tbuckley/cabot-search huggingface dataset:
A nationwide analysis of inpatient outcomes and healthcare utilization in HIV versus non-HIV patients with esophageal cancer.
Authors: Syed Ali Amir Sherazi, Ikechukwu Achebe, Jennifer C Asotibe, Bibek Singh Pannu, Bashar Attar, Shweta Gupta, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2021)

e16106 Background: Esophageal cancer (EC) is an aggressive malignancy with poor 5-year survival rates (19.9%). Due to effective Antiretroviral Therapy, mortality from HIV/AIDS has precipitously decreased leading to longer lifespan and increased risk of developing non-AIDS defining cancers. There is paucity of data regarding outcomes of Esophageal Cancers in patients with HIV (HIV-EC). We undertook this analysis to study the outcomes of HIV-EC with healthcare utilization compared to non-HIV-EC patients. Methods: The Healthcare Cost Utilization Project (HCUP) Nationwide Inpatient Sample was queried to identify patients with HIV and non-HIV-EC using ICD-10 codes. Groups were compared for demographic differences, inpatient mortality, length of stay (LOS) and hospital charges. Secondary outcomes studied included rates of septic shock (SS), Esophageal Obstruction (EO), Anemia, Pneumonia, Tracheoesophageal Fistula (TEF), Upper GI Bleed (UGIB), Acute Kidney Injury (AKI), protein energy malnutrition (PEM). Statistics were performed using the t-test, chi-square test and logistic regression. Results: A total of 330 inpatient admissions with HIV-EC and 117505 with non-HIV-EC were identified. Patients with HIV-EC were significantly younger (mean age 58.5 vs 66.9 years, p &lt; 0.001) with 83% under 65 years of age compared to 41% in non-HIV-EC group (p &lt; 0.001). Higher number of HIV-EC patients were African American (AA) (51.5% vs 10%, p &lt; 0.001) with similar gender ratio (19.7% vs 21.3% women), belonged to lowest income quartile zip codes (42% vs 27%, p = 0.01), more likely to be on Medicaid (36% vs 11%, p &lt; 0.001) and hailed from North East (NE) or Southern regions of the US (79% vs 56%, p = 0.003). The overall mortality rate was significantly higher in the HIV-EC group than non-HIV-EC (13.6% vs 8.8%, p = 0.001). The mean inpatient LOS (7.4 vs 6.98 days) and total hospital charges ($65,358 vs $80,620) were not significantly different between the two groups. Rates of PEM were higher in HIV-EC (61% vs 44%, p &lt; 0.01) but rates of sepsis, SS, UGIB, EO, TEF, Anemia, TLS, AKI were not significantly different than non-HIV-EC. There was no difference in rates of specific medical co-morbidities between groups, although HIV-EC had a significantly higher Charlson Comorbidity Index (p &lt; 0.001). Conclusions: Despite being significantly younger, HIV-EC patients have significantly higher mortality compared to non-HIV-EC. However, the inpatient LOS and total charges were not significantly different. HIV-EC were more likely to be AA on Medicaid and from low-income zip codes from the NE or South of the United States. Further studies are needed to study the role of early diagnosis, perhaps screening in younger patients with HIV to prevent mortality.
Global covid-19 vaccine rollout and safety surveillance—how to keep pace
Authors: Vincent Lo Re, Olaf H Klungel, K Arnold Chan, Catherine A Panozzo, Wei Zhou, Almut G Winterstein
Journal: BMJ (2021)

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Circulating cell free tumor DNA detection as a prognostic tool in advanced pancreatic cancer.
Authors: Gehan Botrus, Pedro Luiz Serrano Uson Junior, Puneet Raman, Adrienne Kaufman, Heidi E. Kosiorek, Mohamad Bassam Sonbol, Mitesh J. Borad, Daniel H. Ahn, Isabela Chang, Leylah Drusbosky, Jason S. Starr, Kabir Mody, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2021)

