bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of tozinameran adverse events among the employees of National Cancer Institute.
Authors: Palacka Patrik , Slopovsky Jan , Zanchetta Katarina , Drgona Lubos , Badurikova Eva , Bernadicova Beata , Baranova Vladimira , Pechan Juraj , Mego Michal
Published: June 2021

e18724

Background: Active immunization seems to be the most effective protection against COVID-19. The objective of this prospective study was to explore the side effects of mRNA vaccine Tozinameran and possible differences in their incidence between different categories of employees at the National Cancer Institute in Bratislava, Slovakia (NCI). Methods: Four hundred and thirteen subjects (89 men) were enrolled into this ongoing prospective study in January, 2021. Median age was 47 years (range 19-79 years). Majority were healthcare professionals (N=306), including nurses (N=125), medical-technical workers (N=89), and physicians (N=42). Presence of side effects was entered by the physicians into electronic data files and their accuracy validated for each subject by an independent investigator. Number of adverse events in the subgroups were compared with log-rank test. Results: At median follow up of 4 weeks, injection site pain (63.0%), pain in the extremity (45.5%), and fatigue (28,6%) belonged among the most common adverse events of Tozinameran. Median number of side effects was 2 (range 0-13). Adverse event incidence was significantly higher in females compare to males (median number 2 vs. 1, P < 0.00001). In a subgroup of healthcare professionals, we found a significantly higher incidence of side effects compared to non-healthcare workers (median number 2 vs. 1, P = 0.00017). Conclusions: In this study, incidence of Tozinameran adverse events was significantly higher in females vs. males and healthcare professionals vs. non-healthcare workers. All side effects were mild and no new safety signals were recognized during follow-up. Key Words: Tozinameran, Active Immunization. COVID-19. Healthcare Professionals. Adverse Events. This study was supported by National Cancer Institute in Bratislava (SK) and OncoReSearch (SK).
Prospective cohort of real-world, curative-intent breast cancer treatment patterns in Malawi.
Authors: Morgan Jennifer , Zuze Takondwa , Elmore Shekinah Nefreteri Cluff , Painschab Matthew , Gondwe Yolanda , Nyasosela Richard , Kajombo Chifundo , Manda Agness , Reeder-Hayes Katherine Elizabeth , Tomoka Tamiwe
Published: June 2021

e18736

Background: Despite increasing availability of curative-intent breast cancer treatment in concordance with the National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA), few descriptions of their application in SSA are available. Our aim was to describe patterns of curative-intent treatment including neoadjuvant (NAC) and/or adjuvant chemotherapy (AdC) and surgery (S) by stage and HIV status, and the association between guideline-concordant treatment completion and overall survival (OS). Methods: We enrolled newly diagnosed breast cancer patients in a prospective cohort study at Kamuzu Central Hospital in Malawi from Dec 2016 – Oct 2018. Unadjusted odds ratios (OR) with 95% CI were calculated to identify factors associated with completion of guideline-concordant treatment, defined as S and at least 4 cycles of NAC or AdC. A logistic regression model was performed using variables with p<0.1. Survival analysis was performed with Kaplan Meier methods and log-rank test. Results: 67 non-metastatic patients were included. 12 (18%) were HIV+; 13 (19%) were Stage II and 54 (81%) Stage III. 46 (69%) began treatment with NAC, of which 39 (85%) were Stage III and 7 (15%) Stage II. 12 (18%) began treatment with S+AdC, of which 5 (42%) were Stage II and 7 (58%) were Stage III. 2 (3%) Stage III patients were treated with palliative chemotherapy (PC). 7 (10%) never received treatment. Overall, 41 (61%) underwent S. In bivariate analysis, factors associated with failure to complete treatment were HIV+ (OR 0.25 CI (0.06-0.99), Stage III (OR 0.10 CI (0.01-0.89) and ER/PR-/HER2+ (OR 0.07 CI (0.01-0.49). In adjusted analysis, ER/PR-/HER2+ (OR 0.12 (0.01-0.97) was associated with failure to complete treatment. HIV+ patients received less NAC than HIV- (2.5 vs 4 cycles; p=0.07) and similar AdC as HIV- (6 vs 6 cycles; p=0.7). Median OS for those who began treatment with NAC was shorter than with S+AdC (28.5 vs 40 months; p=0.01). Median OS for HIV+ vs HIV- who received NAC was 19.7 vs 32.7 months (p=0.10) and received S+AdC was unreached vs 37.1 months (p=0.27). Conclusions: When applying NCCN Harmonized Guidelines for SSA to Malawi, most patients received NAC for curative breast cancer treatment and had significantly shorter OS compared to those receiving upfront S+AdC. Stage III, HIV+, and ER/PR-/HER2+ patients were less likely to complete guideline-concordant treatment which may reflect advanced disease or poor treatment tolerability. Further study is needed to identify barriers to guideline-concordant treatment and inform interventions to improve breast cancer treatment outcomes in Malawi and SSA.[Table: see text]
Clinical characteristics and outcomes of cancer patients with chronic kidney disease and coronavirus disease 2019.
Authors: Mamlouk Omar , Turin Anastasia , D'Achiardi David , Simbaqueba Cesar , Dickson Kodwo , Franco-Vega Maria , Halm Josiah , Mandayam Sreedhar ,   D3CODE Team
Published: June 2021

