality was modified by glucose intolerance (GI). Methods: A total of 12,256 non-pregnant adults from the National Health and Nutrition Examination Surveys-III (1988-1994) were linked to the National Death Index through 2015. The primary predictors were systolic and diastolic BPV, defined as the standard deviation of 3-6 BP readings taken consecutively. Systolic and diastolic BPV were categorized into quintiles (&amp;lt;3, 3-8, 9-12, 13-15, &amp;gt;15 mmHg). We used Cox proportional hazards modeling to assess the risk of all-cause mortality, adjusting for confounders (age, sex, race/ethnicity, mean BP, BMI, lipids, kidney and liver function, c-reactive protein) and the survey design. Analyses were stratified by GI status (yes/no), defined as either a fasting glucose ≥100 mg/dl, HbA1c ≥5.7%, or diabetes medication use. Results: Of the 12,256 participants, 28% had GI. The mean follow-up time was 22.1 years, with a total 3,632 deaths (2,096 [46%] among GI and 1,536 [20%] among non-GI) from all causes. Among those with GI, the highest quintile of diastolic BPV had 60% higher risk of mortality relative to the lowest quintile (unadjusted HR [95% CI] = 1.51 [1.04, 2.23], adjusted HR = 1.60 [1.12, 2.28]). This association did not exist among those without GI (unadjusted HR [95% CI] = 0.87 [0.60, 1.26], adjusted HR = 0.80 [0.58, 1.10]). Those in the highest quintile of systolic BPV had an insignificant increase in risk of all-cause mortality among both GI and non-GI participants (GI: adjusted HR = 1.41 [0.98, 2.01], non-GI: adjusted HR = 1.09 [0.78, 1.51], interaction p=0.34). Conclusion: Only those with GI had a significant positive association between diastolic BPV and all-cause mortality. GI may play a role in modifying this association through changes in vascular autonomic regulation due to autonomic neuropathy. Disclosure A. Visaria: None. T. Dharamdasani: None. D. Lo: None. K. Wickramasinghe: None. R. Malhotra: None.

Thoracoscopic segmentectomy with simple routine bronchoscopic inflation for intersegmental plane identification: short and mid-term outcomes compared with lobectomy.

BackgroundThe technical concepts of thoracoscopic segmentectomy are still evolving. In this study we present a simple bronchoscopy-based intersegmental demarcation technique with short- and mid-term outcomes compared between thoracoscopic segmentectomy and lobectomy.MethodsAll 105 consecutive patients with lung cancer intended to treat with video-assisted thoracoscopic surgery (VATS) segmentectomy were compared to 110 consecutive VATS lobectomies. Short- and mid-term outcome comparison included complications, length of hospital stay, pulmonary functions, and 3-year progression-free and overall survival. Mid-term outcomes were adjusted for age, sex, comorbidities, pulmonary functions, histology, stage and adjuvant treatment.ResultsSegmentectomy patients had more comorbidities (P=0.006), worse pulmonary functions (FEV1%, P=0.005; DLCO/va, P=0.011), poor exercise capacity (P=0.043) and were considered high-risk patients more often (41.9% vs. 25.5%, P=0.011). Major complication rates did not differ between the groups (P=0.718). Mean length of hospital stay decreased after segmentectomy (4.7 vs. 5.9 days, P=0.033). Following segmentectomy, FEV1% slightly improved (1.0%). After lobectomy, the mean decline of FEV1% was 8.1% (P<0.001). Respectively, in high-risk patients, 2.1% improvement and 9.9% decline (P=0.027) were observed. Overall mortality hazard after segmentectomy was similar to that for lobectomy (unadjusted HR 0.80, 95% CI: 0.45–1.44, adjusted HR 0.87, 95% CI: 0.43–1.76). When considering only stage I non-small cell lung cancer, 3-year overall survival after segmentectomy and lobectomy were 86.8% vs. 79.8% (P=0.412) and 3-year recurrence-free survival 93.0% vs. 89.7%, P=0.450.ConclusionsFollowing segmentectomy, regardless of worse surgical candidates, hospital stay was shorter. Furthermore, preservation of lung function also in high-risk patients, was observed without compromising mid-term oncologic outcomes.