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p &lt; 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p &lt; 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.
Elderly patients with unresectable stage 3 NSCLC treated with definitive chemoradiation with or without durvalumab: Safety and outcomes.
Authors: Malcolm Isaiah Ryan, Jessica Weiss, Aline Fusco Fares, Ming Sound Tsao, Geoffrey Liu, Penelope Ann Bradbury, Natasha B. Leighl, Frances A. Shepherd, Adrian G. Sacher, Sally C. M. Lau
Journal: Journal of Clinical Oncology (2021)

8547 Background: Recently, it has been demonstrated that the addition of durvalumab after chemoradiation (CRT) in unresectable stage 3 non-small cell lung cancer (NSCLC) significantly improves overall survival (OS). The benefit of CRT in elderly patients is considered controversial given its increased toxicity. As such, CRT followed by durvalumab in elderly patients may be underutilized despite its demonstrated superiority. The practice pattern at our center is to offer curative treatment unless clearly contraindicated. We sought to investigate the outcomes of elderly patients treated with CRT +/- durvalumab at our center. Methods: We conducted a review of all stage 3 NSCLC patients treated with CRT between 2018 and 2020. Patients were analyzed based on age: &lt; 70 years, ≥70 years. Endpoints evaluated were treatment patterns, toxicity, progression free survival (PFS) and overall survival (OS). Results: We identified 115 stage 3 patients: 44 patients ≥70 years (70-89) and 71 patients &lt; 70 years (34-69). Patients were fit: ECOG 0-1 (98%/97%), mean Charlson comorbidity index (CCI) (1.1/0.9) in elderly vs young patients; p &gt; 0.05. All other baseline characteristics including PD-L1 expression were similar. The chemotherapy regimens (platinum in combination with etoposide, paclitaxel or pemetrexed), dose intensity (97% vs 97%) and percentage of planned cycles received (91% vs 96%) were similar. There were 2 treatment related deaths from CRT among the younger cohort and none in the elderly patients. At the completion of CRT, 75% of elderly and 72% of young patients received durvalumab. Clinician/patient preference was the most common reason for not receiving consolidation durvalumab in older patients (55% vs 25%). The median time to starting durvalumab was 43 days in the elderly and 37 days in young patients (p = 0.19). Durvalumab was well tolerated in the elderly and incidence of grade ≥3 immune-related adverse events was 9% compared to 6% in young patients; p = 0.68. The durvalumab completion rates were 30% in elderly and 24% in young patients; p = 0.22. Median PFS was similar between elderly and young patients (17.9 vs 10.6 months respectively; p = 0.07), even after adjusting for the CCI (HR 0.60; p = 0.07). The 24- and OS rates are also similar (p = 0.93): 77% in elderly and 77% in young patients. Conclusions: Definitive CRT followed by durvalumab can be safely delivered in elderly patients ≥70 years with comparable outcomes. The non-significant trend towards better PFS in elderly patients suggests that only select fit patients are being referred for treatment. In conclusion, all patients should undergo comprehensive oncologic assessment to determine if curative intent treatment can be delivered to avoid undertreatment of elderly patients.
Enhanced Apoptosis: TRAIL‐Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582) (Adv. Healthcare Mater. 11/2021)
Authors: Huan Hou, Kui Su, Chaohong Huang, Qian Yuan, Shuyi Li, Jianwu Sun, Yue Lin, Zhiyun Du, Changhong Ke, Zhengqiang Yuan
Journal: Advanced Healthcare Materials (2021)

The antitumor effect of TNF-related apoptosis-inducing ligand (TRAIL)-loaded cellular endoplasmic reticulum derived nanosomes (ERN-Ts) is investigated in article number 2100030 by Zhengqiang Yuan, Changhong Ke, and co-workers, in a mouse xenograft tumor model. ERN-T has good tumor tropism and with its combined therapy with AZD5582, the antagonist of inhibitors of apoptosis proteins induces strikingly enhanced apoptosis in resistant tumors and thus significantly suppresses tumor growth in vivo.
Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ preservation.
Authors: Iver Nordentoft, Emil Christensen, Karin Birkenkamp-Demtröder, Sunil Deochand, Dillon Maloney, Tomer Lauterman, Kristofer Patel, Imane Bourzgui, Nidhi Ramaraj, Sia Viborg Lindskrog, Mads Agerbaek, Jørgen Bjerggaard Jensen, Ravi Kandasamy, Iman Tavassoly, Boris Oklander, Asaf Zviran, Lars Dyrskjøt
Journal: Journal of Clinical Oncology (2021)

