Unadjusted HR Research Articles

The Effect of Examined Lymph Nodes and Lymph Node Ratio on Pathological Nodal Classification in the Lung Adenosquamous Carcinoma After Lobectomy.

ObjectiveThe effects of examined lymph nodes (LNs) and lymph node ratio (LNR) on pN classification and the prognosis are unclear in lung adenosquamous carcinoma (ASC) patients. Thus, this study aimed to investigate the significance of LNs and LNR in the prognosis of ASC and the impact of the abovementioned factors on the pN classification.MethodsPatients diagnosed with pathological stage T1-4N0-2M0 ASC from the Surveillance Epidemiology and End Results database were included in the study. The primary clinical endpoint was cancer-specific survival (CSS). The optimal cutoff values of the LNs and LNR were determined. An LN indicator, including pN0 #LNs ≤9, pN0 #LNs >9, pN+ #LNR ≤0.53, and pN+ #LNR > 0.53, was developed. Concordance index (C-index) was used to compare the prognostic predictive ability between N classification and LN indicator. The univariable and multivariable Cox regression analyses were used in this study.ResultsThe cohort of 1,416 patients were included in the study. The level of LNs stratified the patients without metastasis of lymph nodes (pN0 #LNs ≤9 vs. pN0 #LNs >9, unadjusted hazard ratio [HR] = 1.255, P = 0.037). Two groups based on the cutoff value of LNR differentiated prognosis of patients with metastasis of lymph nodes (pN+ #LNR >0.53 vs. pN+ #LNR ≤0.53, unadjusted HR = 1.703, P = 0.001). The LN indicator had a much better predictive ability over N classification in this cohort (LN indicator: C-index = 0.615; N classification: C-index = 0.602, P = 0.001).ConclusionsWe explored clinicopathological factors affecting prognosis in resected lung ASC patients. Besides, the LN indicator was confirmed to be played an essential role in affecting the survival rate in ASC patients. The high-level LNs or low-level LNR might be corelated to improved survival outcomes.

Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: A real-world study.

e21534 Background: Nivolumab is approved in the United States and other countries as an adjuvant treatment for patients with completely resected stage III–IV melanoma based on results of the phase 3 CheckMate 238 trial, though the trial enrolled a limited number of patients with stage IIIA disease (AJCC-8). The objective of this real-world study is to describe characteristics, treatment patterns, and outcomes of patients with resected stage IIIA melanoma (AJCC-8) treated with adjuvant nivolumab or monitored with observation. Methods: In this retrospective, chart-review study, physicians from Cardinal Health’s proprietary Oncology Provider Extended Network (OPEN) extracted data from electronic health records of patients who had undergone complete surgical resection of stage IIIA melanoma between Jan. 1, 2018, and Dec. 31, 2019. Recurrence-free survival (RFS) and overall survival (OS) were evaluated from the date of resection and compared between the adjuvant nivolumab and observation cohorts using log-rank tests and adjusted Cox proportional hazards models (covariates included age, sex, race, region, payer type, ECOG PS, and Charlson Comorbidity Index). Discontinuations and deaths due to adjuvant nivolumab toxicity were assessed. Results: This study included 171 patients treated with adjuvant nivolumab and 38 patients monitored with observation. In the adjuvant nivolumab and observation cohorts, respectively, mean age was 57.4 and 68.1 years; most patients were male (59% and 68%) and white (90% and 87%); and median follow-up from resection was 20.7 and 25.0 months. Sentinel lymph node tumor burden of < 1 mm was reported in 12% (n = 20) and 16% (n = 6) of patients in the adjuvant nivolumab and observation cohorts, respectively. The scheduled treatment course with adjuvant nivolumab was completed by 91% of patients (n = 155). RFS and OS rates were numerically higher with adjuvant nivolumab than with observation (Table). There was a trend toward RFS and OS benefit with adjuvant nivolumab versus observation (unadjusted RFS HR 0.53, 95% CI 0.26–1.09; adjusted RFS HR 0.62, 95% CI 0.28–1.40; unadjusted OS HR 0.55, 95% CI 0.19–1.57; adjusted OS HR 0.81, 95% CI 0.25–2.61). Discontinuation of adjuvant nivolumab due to toxicity occurred in 2% of patients (n = 4); no treatment-related deaths were reported. Conclusions: These real-world results confirm that patients with resected stage IIIA melanoma (AJCC-8) have a good prognosis. Treatment with adjuvant nivolumab may provide modest survival benefit over observation in this population, though increased sample size and additional follow-up are warranted.[Table: see text]

Prevalence and outcomes of frailty in older patients with cancer: A prospective study from geriatric oncology clinic.