e18815

Background: Coronavirus disease 2019 (COVID-19) has been associated with higher risk of acute kidney injury (AKI) and mortality rate in cancer patients. The prevalence of CKD in cancer patients is close to 20-30% however there has been limited data about cancer patients with CKD and COVID-19 infection. The aim of this study is to evaluate the clinical characteristics and outcomes of this patient population at a tertiary cancer center. Methods: All patient data — demographics, labs, comorbidities and outcomes — were aggregated and analyzed in the Syntropy platform, Palantir Foundry (“Foundry”), as part of the Data-Driven Determinants of COVID-19 Oncology Discovery Effort (D3CODE) protocol at MD Anderson. The cohort was defined by the following: (1) positive COVID-19 test; (2) baseline eGFR 15-59 ml/min/1.73m2 calculated by chronic kidney disease epidemiology collaboration equation. The baseline GFR and creatinine values used the most temporally proximal lab results within 30 days prior to the patient’s infection. AKI was defined as an absolute change of creatinine ≥0.3 mg/dl above the baseline after the positive COVID-19 test. Results: Out of 790 patients with COVID-19,19.6% had underlying CKD. Among these, 86.5% and 46.5% had history of hypertension and diabetes mellitus, respectively. 77.3% had a solid malignancy and 87.3% of them had metastatic disease. 67.7% were asymptomatic, 14.2% required ICU admission, 10.3% required invasive ventilation support, and 11.6% died within 90 days of the COVID-19 test. AKI developed within the first 30 days in 61.3% and 8.4% required renal replacement therapy. AKI was more prevalent in patients who were hospitalized (84.2% vs. 31.7%, p< 0.001), had concurrent pneumonia (63.3% vs. 36.8%, p< 0.002), required critical care (68.3% vs. 15.8% , p< 0.001), and were on ventilation support (16.8% vs. 0%, p=0.002). There was no significant statistical difference in rates of diabetes (52.6% vs. 36.7%, P of 0.076), tumor staging (metastasis; 95.1% vs. non metastatic 82.6%, p< 0.2) , readmission rate (52.6% vs. 43.3%, p=0.336), and death rate at 30 days (9.5% vs. 3.3%, p=0.205) between the two groups. Conclusions: The overall mortality rate of cancer patients with CKD and positive COVID-19 test was relatively high and close to 1.7 times the rate of patients with no CKD at our tertiary cancer center. AKI is a common complication in CKD patients with concurrent pneumonia and requiring ventilation support, and was associated with increased morality at 90 days.
Impact of cancer- and patient-level factors on provider risk in the Oncology Care Model.
Authors: Chaudhry Basit Iqbal , Yue Andrew , Kaila Shuchita , Sadik Kay , Tran Lisa , Connor Nora
Published: June 2021

e18852

Background: Transferring financial risk from payers to providers to align incentives is central to value-based payment (VBP) reform, including Medicare’s Oncology Care Model (OCM). We simulated the impact of selected cancer- and patient-level factors on providers’ risk in OCM for multiple myeloma (MM), due to its clinical complexity. We hypothesize that risk exposure is sensitive to factors extrinsic to the OCM methodology, including clinical phenotype, disease state and progression rate. Methods: Simulation was used to address omitted variable bias in payer data. We developed 9 key clinical MM scenarios to examine provider risk, based on conceptual frameworks that included patient- and cancer-level factors. The model was parameterized using the Medicare limited data set, research literature and domain knowledge. Twenty factors were varied for each model, e.g. age, autologous stem cell transplant (ASCT). Results: Simulations results showed MM risk for providers depended highly on cancer and patient level factors (see table). For example, high-risk patients were on average $21.5K over target while undergoing ASCT (despite risk adjustment for ASCT) and $18-28K under target for follow on maintenance (maint.) episodes. Conclusions: Provider exposure to risk in OCM is highly sensitive to factors at the cancer and patient level. The distribution of clinical phenotypes, state of disease, and rate of disease progression can significantly impact risk exposure for providers in OCM. New methodologies that model risk in more clinically granular ways are needed to improve VBP in oncology. [Table: see text]
Assessing the use of low value oncology care following the release of Choosing Wisely guidelines.
Authors: Gunn Alexander , Sarver Melissa , Kaplan Samantha J , Zafar Yousuf , Greenup Rachel Adams
Published: June 2021

e18861

Background: Low -value care contributes to the high costs of cancer treatment. Almost a decade has passed since the American Society of Clinical Oncology (ASCO) Choosing Wisely campaign identified costly diagnostic testing, radiographic imaging, and therapies that are routinely utilized in cancer care despite lacking evidence of benefit. We sought to evaluate the impact of ASCO Choosing Wisely guidelines and to identify barriers to and facilitators of guideline adherence. Methods: A systematic review of published literature from 2012-2021 was performed in accordance with PRISMA guidelines on the trend in use of low value oncology care. All ten of ASCO Choosing Wisely Guidelines were selected for inclusion; these included recommendations focused on cancer screening, staging and surveillance imaging, and systemic treatment and support. The following databases were searched for original research based in the United States: PubMed, CINAHL, Embase, Web of Science, Scopus, and ASCO Meeting abstracts. Eligible studies were examined for information on design, population, and study outcomes, which included guideline adherence and facilitators and barriers to implementation. All citations were independently dual-screened in a blinded fashion by authors (AG, MS). Results: 35 independent studies were identified from 3,590 unique citations and included n = 1,130,216 patients. Data sources captured large claims database analyses (13 studies, n = 1,069,289), institutional studies (14 studies, n = 53,358), patient-reported surveys (2 studies, n = 915), and interventional studies (6 studies, n = 6654). Adherence to ASCO Choosing Wisely guidelines ranged from 13% to 100% overall. Use of low value oncology care varied depending on the area of recommendation, such as cancer screening (44% to 77%), staging and surveillance imaging (30% to 100%), and systemic treatment and support (13% to 100%). Adherence was facilitated by: (a) physician awareness of and education around the recommendations; (b) patient engagement; (c) embedded EHR best practice alerts; (d) guideline alignment with insurance payer requirements; and (e) integrated healthcare systems. Barriers to guideline incorporation included perceived patient anxiety and concerns about patient satisfaction; illness-specific practices; and time needed for patient-provider conversations regarding low value care. Conclusions: Adherence to the ASCO Choosing Wisely guidelines is variable across the cancer care continuum. Health system and policy-level interventions are needed to further reduce the overuse of low value care in oncology.
A national study of allogeneic stem cell transplantation for adults with acute myeloid leukemia: Do gender and age above 70 years matter?
Authors: Emole Josephine , Shune Leyla , Lupak Oleksandra , Dias Ajoy Lawrence
Published: June 2021