e16527 Background: Bladder cancer (BC) is the 9th most commonly diagnosed cancer worldwide and each year responsible for 165,000 deaths. Neoadjuvant combination chemotherapy, followed by radical cystectomy, is used for the management of localized muscle-invasive bladder cancer. One of the critical challenges in this therapeutic regimen is monitoring the tumor load to assess therapeutic efficacy – this is typically performed by assessing pathological downstaging in the cystectomy specimen. A high frequency of patients presents with T0N0 at cystectomy (no indication of residual disease), and consequently, it is vital to investigate organ preservation approaches to identify those patients who may qualify for bladder preservation. For precision oncology, we need to develop quantitative and non-invasive diagnostic methodologies to help the oncologist tailor the treatments to individual patients and monitor them for further clinical decision-making. Methods: Cell-free DNA (cfDNA) mutation detection has shown significant promise in its ability to monitor minimal residual disease and disease relapse by detection of cancer mutations in the peripheral blood. However, the combination of low tumor fraction and limited input material obtained from a typical plasma sample restricts the probability of detecting low metastatic burden in cfDNA through current deep targeted sequencing methods. Results: Here we present results from applying whole-genome sequencing (WGS) of cfDNA. We integrate a genome-wide mutation and copy number monitoring approach coupled with advanced signal processing and Artificial Intelligence (AI) for measuring the tumor load from low-input blood samples (̃1mL of plasma) with ultra-sensitive detection. The increased sensitivity allowed clinical detection of tumor fraction down to 8*10 -5 and recurrence detection sensitivity achieving &gt; 65% at the first two months post-surgery. The WGS cfDNA approach is being evaluated on a patient cohort of more than 50 bladder cancer patients with longitudinal plasma sampling during neoadjuvant chemotherapy (response measure), pre-cystectomy (complete response measure), and post-surgery (relapse monitoring). Conclusions: The results indicate the clinical potential of genome-wide mutation integration as an ultra-sensitive, non-invasive diagnostic method for bladder cancer clinical management and bladder organ preservation.
Integrating peripheral biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Toni K. Choueiri, Amber C Donahue, Brian I. Rini, Thomas Powles, John B. A. G. Haanen, James Larkin, Xinmeng Jasmine Mu, Jie Pu, Despina Thomaidou, Alessandra Di Pietro, Paul B. Robbins, Robert J. Motzer
Journal: Journal of Clinical Oncology (2021)

4547 Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients (pts) with aRCC demonstrated prolonged progression-free survival (PFS) and a higher objective response rate with A + Ax vs S. We report the association of blood-based biomarkers with differential responses to treatment. Methods: Biomarkers in pretreatment (pre-tx) and on-treatment (on-tx) blood samples from 886 enrolled pts were correlated with clinical outcomes and molecular profiling data from corresponding tumor samples. Analyses include blood counts of unique populations, T-cell receptor sequencing, circulating cytokines, and serum proteomics by mass spectrometry MALDI-TOF. Results: At baseline, higher pre-tx monocyte counts were associated with shorter PFS in the A + Ax arm (Table). In the S arm, higher pre-tx levels of multiple T-cell–related metrics, including the percent of productively rearranged peripheral T cells, were associated with longer PFS but had no association in the A + Ax arm (Table). Higher pre-tx neutrophil counts were associated with shorter PFS in both arms, but neutrophil-to-lymphocyte ratio (NLR) was only associated with PFS for the S arm (Table). On-therapy biomarkers showed differential post-tx changes in T-cell numbers and clones at C2D1. Tx-specific differences were also seen in non–T-cell populations such as monocytes and neutrophils at multiple time points through C3D1. Serum levels of pre- and on-tx VEGF, CRP, and several interleukins showed differential associations with PFS (eg, higher pre-tx VEGF was associated with shorter PFS in only the S arm) (Table). Specific genomic alterations in tumor tissues were associated with differences in several pre- and on-tx angiokines &amp; cytokines. Conclusions: Response to treatment with first-line A + Ax or S was associated with immune fitness and tx-specific immunomodulation. We identified peripheral biomarkers in pts with aRCC associated with the presence of impactful genomic alterations and differential clinical outcomes. Clinical trial information: NCT02684006. [Table: see text]
System inflammation markers of resectable colorectal cancer patients with different mismatch repair gene status.
Authors: Li Jingjing, Yiwen Zhang, Xu Qi, Qing Wei, Jieer Ying, Luo Cong
Journal: Journal of Clinical Oncology (2021)