e24011 Background: Frail older patients present with increased symptom burden, medical complexity and reduced tolerance to medical and surgical interventions. Data regarding the prevalence of frailty and its association with outcomes, such as overall survival, is limited from India. This study aimed to establish the prevalence of frailty and its association with overall survival (OS) in older patients with cancer. Methods: This was a prospective study conducted in geriatric oncology clinic of Tata memorial hospital (Mumbai India). Patients aged 60 years and above referred to the clinic were included. Frailty was identified using the Rockwoods Clinical frailty scale, and patients with a score of five or more were diagnosed as frail. Demographic details, type of cancer, stage and multi-domains geriatric assessment was done. Cancer and Ageing Research group online toxicity tool was used to assess the chemotherapy toxicity risk. A t-test or two-sample Wilcoxon rank-sum test was used to study the association between frailty status and non-categorical variables and the Pearson chi-squared test was used to measure the association between categorical variables. The Kaplan Meier survival estimation and the Cox proportional hazard model were used to perform the survival analysis. Results: Between June 2018 to January 2022, 909 patients were evaluated and 662 patients with clinical frailty score were included. The median age was 68 (60-86) years and 107 (16%) were above the age of 75 years. The most common malignancies were lung (39%), esophagus (21%) and head and neck (10%); 53% had metastatic disease. 192 (29%) were frail, and it prevalence increased with age. Frailty status was associated with poor OS (unadjusted HR: 2.512; 95% CI: 1.931-3.268). This association was significant even after adjusting for age, gender, BMI and stage of cancer (adjusted HR: 2.104; 95% CI: 1.598-2.770). Frailty was associated with comorbidities such as diabetes (32% vs 23%, p = 0.014), chronic obstructive pulmonary disease (13% vs 7%, p = 0.045) and cardiovascular disease (19% vs 12%, p = 0.017). Among the geriatric domains, frail patients had greater incidence of polypharmacy (52% vs 33%, p < 0.01), slower gait speed (53% vs 12%, p < 0.01), impaired cognition (25% vs 7%, p < 0.01), poor nutritional status (51% vs 17%, p < 0.001), depression (29% vs 8%, p < 0.01) and anxiety (14% vs 5%, p < 0.01). Conclusions: The prevalence of frailty among older cancer patients is high. It is associated with poor physical, cognitive and psychological resilience and is associated with poor overall survival. Our study supports the routine assessment of frailty in older patients with cancer to guide treatment decisions. Clinical trial information: CTRI/2020/04/024675.

Codon-specific KRAS mutations predict overall survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated with targeted agents, but clinical-grade genomic biomarkers for chemotherapies are currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved for the treatment of late-stage metastatic colorectal cancer (mCRC). We aimed to find genomic biomarkers to improve patient selection for FTD/TPI treatment in mCRC. Methods: In a discovery cohort of FTD/TPI-treated mCRC patients (n = 37), genome-wide somatic variants were tested for association with treatment duration and overall survival (OS). In vitro drug testing on isogenic cell lines and patient-derived mCRC organoids, as well as a re-analysis of the double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800) were performed to support our findings. Results: In the discovery cohort, KRAS codon G12 (KRASG12) mutation status was the only significant genomic determinant of poor outcome of FTD/TPI treatment, which could be replicated in vitro by drug testing on isogenic cell lines and PDOs. In these models, KRASG12 mutations were associated with increased resistance to FTD-induced (geno)toxicity in vitro. KRASG12-based resistance was absent for the closely related chemotherapeutic 5-FU. In the RECOURSE study, KRASG12 mutations were predictive biomarkers for reduced OS benefit of FTD/TPI vs placebo (unadjusted interaction P= 0.0017, adjusted interaction P= 0.017). For patients with KRASG12 mutations, OS was not significantly prolonged with FTD/TPI vs placebo (n = 279; HR, 0.97; 95% CI, 0.73−1.20; P= 0.85). An exploratory analysis showed that the KRASG13 mutant subgroup demonstrated clearly prolonged OS with FTD/TPI vs placebo (n = 60; unadjusted HR, 0.29; 95% CI, 0.15−0.55; P< 0.001; adjusted HR, 0.20; 95% CI, 0.092−0.45; P< 0.001), which was significantly more pronounced as compared to the KRASG12 mutant and KRASWT populations (adjusted interaction P< 0.001 and P= 0.036, respectively). Conclusions: Together, KRASG12 mutations were associated with reduced OS benefit of FTD/TPI treatment, with potential implications for ̃28% of patients with metastatic colorectal cancer now considered for treatment with FTD/TPI. Furthermore, our data show that genomics-based precision medicine may be possible for a subset of chemotherapies.

Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study.