e19020

Background: Allogeneic stem cell transplantation (alloSCT) is increasingly being offered to older patients with acute myeloid leukemia (AML) due to availability of reduced-intensity conditioning regimens and better supportive care. Though studies have shown improving alloSCT survival outcomes in older age groups, it is still not known if older age confers higher mortality and morbidity during transplant hospitalization. We queried a national inpatient database to evaluate in-hospital mortality and resource utilization during alloSCT for AML in patients >70 years compared to a younger age group. Methods: We conducted a retrospective study of alloSCT for AML patients ≥ 18 years using the 2018 National Inpatient Sample database. Hospitalizations were selected using International Classification of Disease, tenth revision (ICD-10) codes. Demographics, comorbidities, transplant, and outcome variables were compared between a reference age group (18-70 years) and a comparator group (> 70 years). Study outcomes were in-hospital mortality, length of stay (LOS) and transplant complications. Regression models were fit to assess the association between predictors and outcomes. Results: During the study period, 2610 alloSCT met the inclusion criteria. This cohort consisted of 50% males and 77% Caucasians. Only 7% of these alloSCT were performed for patients > 70 years. Patients >70 yrs had a lower proportion of females compared to the reference age group (32% versus 52%, p<0.01). There were no significant differences in racial distribution, Charlson comorbidity index or median income between the 2 age groups. In-hospital mortality rates for the reference age group versus >70 years were 3% and 5% respectively (p=0.35). In a multivariable model, we found no association between age >70 years and in-hospital transplant mortality. Acute graft versus host disease was more frequent among the reference age group (14% versus 2%, p=0.04), but there were no differences in LOS or rates of graft failure, respiratory failure, sepsis, and acute renal failure between the 2 groups. Conclusions: Despite similar in-hospital transplant outcomes as their younger counterparts, patients >70 years comprised only a small proportion of alloSCT performed for AML in our study. Females were more disproportionately affected by this age disparity. More studies are necessary to identify barriers to alloSCT for older AML patients, more so for older females.
Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma treated with R-CHOP.
Authors: Qin Yan , Chen Haizhu , Liu Peng , Zhang Changgong , Yang Jianliang , Gui Lin , He Xiaohui , Zhou Liqiang , Zhou Shengyu , Jiang Shiyu , Jiang Hongxin , Shi Yuankai
Published: June 2021

e19549

Background: Unlike BCL2 translocation ( BCL2TR), limited data about the prognostic significance of BCL2 mutations ( BCL2MUT) and BCL2 copy number variations in diffuse large B-cell lymphoma (DLBCL) is available, especially in the era of immunochemotherapy. Predicting outcomes at the time of diagnosis is of extreme importance. Methods: In this study, we performed probe capture-based high resolution sequencing on 191 Chinese patients with de novo DLBCL, attempting to comprehensively describe BCL2 genetic alterations and several other genes. We also examined correlation between genetic alterations and outcomes in 164 patients treated with R-CHOP. BCL2, MYC and BCL6 protein was determined by immunochemistry. Results: Of all the 191 patients, BCL2 gain/amplificatio n ( BCL2GA/AMP) and BCL2MUT occurred in 9.4% and 8.9% of patients, respectively, and only 4.2% of cases harbored BCL2TR. As a result, BCL2 alteration, comprised of the above three genetic alterations, was observed in 18.3% of patients. Compared to patients with the absence of BCL2 alteration, the 5-year progression-free survival (PFS) (13.7% vs 40.8%, P= 0.003) and overall survival (OS) (34.0% vs 70.9%, P= 0.036) were significantly inferior in cases that harbored BCL2 alteration. Importantly, patients who harbored BCL2GA/AMP also had remarkably inferior PFS (5-year PFS, 11.1% vs 38.3%, P< 0.001) and OS (5-year OS, 22.1% vs 69.6%, P= 0.009) compared to those without BCL2GA/AMP. By contrast, neither BCL2MUT nor BCL2TR were significantly prognostic for survival. Multivariate analysis showed that the presence of BCL2 alterations, especially BCL2GA/AMP, TP53 mutation and International Prognostic Index (IPI) were significantly associated with inferior PFS and OS. Novel prognostic models were constructed based on 3 risk factors, including BCL2 alteration (Model 1) or BCL2GA/AMP (Model 2), TP53 mutation and IPI, stratifying patients into three risk groups with different outcomes. According to Model 1, the 5-year PFS were 65.9%, 25.9%, and 12.9% ( P< 0.001), and 5-year OS were 89.4%, 65.0% and 16.4% ( P< 0.001), respectively, for the low-risk, intermediate-risk and high-risk groups. In Model 2, the 5-year PFS was 56.9% for the low-risk, 24.1% for the intermediate-risk and 14.3% for the high-risk group ( P< 0.001), and 5-year OS were 86.6%, 60.9% and 16.9% for the three risk groups ( P< 0.001), respectively. Conclusions: This study demonstrated that, in patients treated with R-CHOP, the presence of BCL2 alteration, especially BCL2GA/AMP, and TP53 mutation were significantly associated with inferior outcomes independent of IPI. The novel prognostic models we proposed could aid in individual risk prediction for DLBCL patients treated with R-CHOP. Further validation of this prognostic model is warranted.
Prognostic biomarkers for primary Sjögren's syndrome-associated non-Hodgkin's lymphoma.
Authors: Ma Kevin Sheng-Kai , Velarde Lopez Angel Alfonso
Published: June 2021