e15612 Background: Clinical trials suggested that solid tumors with MSI-high or dMMR are associated with responses to programmed cell death 1 inhibitors. Understanding the associations of MMR status with clinicopathological characteristics in CRC patients would help further guide clinical treatment and explore the pathogenetic mechanisms of this disease. Methods: Bioinformatics analysis was used to identify the differential expression genes between CRC patients with different MMR status. 208 resectable colorectal cancer patients, including 104 dMMR patients and 104 matched pMMR patients were retrospectively analyzed. Clinicopathological data, including age, gender, tumor location, histological subtype, tumor grade, tumor stage, regional lymph node (LNs) metastasis, American Joint Committee on Cancer (AJCC) 8th edition stage, perineural invasion, vascular invasion, number of retrieved LNs, number of metastatic LNs, systemic inflammation markers, including C-reactive protein (CRP), lactic dehydrogenase (LDH), albumin, neutrophil, monocyte, lymphocyte, platelet and survival were retrospectively reviewed. Results: Bioinformatics analysis shown chemokine-mediated signalling pathway and inflammatory response were the main differences in gene expression between dMMR and pMMR CRC patients. In all 208 CRC patients, those with dMMR were more frequently located in right side, with more mucinous adenocarcinoma, and with more grade 3 for tumor grade. Patients with dMMR had earlier AJCC stage than pMMR ones. Meanwhile, lymph nodes (LNs) metastasis was more frequently in dMMR patients compared with pMMR patients. Interestingly, CRC patients with dMMR were able to remove more regional lymph nodes during surgery, but with less metastati. Resectable CRC patients with dMMR were more likely to have higher level of neutrophil, monocyte, platelet, NLR, PLR, MLR, CAR, GPS and CRP. In CRC patients with dMMR, the patients with higher level of PLR, MLR, CAR and co-effect present had shorter OS significantly. It was interesting to note that the prognosis of high level of systemic inflammatory markers did not predict long OS in pMMR CRC patients. Conclusions: dMMR CRC has presented a comprehensively distinct systemic inflammatory microenvironment. The systemic inflammatory response can predict oncological outcomes in CRC patients with dMMR.
SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity
Authors: Chihiro Motozono, Mako Toyoda, Jiri Zahradnik, Akatsuki Saito, Hesham Nasser, Toong Seng Tan, Isaac Ngare, Izumi Kimura, Keiya Uriu, Yusuke Kosugi, Yuan Yue, Ryo Shimizu, Jumpei Ito, Shiho Torii, Akiko Yonekawa, Nobuyuki Shimono, Yoji Nagasaki, Rumi Minami, Takashi Toya, Noritaka Sekiya, Takasuke Fukuhara, Yoshiharu Matsuura, Gideon Schreiber, Terumasa Ikeda, So Nakagawa, Takamasa Ueno, Kei Sato
Journal: Cell Host & Microbe (2021)

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
eMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.
Authors: Sara M. Tolaney, Lesley Fallowfield, Peter A. Kaufman, Eva M. Ciruelos, Mary Corona Gainford, Yi Lu, Karla Hurt, Heather Ann Wasserstrom, Yanyun Chen, Shom Goel
Journal: Journal of Clinical Oncology (2021)

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 &amp; 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.