4514 Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P<0.0001); PFS2 rates at 24 and 36 mos are in the Table. The unadjusted OS HR for LEN + PEMBRO vs SUN (from the primary analysis [Motzer 2021, NEJM]) was 0.66 (95% CI 0.49–0.88); the HR for OS adjusted for subsequent therapy was 0.54 (bootstrap 95% CI 0.39–0.72). Conclusions: LEN + PEMBRO had a statistically significant and clinically meaningful benefit over SUN in the CLEAR study. These findings remained consistent after accounting for subsequent therapies, as evidenced by prolonged PFS2 and adjusted OS. Results further support LEN + PEMBRO as a standard of care in 1L aRCC. Clinical trial information: NCT02811861. [Table: see text]

OP0039 RISK OF ARRHYTHMIA AMONG NEW USERS OF HYDROXYCHLOROQUINE: A LONGITUDINAL POPULATION-BASED COHORT STUDY ON NEWLY DIAGNOSED RHEUMATOID ARTHRITIS AND SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS

BackgroundPrevious findings on hydroxychloroquine (HCQ) use and the risk of arrhythmia are contradictory and low-level evidence-based results. Additional research is required to evaluate the safety profile of HCQ to arrhythmia in managing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).ObjectivesTo assess the association between HCQ initiation and risk of incident arrhythmia among newly diagnosed RA and SLE patients.MethodsAll patients with incident RA or SLE and no arrhythmic events or anti-arrhythmic medications and no HCQ use prior to disease index date in British Columbia, Canada, between January 1997 and March 2015 were identified using administrative databases. HCQ initiator and HCQ non-initiator groups were identified and matched 1:1 by propensity scores using baseline confounders on demographics including presence of RA or SLE disease and duration of disease prior to the index date of HCQ initiators or non-initiators, comorbidities, other medications, and healthcare utilization. Matching was done within the same calendar year to account for a potential secular trend in HCQ use and risk of arrhythmia. Outcomes were any new arrhythmias, atrial fibrillation, abnormal electrocardiogram including prolonged QT syndrome and conduction disorder, and other unspecified arrhythmias during follow-up. We used Cox proportional hazard models with death as a competing event to assess the association of HCQ initiation and the outcomes.ResultsWe identified 11,518 HCQ initiators (10,655 RA and 863 SLE patients, mean ± SD age 55.9 ± 15.1 years, 76.1% female) and 11,518 HCQ non-initiators (10,639 RA and 879 SLE patients, mean ± SD age 56.0 ± 16.2 years, 76.4% female) after 1:1 propensity score matching. Over the mean follow-up of eight years, there were 1,610 and 1,646 incident arrhythmias in the HCQ initiator and non-initiator groups, respectively. The crude incidence rates of arrhythmia were 17.5, and 18.1 per 1,000 person-years, respectively. Cumulative risk of incident arrhythmia remained similar for both groups. (Figure 1). Adjusted hazard ratio (aHR) of incident arrhythmia from the Cox proportional hazard model for HCQ initiators was 0.99 (95% CI: 0.92-1.06) compared to non-initiators (Table 1). The corresponding aHRs for HCQ initiators in subtypes of arrhythmia – atrial fibrillation, abnormal electrocardiogram, and other unspecified arrhythmias were 0.95 (95% CI: 0.84-1.06), 1.04 (95% CI: 0.87-1.26), and 0.96 (95% CI: 0.86-1.08), respectively.Table 1.Incident arrhythmias of any type among RA and SLE patients initiating HCQ prescription compared with HCQ non-initiatorsHCQ initiatorHCQ non-initiatorParticipants (number)11,51811,518Mean follow-up (years)8.007.89Events (number)1,6101,646Crude incidence rate per 1000 person-years17.4818.12Unadjusted HR (95% CI)0.98 (0.91-1.05)1.00 (reference)Adjusted# HR (95% CI)0.99 (0.92-1.06)1.00 (reference)Abbreviations: HCQ, hydroxychloroquine; HR, hazard ratio.#The multivariable Cox proportional hazard model was adjusted for baseline confounders on demographics, comorbidities, medications, and healthcare utilization.Figure 1.Cumulative risk of incident arrhythmias for HCQ initiators and non-initiators over the follow-up time.ConclusionThere is no increased risk of any type of arrhythmia among new users of HCQ in RA and SLE patients. We believe the results of this large cohort study will add to the confidence with which HCQ can be used in RA and SLE management.Disclosure of InterestsNone declared.

Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus.

