Large Cohort Of Cancer Patients Research Articles

Pulmonary Embolism and the Impact of Concomitant Deep Vein Thrombosis on Outcomes Among Cancer Patients

Intro: Venous thromboembolism (VTE) is a common cause of death among cancer patients, second only to cancer progression. Identifying factors predicting worse outcomes among cancer patients with VTE would be useful clinically. For cancer patients with pulmonary emboli (PE), it remains unclear whether concomitant leg deep vein thrombosis (DVT) as a source for further embolization adversely impacts this risk. The aim of this project was to determine the impact of residual DVT on adverse outcomes among cancer patients suffering acute PE. Methods: Consecutive patients with confirmed acute PE (March 1, 2013 - June 30, 2021) underwent ultrasound (US) imaging and were divided into two groups depending on the presence or absence of leg DVT. PE severity was classified based on AHA criteria. Patients were followed prospectively for VTE recurrence, major and clinically relevant non-major bleeding (CRNMB) and all-cause mortality. Results: Over the study interval, 1,035 cancer patients with PE were enrolled (Table 1). Of these, 375 (36.2%) had leg DVT confirmed by US. Patients with leg DVT were older (64.2 vs 61.4 years, p = 0.01), heavier (90.2 vs 85.1 kg, p <0.001), with lower metastatic disease prevalence (49.1% vs 57.1%, p = 0.01) compared to those without leg DVT. Cancer type distribution also differed between groups. PE patients with DVT more often had prostate, genitourinary, and hematologic cancers while those without DVT more often had pancreatic and breast cancers. Patients with DVT more often had symptomatic PE (48.2% vs. 35.9%, p < 0.001), massive (2.9% vs 0.5%, p < 0.001), and submassive (22.0% vs 7.6%, p < 0.001). Patients with DVT more often received unfractionated heparin (39.5% vs 18.7%, p < 0.001) whereas those without DVT were more frequently treated with low molecular weight heparin (57.5% vs. 44.3%, p <0.001), and apixaban (16.4% vs. 11.7%, p < 0.05). Anticoagulant duration, VTE recurrence, major bleeding and CRNMB were similar between groups (Table 2). Conclusion: Among a large cohort of cancer patients with pulmonary emboli, significant clinical and cancer specific differences exist comparing those with and without leg DVT.While theoretically increasing the risk of recurrent embolization, the presence of residual DVT does not appear to adversely impact important outcomes among cancer patients adequately treated with anticoagulation.

Emergency department visits among patients receiving systemic cancer treatment in the ambulatory setting

BackgroundMost patients receive systemic cancer treatment in the ambulatory setting. However, during their treatment journey, patients experience complications that necessitate emergency department (ED) visits. Few studies evaluated the burden of such visits and their characteristics. This study aimed to evaluate the incidence and characteristics of ED visits among adult cancer patients receiving systemic cancer treatment in the ambulatory setting.MethodsA retrospective observational study was conducted at a comprehensive cancer center in Jordan. Utilizing the medical records database, we identified all patients treated in the chemotherapy infusion units, between January and December 2021. Patients who received only supportive therapy were excluded. The proportion of patients who required ED visits, their characteristics, types of cancer treatments received, and reasons for ED visits were recorded.ResultsOver the study period, 4985 patients received 38,803 treatment cycles in the infusion units. Among those, 2773 (55.6%) patients had 10,061 ED visits. Patients who presented to the ED had a mean age of 53.7 ± 13.8 (SD) years and 1763 (63.6%) were females. The most common types of malignancies were breast (39.5%) and gastrointestinal (20%). The most common cancer treatments associated with ED visits were platinum-based (24.8%), immune-mediated/targeted therapy (15.3%), and hormonal (12.3%). The most common admission diagnoses were neuromuscular/skeletal symptoms (34.8%) and gastrointestinal symptoms (20.2%).ConclusionsIn a large cohort of cancer patients receiving cancer treatment in the ambulatory setting, over half of them required at least one ED visit. Most visits were for neuromuscular/skeletal and gastrointestinal symptoms. Future studies should identify measures to reduce ED visits to enhance the patients’ quality of life and outcomes and optimize resources.

Spine MRI Identifies Clinically Relevant Findings in Patients With Cancer Presenting With Back Pain.