e19563

Background: Bidirectional relationship between non-Hodgkin’s lymphoma (NHL) and Sjögren’s syndrome (SS) has been recognized in large-scale cohort studies. We identified significant differentially expressed genes for SS-associated NHLs, and evaluated whether these genes could serve as a prognostic biomarker of diffuse large B-cell lymphoma (DLBCL). Methods: RNA-sequencing data from whole-transcriptome expression profiling were compared in a canonical pathway analysis using z-score and p-value visualization to identify significant differentially expressed genes and underlying cellular mechanisms for SS-associated NHLs including Burkitt lymphoma (BL), DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Collected biopsies included lymphoma biopsies for BL (n = 59), DLBCL (n = 88), FL (n = 65), MCL (n = 43), and MZL (n = 23), sorted B cells from healthy donors (n = 10), as well as parotid gland tissues for SS (n = 17). RNA-seq data with P values less than 0.05 or -log10(P) larger than 1.3 were considered significant, and positive z-scores indicated up-regulation while negative z-scores indicated down-regulation. After screening potential biomarkers through canonical pathway analysis, significant differentially expressed genes were subjected to survival analysis with genomic and clinical data of 420 DLBCL patients from The Cancer Genome Atlas (TCGA) using a log-rank test. Area under the ROC curve (AUC) was derived to validate the predictive ability of the survival model. Results: Among all genes involved in SS-associated NHLs, 16 genes were significantly differentially expressed in all types of NHLs. These genes included CXCL13, SEPP1, COL1A1, RGS13, IGFBP7, COL3A1, SPARCL1, GABBR1, SLC40A1, CXCL14, CXCL12, CXCL9, CCL19, VCAM1, C3, and CLU. The fold changes of the 16 genes for DLBCL were 465.67, 209.68, 436.94, 366.94, 189.59, 456.09, 195.37, 152.05, 90.29, 26.29, 215.18, 72.06, 51.09, 91.91, 74.70, and 20.88, respectively. Among all SS-associated pathways underlying NHL pathogenesis, the endocannabinoid system-driven cancer inhibition pathways were most significantly altered in SS-associated NHLs. The z-scores of the cancer inhibition pathway were -0.14 for BL (-log10(P) = 4.54), -1.298 for DLBCL (-log10(P) = 3.00), -0.33 for FL (-log10(P) = 4.67), -0.87 for MCL (-log10(P) = 3.77), and -2.61 for MZL (-log10(P) = 4.31). Survival analysis revealed that together the 16 genes may serve as a prognostic biomarker of DLBCL (hazard ratio = 3.57, 95% CI = 2.53–5.03), which was statistically significant (log rank test P < 0.0001) and reliable (AUC = 0.897). Conclusions: Significant differentially expressed genes underlying the pathogenesis for SS-associated NHLs may be used as a biomarker for predicting the survival rate of DLBCL. Further studies are warranted to elucidate the functional association between these differentially expressed genes.
Adult malignancy-associated hemophagocytic lymphohistiocytosis: Case series.
Authors: Leão Inês , Couto Maria Eduarda , Marinho Joana Catarina Lima , Oliveira Isabel , Martins Ângelo , Mariz Mário
Published: June 2021