Fragility fractures are an important hallmark of aging and an increasingly recognized complication of Type 2 diabetes (T2D). T2D individuals have been found to exhibit an increased fracture risk despite elevated bone mineral density (BMD) by dual x-ray absorptiometry (DXA). However, BMD and FRAX-scores tend to underestimate fracture risk in T2D. New, reliable biomarkers are therefore needed. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity. Serum miRNA-classifiers were recently found to discriminate T2D women with and without prevalent fragility fractures with high specificity and sensitivity (AUC > 0.90). However, the association of circulating miRNAs with incident fractures in T2D has not been examined yet. In 168 T2D postmenopausal women in the AGES-Reykjavik cohort, miRNAs were extracted from baseline serum and a panel of 10 circulating miRNAs known to be involved in diabetic bone disease and aging was quantified by qPCR and Ct-values extracted. Unadjusted and adjusted Cox proportional hazard models assessed the associations between serum miRNAs and incident fragility fracture. Additionally, Receiver operating curve (ROC) analyses were performed. Of the included 168 T2D postmenopausal women who were on average 77.2 ± 5.6 years old, 70 experienced at least one incident fragility fracture during the mean follow-up of 5.8 ± 2.7 years. We found that 3 serum miRNAs were significantly associated with incident diabetic fragility fracture: while low expression of miR-19b-1-5p was associated with significantly lower risk of incident fragility fracture (HR 0.84 (95% CI: 0.71-0.99, p = 0.0323)), low expression of miR-203a and miR-31-5p was each significantly associated with a higher risk of incident fragility fracture per unit increase in Ct-value (miR-203a: HR 1.29 (95% CI: 1.12-1.49), p = 0.0004, miR-31-5p HR 1.27 (95% CI: 1.06-1.52), p = 0.009). Hazard ratios of the latter two miRNAs remained significant after adjustments for age, body mass index (BMI), areal bone mineral density (aBMD), clinical FRAX or FRAXaBMD. Women with miR-203a and miR-31-5p serum levels in the lowest expression quartiles exhibited a 2.4-3.4-fold larger fracture risk than women with miR-31-5p and miR-203a serum expressions in the highest expression quartile (0.002 ≤ p ≤ 0.039). Women with both miR-203a and miR-31-5p serum levels below the median had a significantly increased fracture risk (Unadjusted HR 3.26 (95% CI: 1.57-6.78, p = 0.001) compared to those with both expression levels above the median, stable to adjustments. We next built a diabetic fragility signature consisting of the 3 miRNAs that showed the largest associations with incident fracture (miR-203a, miR-31-5p, miR-19b-1-5p). This 3-miRNA signature showed with an AUC of 0.722 comparable diagnostic accuracy in identifying incident fractures to any of the clinical parameters such as aBMD, Clinical FRAX or FRAXaBMD alone. When the 3 miRNAs were combined with aBMD, this combined 4-feature signature performed with an AUC of 0.756 (95% CI: 0.680, 0.823) significantly better than aBMD alone (AUC 0.666, 95% CI: 0.585, 0.741) (p = 0.009). Our data indicate that specific serum microRNAs including senescent miR-31-5p are associated with incident fragility fracture in older diabetic women and can significantly improve fracture risk prediction in diabetics when combined with aBMD measurements of the femoral neck.

Characteristics and survival of patients with cancer with intended off-label use—a cohort study

ObjectiveTo describe the characteristics and the survival of patients with cancer with intended off-label use (OLU) cancer treatment and reimbursement request.DesignCohort study using medical record data.SettingThree major cancer centres in...

The Difference and Significance of Parietal Pleura Invasion and Rib Invasion in Pathological T Classification With Non-Small Cell Lung Cancer.

ObjectiveThis study was to explore the difference and significance of parietal pleura invasion and rib invasion in pathological T classification with non-small cell lung cancer.MethodsA total of 8681 patients after lung resection were selected to perform analyses. Multivariable Cox analysis was used to identify the mortality differences in patients between parietal pleura invasion and rib invasion. Eligible patients with chest wall invasion were re-categorized according to the prognosis. Cancer-specific survival curves for different pathological T (pT) classifications were presented.ResultsThere were 466 patients considered parietal pleura invasion, and 237 patients served as rib invasion. Cases with rib invasion had poorer survival than those with the invasion of parietal pleura (adjusted hazard ratio [HR]= 1.627, P =0.004). In the cohort for parietal pleura invasion, patients with tumor size ≤5cm reached more satisfactory survival outcomes than patients with tumor size >5cm (unadjusted HR =1.598, P =0.006). However, there was no predictive difference in the cohort of rib invasion. The results of the multivariable analysis revealed that the mortality with parietal pleura invasion plus tumor size ≤5cm were similar to patients with classification pT3 (P =0.761), and patients for parietal pleura invasion plus tumor size >5cm and pT4 had no stratified survival outcome (P =0.809). Patients identified as rib invasion had a poorer prognosis than patients for pT4 (P =0.037).ConclusionsRib invasion has a poorer prognosis than pT4. Patients with parietal pleura invasion and tumor size with 5.1-7.0cm could be appropriately up-classified from pT3 to pT4.