e19579

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome, with a challenging diagnosis (pediatric HLH-2004 criteria) and treatment (HLH-1994 protocol). Recently, HScore has adapted these diagnostic criteria to the adult population. Malignancy-associated HLH (M-HLH) can occur as the first manifestation of an unknown malignancy or after / during the treatment of a known cancer. This study evaluates features and outcomes of M-HLH in adult patients. Methods: Retrospective cohort study of all patients diagnosed with M-HLH in a single institution during 2013-2020. HLH-2004 and HScore criteria were used for diagnosis. Patients’ demographics, clinical and laboratory features, treatment and mortality were reviewed. Results: Eleven patients were analyzed. Ten fulfilled 5 of the HLH-2004 diagnostic criteria and one other had a HScore > 190 (80% probability of M-HLH). Median age was 68 years (IQR 62-71), and 54.5% were females. The median time between hospital admission and M-HLH diagnosis was 9 days (IQR 7-16). The most common malignancy was diffuse large B-cell lymphoma (36.4%), followed by Hodgkin lymphoma (18.2%), multiple myeloma (18.2%), myelodysplastic syndrome, T-cell and follicular lymphoma (9.1% each). Malignancy and HLH diagnosis were simultaneous in 54.5% of the cases (4 newly diagnose, 2 disease-progression); the remaining 5 patients were in remission (median time from cancer diagnosis to HLH of 9.9 months (IQR 5.1–38.3)). One patient also had an autoimmune disorder. An infectious co-trigger was identified in 81.8% of patients (virus in 45.5%, fungous in 36.4%, bacteria in 27.3%). The triad of fever, splenomegaly and cytopenia was present in 36.4% of patients. All had increased sCD25 and ferritin, with a median concentration of 7612U/mL (IQR 2631–34161) and 13269µg/L (IQR 6381–17911), respectively. The ratio between sCD25 and ferritin was 1.09 (IQR 0.13–3.05). Morphological M-HLH was documented in 8 out of the 9 biopsied cases. The HLH-1994 protocol was prescribed in 54.5% of patients (including intrathecal methotrexate in 2 patients), steroids as monotherapy were used in 18.2% and malignancy-specific chemotherapy in 36.4%. All but one patient initiated broad spectrum antibiotics at hospital admission, with an antifungal in 45.5% and an antiviral (valganciclovir) in 27.3%. At the time of analysis 63.6% of patients had died (overall, 54.5% within 3 months since M-HLH diagnosis). Conclusions: Most symptoms of M-HLH are common and unspecific, demanding a clinical suspicion and an early evaluation of ferritin, sCD25, triglycerides and fibrinogen. Co-triggers are frequent and their treatment is advisable. The disease has an unfavorable prognosis in a short period of time. This rare case series increases awareness about M-HLH (urgent need of updated diagnostic criteria and more efficient adult-adapted treatment strategies).
Clinical presentation of multiple myeloma by race/ethnicity and Asian subgroup in an integrated healthcare system.
Authors: Khan Adnan Ahmed , Fatoki Raleigh Ayoolu , Carpenter Diane M. , Lo Joan C. , Baer David M.
Published: June 2021

e20012

Background: Several US studies have evaluated ethnic differences in patients with multiple myeloma (MM), but few have focused on populations other than non-Hispanic Whites and Blacks. We examined ethnic differences in a contemporary cohort of MM patients and their presenting laboratory findings in a large, insured, community-based population, including findings across Asian American subgroups. Methods: Using the Kaiser Permanente Northern California (KPNC) Cancer Registry, we identified all new cases of MM from 2010-2018 and obtained data on age, sex, race/ethnicity, Asian subgroup, and presenting hemoglobin, calcium, and estimated renal function (eGFR derived from serum creatinine) from health plan databases. Moderate to severe anemia was defined by hemoglobin <10 g/dL, hypercalcemia by calcium >11 mg/dL, and chronic kidney disease (CKD) by eGFR: stage 3 (eGFR 30-59) and stages 4-5 (eGFR <30). MM incidence was estimated using membership denominators. Results: There were 2224 new MM cases (mean age 68y, 60% male) in 2010-2018, with an annual MM incidence of 7.9-9.8/100,000. Table 1 compares presentation by race/ethnicity. Non-Whites (45%) were more likely to present at age <65 than non-Hispanic Whites (30%, p<0.01). Black (43%) and Asian (39%) adults were more likely to present with hemoglobin <10 g/dL than non-Hispanic Whites (27%, p<0.01); Black adults were more likely to present with hemoglobin <10 g/dL than Hispanic adults (31%, p=0.02). Among the primary Asian subgroups, proportions with hemoglobin <10 g/dL were 38% (East Asian), 43% (Filipino), and 45% (South Asian). Blacks were more likely to present with CKD stage 4-5 (19.5%) than other races/ethnicities (p=0.04); differences between White vs non-White or Asian vs non-Asian were not significant. In Asians, 12.7% (South Asian) and 19.0% (Filipino, East Asian) presented with CKD 4-5. Asians were least likely to present with hypercalcemia (6.7%, p=0.03), and this was similar for Asian subgroups. Conclusions: We observed ethnic differences in MM presentation in a large integrated healthcare system. Blacks were more likely to have CKD stage 4-5 and hemoglobin <10 g/dL than non-Hispanic Whites. Asians were more likely to have CKD stage 4-5 than non-Hispanic Whites but least likely to have hypercalcemia. This is one of the first studies to identify Asian subgroups and examine variation across East Asians, Filipinos, and South Asians. Analyses examining ethnic differences in survival among MM patients are in progress.[Table: see text]
Patient-reported efficacy and toxicity in CAR T-cell therapy for multiple myeloma via Internet-based platforms.
Authors: Sweeney Nathan W. , Franco Hernandez Eduardo , Cole Nolan , Goldsmith Scott Ryan , Crees Zachary , Ahlstrom Jenny
Published: June 2021

e20024

Background: Chimeric antigen receptor (CAR) T-cell therapies are in clinical development for multiple myeloma (MM). Patient-reported outcomes (PRO) can provide valuable insights into how patients perceive the relative risks and benefits of these new therapies. This study aimed to evaluate CAR T-cell therapy in relapsed/refractory MM (RRMM) patients. Methods: We utilized HealthTree Cure Hub for Multiple Myeloma to analyze patient-reported data from 17 patients who participated in CAR T-cell clinical trials. In this study, we examined total prior lines of therapy, time to next treatment (TNT), overall survival (OS), patient-reported toxicity and severity, and patient-reported outcomes (myeloma reduction or no myeloma reduction). The Kaplan-Meier model was used to calculate overall survival. The severity of toxicity was assessed using a 1 to 10 scale (1 = minimal and 10 = severe). Results: Our analysis of the 17 patients found a median of 10 lines of therapy prior to CAR T-cell treatment. Ten patients had no new treatments to report at the time of this study, 5 patients reported new treatment with a median TNT of 15.9 months, and for 2 patients we did not have data. The median OS was 24 months (95% CI 21-30 months). The probability that a patient remained alive at 2 years was 0.48 (95% CI: 0.195, 1). Four of the 17 patients died with a median of 22.5 months post-CAR T-cell therapy. Two of these patients died without reporting a change in treatment. There was a total of 36 different side effects reported by patients as a result of the therapy. Table lists the side effects experienced by 2 or more patients and the corresponding average severity. Finally, 76% of patients treated with CAR T-cell therapy reported a reduction in their myeloma, four of these patients had m-protein levels reported and saw an average decrease of 93%. Of the remaining patients, three (18%) reported little to no reduction in their myeloma, and one patient (6%) did not know their response at the time of this analysis. Conclusions: Our investigation of patient-reported results suggests an emerging and viable immunotherapy treatment option for RRMM, with encouraging outcomes and manageable side effects. Future directions include analysis of genetics and treatment options post CAR T-cell therapy. These data highlight the expedited benefit of using PROs via an online platform, like HealthTree Cure Hub, to assess new therapeutics in the research community.[Table: see text]
Diagnostic signatures for lung cancer by gut microbiome and urine metabolomics profiling.
Authors: Qiu Bo , Xi Yu , Li Ying , Xie XinQiang , Liu FangJie , Wu Lei , Liang TingTing , Li Longyan , Feng Ying , Guo JinYu , Wang DaQuan , Zeng Yu , Yang Lingshuang , Zhang Jumei , Wang Juan , Chen Moutong , Xue Liang , Ding Yu , Wu QingPing , Liu Hui
Published: June 2021

e20514

Background: To develop the diagnostic signatures for lung cancer (LC) by gut microbiome and urine metabolomics profiling with multi-omics approach. Methods: We surveyed 145 Fecal Samples and 120 Urine Samples in a cohort containing 109 LC patients and 50 healthy individuals. The total cohort had been separated into testing set and validation set. The testing set comprised 47 patients and 20 healthy individuals (8 first-degree relatives and 12 non-relatives), while the validation set had 48 patients and 30 healthy individuals (14 first-degree relatives and 16 non-relatives). The urine research set comprised 100 patients and 18 first-degree relatives as healthy individuals. Gut microbiota was analyzed through the 16S ribosomal RNA (rRNA) gene sequencing and shotgun metagenomics. Urine untargeted metabolomics was analyzed by liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Results: LC patients had a significant shift of intestinal microbiota composition and functional genes distribution compared with healthy individuals. Diagnostic model had been achieved by combining gut microbiome and urine metabolomics profiling, the area under curve (AUC) of the testing set was 0.9997. The model performed reasonably well in the validation set with the AUC of 0.9769. We also found a significant decrease of Prevotella in LA-NSCLC patients and it was negatively correlated with multiple functions in KEGG level 2 in healthy individuals. Conclusions: The current study employs a multi-omics approach, analyses the fecal microbiome and urine metabolites from LC patients and healthy individuals/relatives using a standardized pipeline, and identified disease-associated microbiome shifts across datasets using statistical analysis. We inferred a microbiome-metabolite catalog and its molecular pathway and functional link to host targets, which could be further utilized to aid lung cancer diagnosis and treatment decision.
Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in pulmonary nodules presenting as ground-glass opacity.
Authors: Peng Muyun , Yu Fenglei , Chen Xiaofeng , Bai Jing , Xia Xuefeng , Xing Guanlan
Published: June 2021

e20516

Background: GGO-associated pulmonary nodule has been known as radiological appearances of early stage and exhibit more indolent biological behavior. The correlation of different driver gene and radiological features remain poorly understood. Methods: We performed high-depth sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients with a custom 1021-gene panel. 130 were multiple pulmonary nodules from 58 patients (2-4 samples per patient). Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry and multiplex immunofluorescent staining were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Results: Mixed GGO enriched in the pathology of invasive LUAD comparing to pure GGO (182/216 vs 73/118, p < 0.001). 88.0% (294/334) of GGO-associated nodules carried at least one gene mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway and these driver genes were mutual exclusive to each other. T790M mutation was detected in one patient who had a nodule with CTR > 0.5 and was pathologically defined as MIA. 96.4% (54/56) multiple pulmonary nodules from the same patients showed distinct oncogenic alterations, but 72.4% (42/58) patients carried at least one mutant gene in RTK/RAS pathway across each pulmonary nodule. Nodules with ERBB2/ BRAF/ MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations, showing fewer mutations in radiology status of mGGO or pathology of invasive LUAD. KRAS-mutant subgroup possessed the highest expression of Ki-67 and PD-L1, more infiltration of CD4+ T cell and CD8+T cell. The second highest Ki67-expression was in EGFR-mutant subgroup, together with more CD8+T cell. For EGFR-mutant nodules, co-mutations with TP53 or RBM10 enriched in nodules with CTR > 0.5 and showing higher values of mean CT attenuation and TMB, which may relate to GGO evolution or invasiveness progression. Conclusions: This study elucidated a comprehensive genomic landscape of Chinese radiologically detected GGO-associated pulmonary nodules and highlighted different driver patterns of RTK/RAS pathway corresponding to radiologic features. Our findings provided valuable insight for further research on driver event of RTK/RAS pathway and cancer interception of GGO-associated pulmonary nodules.
Association between CNVs of BMI-related gene and survival status of LUAD and LUSC patients.
Authors: Luo Haifeng ,   UCSF
Published: June 2021