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients

The prevalence and clinical relevance of pathogenic germline variants in MMR genes have not been investigated in large series of breast cancers. In this study, we screened the germline variants in MMR genes in 8085 consecutive Chinese breast cancer patients, and investigated the MMR/PD-L1 protein expression and tumor mutation burden (TMB) of breast tumors from MMR variant carriers. We found that 15 of 8085 patients (0.19%) carried a pathogenic germline variant in MMR genes. Compared with non-carriers, MMR variant carriers might have worse recurrence-free survival (unadjusted hazard ratios [HR] = 2.70, 95% CI: 1.12–6.49, P = 0.027) and distant recurrence-free survival (unadjusted HR = 3.24, 95% CI: 1.45–7.22, P = 0.004). More importantly, some of the breast cancers from MMR carriers displayed MMR protein loss (5/13), TMB-high (2/10), and PD-L1 positive expression (9/13). This study showed that MMR variant carriers were rare in breast cancer. They might have worse survival and part of them might benefit from immunotherapy.

Outcomes in Patients with Commercial HeartMate 3 LVAD: A Comparative Analysis of Non-Trial versus Trial Like Cohorts

<h3>Purpose</h3> Patient selection for real world use of the HeartMate 3 (HM3) left ventricular assist device differs from that of clinical trials. We assessed adverse event rates between "non-trial like" (NTL) and "trial like" (TL) patients who underwent commercial HM3 implantation. <h3>Methods</h3> A single-center, retrospective cohort study of 79 consecutive patients who underwent primary HM3 implant from 1/2019 to 10/2020 with ≥ 1-year follow-up was performed. Patients were identified as NTL if they met ≥ 1 exclusion criteria from the MOMENTUM 3 clinical trial and TL if they met no exclusion criteria. The primary outcome was freedom from composite events of death, LVAD-related infection (LVADI), and hemocompatibility-related adverse events (HRAE) including major gastrointestinal bleed, all-cause stroke, and pump thrombosis. <h3>Results</h3> Of the 79 patients, 32 (41%) were categorized as NTL due to: low prealbumin (<15 mg/dL) and/or albumin (<3 g/dL) levels (n=23), ongoing ECMO support prior to implant (n=3), psychosocial factors (n=2), creatinine >2.5mg/dL (n=2), total bilirubin >2.5mg/dL (n=1), and peripheral vascular disease (n=1). Both NTL and TL patients were similar in age, sex, race, and INTERMACS profiles. Compared to the TL group, the NTL group had a lower 1-year event-free survival (28% vs. 68%, unadjusted HR [95% CI]: 3.2 [1.7-6.1], p=0.001; Fig1A&B). One year survival was 84% in NTL group vs. 98% in TL group (p=0.06). The NTL group had an increase in HRAEs (p=0.005) and a trend toward more LVADI (p=0.051). There were more episodes of major gastrointestinal bleeds (p=0.006) and use of post-operative RVAD (p=0.014) in the NTL group. In an unadjusted analysis of all patients, having both low prealbumin and albumin was associated with increased risk of the primary outcome (unadjusted HR [95% CI]: 2.2 [1.2-4.2], p=0.016). <h3>Conclusion</h3> In a single-center experience of HM3 patients, those outside of traditional clinical trial eligibility had a significantly lower event-free survival.

Impact of HIV Infection on Outcomes After Left Ventricular Assist Device Implantation: An INTERMACS Analysis

<h3>Purpose</h3> The impact of HIV infection on outcomes after left ventricular assist device (LVAD) implantation is unknown. The purpose of this analysis was to assess the impact of HIV infection on post LVAD survival using STS Intermacs data. <h3>Methods</h3> NIH BioLINCC Intermacs data were utilized for this analysis (implants between June 2005- Dec 2017). Patients with missing HIV data or coded as total artificial heart were excluded. Survival to 2 years between first time LVAD recipients with and without HIV infection was assessed using Kaplan-Meier curves and multivariable Cox regression, adjusting for age, body mass index, race, marital status, drug use, ischemic cardiomyopathy, destination therapy (DT), and INTERMACS status. Patients were censored at time of transplant, or recovery. Occurrence of adverse events by 6 months were also compared. <h3>Results</h3> A total of 15,465 patients were included in this analysis (HIV infection: 49, Non-HIV: 15,416) The median follow up time was 12.8 months. Patients with HIV infection were younger and were more likely to be black, destination therapy, and single. Ninety percent of patients with HIV infection were on any anti-retroviral therapy with a median CD4 count of 554 cell/mm³ [IQR: 345, 924]. HIV infection was associated with increased mortality on LVAD support, which reached statistical significance in the adjusted models (unadjusted HR: 1.55, 95% CI; 0.93-2.57, p=0.09, adjusted HR: 1.82, 95% CI; 1.09 -3.04, p 0.020, <b>Figure</b>). Among those with and without HIV infection, there were no statistically significant differences in adverse events (infection, stroke, device malfunction, bleeding) by 6 months post implant. <h3>Conclusion</h3> In this small sample of LVAD patients with HIV infection, survival was lower compared to those without HIV infection. Further data are needed to confirm these findings and determine potential mechanisms of increased mortality.