e20524

Background: In recent decades, many GWAS studies help to discover the gene related to BMI or obesity. FTO, BDNF, LEPR, MC4R, SH2B1, GNPDA2, INSIG2, KCTD15, LEP, MTCH2, NEGR1, NPC1, PCSK1, POMC, TMEM18 and UCP2 are 16 genes showing most significant association with BMI. Those genes impact BMI by either alternating sex hormone metabolism, influencing insulin and insulin-like growth factor, or mediating inflammatory and adipokines. Those pathways impact cancer cells also. Here we report the association between copy number variables (CNV) of those genes and outcome of lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). Methods: 522 individuals in LUAD dataset of TCGA and 504 individuals in LUSC dataset of TCGA are included in this study. CNVs of each gene are main predictors, the survival time is the main outcome in the study, and gender, tumor stage, smoking status are chosen to adjust model. Multivariable Cox models are generated for LUAD patients and LUSC patients respectively. To control false discovery rate (FDR), Benjamini-Hochberg procedure is employed. Results: For LUAD patients, tumor stages impact survival status significantly, but age, gender and smoking status don’t impact survival time significantly. At the same time, CNV of TMEM18 has hazard ratio of 0.0353 (95% CI: 0.0032, 0.3910), which means the gain of genetic materials on the position of TMEM18 gene will protect patients to die after diagnosis of LUAD, and the effect is extremely large. The p-value of 0.006 is less than 0.00625, which is derived with Benjamini-Hochberg procedure with false discovery rate of 0.1. For LUSC patients, only serious tumor stages, tumor stage III and tumor stage IV, impact survival status significantly, and old age will cause patients die earlier significantly. Neither gender nor smoking status don’t impact survival status significantly. When adjusting age, gender, smoking status, and tumor stage, gain of genetic materials on the position of NEGR1 gene does increase the risk of death significantly, and the hazard ratio of CNV of NEGR1 is 9.920 (95% CI: 1.237, 79.552). The p-value of 0.031 is large than 0.00625, which is derived with Benjamini-Hochberg procedure with fase discovery rate of 0.1. Conclusion: Copy number variable of TMEM18 gene impact outcome of LUAD patients significantly. The gain of TMEM18 genetic materials protects patients to die, meanwhile the loss of TMEM18 genetic materials cause patients to have shorter overall survival time. TMEM18 affect the central nervous system to imbalance energy metabolism in previous murine models, and here we found TMEM18 has significant impact on survival status of LUAD patients, so the transmembrane protein gene TMEM18 may be a key factor to outcome of LUAD.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: A single-arm phase I study.
Authors: Zhang Minna , Chen Xueqin , Jiang Hong , Wang Jiaoli , Ye Jian , Ma Shenglin , Xia Bing
Published: June 2021

e20583

Background: Current standard of care for SCLC relapsed within six months after first-line treatment was mainly chemotherapy alone, such as irinotecan or docetaxel, of which the clinical benefit is unsatisfactory. Anlotinib, a novel oral multi-target tyrosine kinase inhibitor primarily targeting VEGFR2/3, FGFR1-4, PDGFRα/β and c-Kit, significantly improved progression-free survival (PFS) and overall survival (OS) for SCLC in third-line setting and beyond treatment (ALTER1202 trial). Here, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anlotinib combined with irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible patients with cytologically or histologically confirmed SCLC, aged 18-75 years, ECOG PS 0-1, relapsed within six months after first-line platinum-based treatment, received anlotinib (12mg, QD, from day 1 to 14 of a 21-day cycle) combined with irinotecan (65mg/m2, day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m2, q3w, up to 4 cycles) until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: Between March 2020 and February 2021, 21 patients with a median age of 61.7 years, male (76.2%), ECOG PS 1 (81.0%), brain metastasis (42.9%), liver metastasis (38.1%), were enrolled in this trial. At data cut-off (February 8, 2021), 15 patients were evaluable, among which 5 patients reached partial response (PR) and 8 had stable disease (SD). The ORR was 33.3% (5/15) and the DCR was 86.7% (13/15), respectively. The median PFS was 4.0 months (95%Cl: 3.18-4.83). The most common grade 1-2 treatment-related adverse events (TRAEs) were weakness (64.7%), anorexia (41.2%), anemia (29.4%), hypertension (23.5%), leukopenia (17.6%), oral mucositis (17.6%). Grade 3 TRAEs mainly included leukopenia (11.8%), thrombocytopenia (11.8%) and anemia (5.9%). There were no grade 4 or higher toxicities. Conclusions: Anlotinib combined with irinotecan or docetaxel showed promising ORR, DCR and PFS in SCLC relapsed within six months after first-line platinum-based treatment and was well-tolerated. No unexpected toxicities were observed. Further exploration and longer follow-up are ongoing. Clinical trial information: NCT04757779.
Possible immunologic predictors of the PD-1/PD-L1 checkpoint inhibitors' efficiency in lung cancer patients.
Authors: Zlatnik Elena Yu. , Kit Oleg I. , Bondarenko Elena S. , Sagakyants Aleksandr B. , Teplyakova Maria A. , Vladimirova Liubov Yu , Storozhakova Anna E. , Novikova Inna A. , Abramova Natalia A. , Popova Irina L. , Ryadinskaya Ludmila A. , Agieva Aza A. , Alieva Faina V. , Novoselova Kristina A. , Tikhanovskaya Natalia M. , Kalabanova Elena A. , Kabanov Sergey N. , Tishina Anna V. , Lazutin Yuriy N.
Published: June 2021