Association between maternal smoking and survival among infants with trisomy 21

Trisomy 21 (T21) is common, with affected infants having an increased risk of infant mortality (5.9-7.1%). Maternal smoking is associated with infant mortality in the general population, and we evaluated if similar associations were present among infants with T21. We identified infants with T21 from the Texas Birth Defects Registry, and maternal smoking and infant vital status were obtained from linked birth and death certificate data, respectively. Cox proportional hazards regression models were used to calculate hazard ratios between maternal smoking and death between 0 to ≤ 364 days, 28-364 days, and 0-27 days. We found a significant association between maternal smoking and death between 0 to ≤ 364 (unadjusted HR 1.72, 95% CI 1.07, 2.77), which was no longer statistically significant after adjustment for covariates (adjusted HR 1.55, 95% CI 0.94, 2.56). A similar pattern was observed for death between 28-364 days (adjusted HR: 1.68, 95% CI 0.93, 3.03), whereas the association for 0-27 days (adjusted HR: 1.30, 95% CI 0.51, 3.29) was not statistically significant before and after adjustment. The observed magnitudes of associations were similar to previous estimates among the general population. Further work considering the role of other maternal and infant risk factors and social determinants of health is necessary to better understand the observed results.

Abstract P2-13-42: Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial

Abstract Background: The poor prognostic value of young age at diagnosis appears to vary according to breast cancer (BC) subtype, although this has been studied mainly in hormone receptor-positive (HR+) disease, with limited data in HER2-positive BC and short follow-up. Limited evidence exists on the benefit of anti-HER2 therapy in young women with BC. Considering that age has historically been a rationale for overtreatment, further research efforts to better investigate the prognostic and predictive value of age are needed. This exploratory analysis conducted within the APHINITY trial aimed to investigate the prognostic and predictive value of young age in patients with HER2-positive early BC treated with modern chemotherapy and concurrent anti-HER2 targeted treatment. Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in patients with HER2-positive early BC investigating the benefit of adding pertuzumab to adjuvant chemotherapy plus trastuzumab. For the purpose of the present analysis, 40 years of age at enrolment was used as the cut-off to distinguish between young (≤40 years) and older (&amp;gt;40 years) cohorts. Invasive disease-free survival (IDFS) was the primary endpoint. IDFS irrespective of treatment arm and the benefit of adding pertuzumab were evaluated in all patients by comparing the young and older cohorts and then according to centrally-assessed hormone receptor status. Univariate and multivariable Cox proportional hazard models were used to assess the prognostic and predictive value of age on IDFS as a continuous and dichotomous variable (≤40 years and &amp;gt;40 years). A STEPP analysis was also conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results: Out of 4,804 patients in the ITT population, 768 (16.0%) were ≤40 years at enrollment. Patients in the young cohort were less overweight/obese (29.3% vs. 50.4%), underwent mastectomy more frequently (63.2% vs. 52.6%), had higher rates of node positive (66.4% vs. 61.8%) and HR+ (71.7% vs. 64.9%) BC as compared to those in the older cohort (all p&amp;lt;0.05). Among patients with HR+ BC that received adjuvant endocrine therapy in the young cohort (n=498), 132 (26.5%) underwent ovarian function suppression while 324 (65.1%) received tamoxifen alone. Overall median follow-up was 74 months (IQR 62-75 months). 6-year IDFS was 88% and 89% in the young and older cohorts, respectively. In univariate and multivariable analyses, young age was not prognostic as dichotomous (unadjusted HR 1.06; 95% CI 0.84-1.33; adjusted HR 1.07; 95% CI 0.84-1.35) nor as continuous (unadjusted HR 1.00; 95% CI 1.00-1.01) variables. The lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No significant interaction was observed between age and treatment effect (Pinteraction=0.605). The addition of pertuzumab improved IDFS for both patients in the young (6-year IDFS 89% vs. 87%; adjusted HR 0.86; 95% CI 0.56-1.32) and older (6-year IDFS 91% vs. 88%; adjusted HR 0.75; 95% CI 0.62-0.92) cohorts. By analyzing the potential predictive value of age according to hormone receptor status, similar results were observed. The STEPP analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate prognostic or predictive value in long-term follow-up, irrespective of hormone receptor status and anti-HER2 treatment modalities. These results may help to improve the care of young women with BC, highlighting that, in the current era of precision medicine, age alone is not a reason to expect a different disease outcome or treatment benefit. Citation Format: Matteo Lambertini, Shona Fielding, Sibylle Loibl, Wolfgang Janni, Emma Clark, Maria Alice Franzoi, Debora Fumagalli, Carmela Caballero, Luca Arecco, Sharon Salomoni, Noam F Ponde, Francesca Poggio, Hee Jeong Kim, Cynthia Villarreal-Garza, Olivia Pagani, Shani Paluch-Shimon, Alberto Ballestrero, Lucia Del Mastro, Martine Piccart, Jose Bines, Ann H. Partridge, Evandro de Azambuja. Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-42.

Adjuvant gemcitabine (GEM) versus gemcitabine plus capecitabine (GEMCAP) in resected pancreatic adenocarcinoma: A retrospective analysis.

547 Background: For patients who underwent curative-intent upfront surgery, adjuvant chemotherapy is the current standard of care. The previous, randomized phase 3 ESPAC-4 study showed significantly improved overall survival (OS) with GEMCAP compared to GEM. However, this study was conducted in European countries and its implication in Asian patients has not been explored yet. We conducted a retrospective analysis to evaluate the efficacy and safety of GEMCAP compared to GEM regimen. Methods: Between January 2017 and December 2020, a total of 292 patients who received adjuvant GEM or GEMCAP after curative-intent surgery in Asan Medical Center, Seoul, Korea, were included in this retrospective analysis. Results: Adjuvant GEM and GEMCAP were administered in 161 patients (55.1%) and 131 patients (44.8 %), respectively. Compared the GEMCAP group, age of patients were significantly older in the GEM group (median 66 vs 63 yo, p = 0.025); otherwise, there was no significant difference in baseline characteristics between two groups. With the median follow-up duration of 39.4 months (95% CI 36.9 - 45.0 months) in GEM group and 39.4 months (95% CI 34.7-41.6 months) in GEMCAP group, the median OS was 36.8 months (95% CI 29.7-43.5 months) and 46.1 months (95% CI 31.5 months – not reached) in the GEM group and GEMCAP group, respectively (unadjusted HR 0.72, 95% CI 0.51-1.02, p = 0.065). The median recurrence-free survival was 14.3 months (95% CI, 12.9-17.7 months) and 17.0 months (95% CI, 13.3-28.8 months) in the GEM group and GEMCAP group, respectively (p = 0.52). In the GEMCAP group, hand-foot skin reaction (any grade, 15.27 % vs 0.62 %, p &lt; 0.001), neutropenia (78.6% vs 67.7%, p=0.037) and thrombocytopenia (30.53% vs 20.5%, p=0.035) were more common in the GEMCAP group compared to the GEM group. In multivariate analysis, adjuvant GEMCAP was significantly associated with better OS compared to adjuvant GEM (adjusted HR 0.64, 95% CI, 0.44-0.91, p = 0.014). Otherwise, moderate or poor histologic grade, lymph node positive, positive resection margin, and elevated CA 19-9 levels (&gt; median) were significantly associated with poorer OS. Conclusions: In this retrospective analysis for Korean patients, adjuvant GEMCAP showed consistent clinical outcomes shown in the ESPAC-4 trial. As mFOLFIRINOX is the new standard of care for medically fit patients with resected pancreatic adenocarcinoma, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.

Traumatic brain injury, cardiovascular disease, and risk of dementia among older US Veterans

ABSTRACT Objective Traumatic brain injury (TBI) is associated with elevated rates of cardiovascular disease (CVD), and both CVD and TBI are risk factors for dementia. We investigated whether CVD and its risk factors underlie the association between TBI and dementia. Materials and Methods Cox proportional hazards models among 195,416 Veterans Health Administration patients age 55+ with TBI and a non-TBI, age/sex/race-matched comparison sample. Results Veterans +TBI were more likely to have any CVD diagnosis (24% vs 36% p = <0.001) or risk factor (83 vs. 90% p < .001) compared to -TBI. During follow-up (mean ~7 years), 12.0% of Veterans with TBI only (HR: 2.17 95% CI 2.09–2.25), and 10.3% with CVD only developed dementia (HR 1.21 95% CI 1.15–1.28), compared to 6.5% with neither. There was an additive association between TBI and CVD on dementia risk (HR 2.51, 95% CI 2.41–2.61). Among those +TBI (±CVD), risk was minimally attenuated by adjustment for CVD/CVD risk factors (unadjusted HR: 2.38, 95% CI: 2.31–2.45; adjusted HR: 2.17, 95% CI 2.10–2.23). Conclusions Older veterans TBI have increased prevalence of CVD/CVD risk factors. TBI and CVD had an additive statistical association, with dementia risk increased by ~2.5-fold. However, CVD accounted for little of the association between TBI and dementia. More research is needed to understand mechanisms of TBI-dementia and inform clinical guidelines post-TBI.

Functional MAOB Gene Intron 13 Polymorphism Predicts Dyskinesia in Parkinson's Disease.

Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOBCC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089–0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039–0.520]; p=0.003) than MAOBTT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

Frailty Measures of Patient-reported Activity and Fatigue May Predict 1-year Outcomes in Ambulatory Advanced Heart Failure: A Report From the REVIVAL Registry

BackgroundThe Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes. Methods and ResultsHF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan–Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52–5.24; adjusted HR 3.41, 95% CI 1.79–6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14–3.41; adjusted HR 2.11, 95% CI 1.21–3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004). ConclusionsThe HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population.