e21035

Background: Immunotherapy with PD-1/PD-L1 check-point inhibitors (CPI) is a new trend in oncology. Their effect significantly depends on the patients` immune status. The aim of the study was to search the immunologic parameters of lung cancer (LC) patients receiving immunotherapy as factors that could predict their effect. Methods: 20 patients (12 male and 8 female) with LC had adenocarcinoma – 15 (75%), squamous cell carcinoma – 5 (25%). PD-1/PD-L1 CPI were used: 9 patients received atezolizumab (43%), 9 (43%) – pembrolizumab and 3 (14%) – nivolumab. The effect of therapy was evaluated according to imRECIST v.1.1. Factors of cell-mediated immunity were assessed by flow cytometry before treatment including immunotherapy. CD8+CD279+, CD4+CD279+, TLR2, TLR4, TLR3, TLR8 were studied. Results: Complete response was observed in 2 (9%) patients, partial response in 5 (24%), stabilization in 4 (19%) and progression in 8 (38%). In one patient the treatment was cancelled due to the development of immune-mediated complication (Guillain-Barre syndrome). The factors studied varied depending on different effect. In cases of LC stabilization/progression the initial amount of CD8+CD279+ cells were twice lower than in cases with complete/partial response. In the first group CD8+CD279+ cells` level before the treatment was 0,1-3,4%, while in the other group 4,1-9% (7,0±1,16%). In patients with stabilization/progression CD4+CD279+ cells` level before the immunotherapy was 0,1-3,3 and in patients with response to treatment 1,4-7,8% (3,4±0,8%) of total CD4+ lymphocytes. Besides, the LC patients with different effect of treatment had different initial amount of CD4+ Tem cells: stable response to CPI developed in patients with their higher levels (40,8±3,9%) vs 15,3±3,9% in cases of tumor progression (p < 0.05). Initial high expression of TLR2 and TLR4 as well as low expression of TLR3 and TLR8 on monocytes in patients with response to immunotherapy suggests the contribution of innate immunity to its effect. Conclusions: Complete or partial response should be expected in cases of initially high per cent of T lymphocytes (CD4+, CD8+) CD4+ Tem cells and TLR2+, TLR4+ as well as low amount of TLR3+ and TLR8+ monocytes. These factors should be studied in future as predictive factors for effectiveness of CPI.
An integrative scoring system for survival prediction following gefitinib therapy in non-small cell lung cancer: From a long-term real-world study.
Authors: Guan Shaoxing , Chen Xi , Chen Youhao , Huang Min , Zhang Li , Wang Xueding
Published: June 2021

e21041

Background: Gefitinib is first-line therapy for patients with EGFR-activating mutation in non-small cell lung cancer (NSCLC). Meanwhile, ̃30% patients were progression within 12 months even harboring EGFR-activating mutation. Furthermore, integrative scoring models for prediction of gefitinib outcomes are still lacking. Variations in genes of DNA repair and cell cycle pathway may have potential impacts on proliferation, migration and invasion of tumor cells. Therefore, we investigated a series of single nucleotide polymorphisms (SNP) in DNA repair and cell cycle genes based on an efficient algorithm machine learning algorithm for establishing an integrative scoring system for survival prediction following gefitinib therapy in NSCLC patients. Methods: A total of 282 patients with activating EGFR mutations were enrolled and divided into train cohort and test cohort, randomly. 125 SNPs in 47 candidate genes were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. Predictive features were selected by randomForestSRC, an efficient algorithm machine learning algorithm to analyze survival data, for PFS following gefitinib therapy. The top candidate variables were presented into COX regression models with hazard ratio as weight for each predictor (HR = 1-1.49 = 1; HR = 1.5-2.49 = 2; HR = 2.5-3.49 = 3), providing p < 0.1. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: The progression risk predictive model was established by random forest survival and validated by COX regression analysis, included XRCC1 rs3213263(CT vs CC, RR = 1.997, 95%CI = 1.314-3.036, p = 0.001), FOXO3 rs75544369(GA vs GG, RR = 1.942, 95%CI = 1.139-3.309, p = 0.012), FOXM1 rs2302257(CC vs GG, RR = 2.889, 95%CI = 1.477-5.691, p = 0.002) and ERCC1 rs10408989(TT vs GT, RR = 1.735, 95%CI = 1.152-2.613, p = 0.008; GG vs GT, RR = 3.788, 95%CI = 1.625-8.832, p = 0.002). The progression risk score ranged from 0-10. 49 patients (25.52%) and 20 patients (22.22%) were scored 0, 18(9.38%) and 10(11.11%) patients were scored more than 5 in train cohort and test cohort, respectively. According to the risk score of patients, we divided the patients into four groups, the median PFS were 26.23(95%CI:14.23-35.37), 16.80(95%CI:12.87-23.60), 11.13(95%CI:8.87-16.70) and 6.25 (95% CI:4.43-11.67) months for 0, 2, 3&4 and ≥5 group (p < 0.0001) in the train cohort. Meanwhile, the median PFS were 18.80(95%CI:11.80-64.53),13.60(95%CI:9.17-27.33), 13.47(95%CI:9.83-18.40), 13.47(95%CI:9.83-18.40) and 7.40(95%CI:3.33- NA) months for 0, 2, 3&4 and ≥5 group in validation cohort (p = 0.0017). Conclusions: The risk score system is a simple tool for risk stratification in patients undergoing gefitinib. Widespread application of the score system will require further independent validation.