Comparison of Effect of Ischemic Postconditioning on Cardiovascular Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention With Versus Without Thrombectomy

In patients with ST-segment elevation myocardial infarction (STEMI), ischemic postconditioning (iPOST) have shown ambiguous results in minimizing reperfusion injury. Previous findings show beneficial effects of iPOST in patients with STEMI treated without thrombectomy. However, it remains unknown whether the cardioprotective effect of iPOST in these patients persist on long term. In the current study, all patients were identified through the DANAMI-3-iPOST database. Patients were randomized to conventional primary percutaneous coronary intervention (PCI) or iPOST in addition to PCI. Cumulative incidence rates were calculated, and multivariable analyses stratified according to thrombectomy use were performed. The primary end point was a combination of cardiovascular mortality and hospitalization for heart failure. From 2011 to 2014, 1,234 patients with STEMI were included with a median follow-up of 4.8 years. In patients treated without thrombectomy (n=520), the primary end point occurred in 15% (48/326) in the iPOST group and in 22% (42/194) in the conventional group (unadjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41 to 0.94, p=0.023). In adjusted Cox analysis, iPOST remained associated with reduced long-term risk of cardiovascular mortality (HR 0.53, 95% CI 0.29 to 0.97, p=0.039). In patients treated with thrombectomy (n=714), there was no significant difference between iPOST (17%, 49/291) and conventional treatment (17%, 72/423) on the primary end point (unadjusted HR 1.01, 95% CI 0.70 to 1.45, p=0.95). During a follow-up of nearly 5 years, iPOST reduced long-term occurrence of cardiovascular mortality and hospitalization for heart failure in patients with STEMI treated with PCI but without thrombectomy.

132 Clinical characteristics and outcomes of a contemporary, real-world, single-centre cohort of patients with advanced heart failure

Abstract Aims An increasing number of patients with heart failure (HF) progresses to an advanced stage, characterized by persistent and sever symptoms and worse prognosis. A detailed characterization of patients with advanced HF is needed to optimize clinical management and timely refer for heart transplant or left ventricular assist device implantation. Methods and results A retrospective analysis was performed on patients with HF who were admitted to hospital or performed an outpatient visit at our centre (Spedali Civili di Brescia, Brescia, Italy) from 1 January 2020 to 31 December 2020, and who had at least one of the following high-risk characteristics: (1) previous or ongoing requirement for inotropes; (2) persisting New York Heart Association (NYHA) class III or IV and/or persistently high natriuretic peptides (BNP or NT-proBNP); (3) end-organ dysfunction, defined as worsening renal or liver dysfunction in the setting of HF; (4) ejection fraction (EF) &amp;lt;20%; (5) recurrent appropriate defibrillator shocks; (6) more than 1 hospitalization for HF in the last year; (7) persisting fluid overload and/or increasing diuretic requirement; (8) consistently low blood pressure (systolic blood pressure &amp;lt;90–100 mmHg); and (9) inability to up-titrate or need to decrease/cease HF therapies, such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, or mineralocorticoid receptor antagonists. The updated 2018 Heart Failure Association (HFA)—European Society of Cardiology (ESC) criteria for defining advanced HF were evaluated. The primary endpoint was all-cause mortality; secondary endpoints were a composite of all-cause mortality or hospitalization for HF and a composite of all-cause mortality or hospitalization for any reason. Among 493 patients with HF who were hospitalized or performed an outpatient visit in 2020, 230 (46.7%) had at least one high risk criterion and were included in the study. Mean age was 75.5 ± 11.9 years, 156 patients (67.8%) were men, and 160 patients (69.6%) were hospitalized and included as inpatients. Median EF was 38% [interquartile range (IQR): 25–50%] and 117 patients (50.9%) had HF with reduced EF (&amp;lt;40%); median NT-proBNP was 4044 (IQR: 2262–7664) pg/mL. Among the included 230 patients, 38 (16.5%) had all four updated HFA-ESC criteria defining advanced HF, 53 (23.0%) had American College of Cardiology (ACC)/American Heart Association (AHA) stage D, 21 (9.1%) had INTERMACS profile 1–3. In-hospital mortality was 10.6% (among inpatients). After a median follow-up of 301 (214–442) days, a total of 62 patients died (27.0%), and the secondary endpoints of all-cause death or HF hospitalization and all-cause death or any hospitalization were observed in 107 (46.5%) and 139 (60.4%) patients, respectively. Patients fulfilling all four updated HFA-ESC criteria for advanced HF had a higher risk of all-cause mortality (unadjusted HR: 2.06; 95% CI: 1.18–3.60; P = 0.011), also after adjustment for covariates of interest (adjusted HR: 2.20; 95% CI: 1.03, 4.70; P = 0.041). Conclusions In our contemporary, real-world cohort of HF patients with high-risk characteristics, mid-term prognosis was poor, and the use of updated HFA-ESC criteria defining advanced HF identified a subset at increased risk of mortality.