This is a retrospective, cross-sectional study. The primary aim was to identify the diagnostic yield of spine magnetic resonance imaging (MRI) in detecting malignant pathology in cancer patients with back pain. We also sought to evaluate the role of MRI extent ( i.e. regional vs. total) in identifying malignant pathology. No prior study has systematically investigated the yield of spine MRI in a large cohort of cancer patients. Spine MRI reports from 2017 to 2021 for back pain (acute and nonspecified chronicity) in cancer patients were reviewed to identify clinically relevant findings: malignant (1) epidural, (2) leptomeningeal, (3) intramedullary, (4) osseous disease, and (5) fracture. Logistic regression was used to evaluate the association between MRI extent and the presence of cancer-related findings. For patients with multiple MRIs, short-interval scans (≤4mo) were evaluated to assess the yield of repeat imaging. At least one cancer-related finding was identified on 52% of 5989 spine MRIs ordered for back pain and 57% of 1130 spine MRIs ordered specifically for acute back pain. The most common pathology was malignant osseous disease (2545; 43%). Across all five categories, most findings (77%-89%) were new/progressive. Odds of identifying a finding were significantly higher with total versus regional spine MRIs ( P <0.001). Although only 14 patients had a positive regional MRI followed shortly by a positive total spine MRI, most of these repeat total spine MRIs (78%) identified findings outside the scope of the initial regional scan. Twenty-one patients had both computed tomography and MRI within 30 days of each other; eight (38%) had compression fractures appreciated on MRI but not on computed tomography. Our findings suggest imaging the total spine in cancer patients with back pain given higher odds of identifying malignant pathology and instances of capturing otherwise not visualized disease. Further work is warranted to confirm these findings.

Total mutational load and clinical features as predictors of the metastatic status in lung adenocarcinoma and squamous cell carcinoma patients

BackgroundRecently, extensive cancer genomic studies have revealed mutational and clinical data of large cohorts of cancer patients. For example, the Pan-Lung Cancer 2016 dataset (part of The Cancer Genome Atlas project), summarises the mutational and clinical profiles of different subtypes of Lung Cancer (LC). Mutational and clinical signatures have been used independently for tumour typification and prediction of metastasis in LC patients. Is it then possible to achieve better typifications and predictions when combining both data streams?MethodsIn a cohort of 1144 Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LSCC) patients, we studied the number of missense mutations (hereafter, the Total Mutational Load TML) and distribution of clinical variables, for different classes of patients. Using the TML and different sets of clinical variables (tumour stage, age, sex, smoking status, and packs of cigarettes smoked per year), we built Random Forest classification models that calculate the likelihood of developing metastasis.ResultsWe found that LC patients different in age, smoking status, and tumour type had significantly different mean TMLs. Although TML was an informative feature, its effect was secondary to the "tumour stage" feature. However, its contribution to the classification is not redundant with the latter; models trained using both TML and tumour stage performed better than models trained using only one of these variables. We found that models trained in the entire dataset (i.e., without using dimensionality reduction techniques) and without resampling achieved the highest performance, with an F1 score of 0.64 (95%CrI [0.62, 0.66]).ConclusionsClinical variables and TML should be considered together when assessing the likelihood of LC patients progressing to metastatic states, as the information these encode is not redundant. Altogether, we provide new evidence of the need for comprehensive diagnostic tools for metastasis.

Patient-reported toxicity and quality of life following Sars-CoV-2 vaccination in adults and children with cancer.

LBA12068 Background: There is limited published data regarding safety and toxicity of Sars-CoV-2 vaccination in patients with cancer. This may contribute to vaccine hesitancy amongst some members of this vulnerable cohort (Nguyen 2022). Methods: SerOzNET (ACTRN12621001004853) is a large prospective cohort study of adults and children with cancer undergoing Sars-CoV-2 vaccination. Participants undertake surveys by text message link sent to their mobile phone, or on an iPad provided in clinic. A validated hesitancy survey is undertaken at enrolment (Oxford COVID-19 Vaccine Confidence and Complacency Scale), and prior to the 3rd vaccine dose. For children, a parental survey is also collected. Quality of life is assessed with serial EORTC QLQ-C30 (adults) or PedsQL (children, self- and parent- report) at baseline and serially throughout the study. Patient- reported vaccine toxicity is assessed by patient-reported CTCAE items for common vaccine related AEs and patient-reported impact of vaccination on cancer treatment (delays, hospitalisations). Medically ascertained vaccine toxicity is assessed by study investigators one month after the 3rd vaccination dose. Results: Five hundred and four participants have been enrolled (403 adults (80%) and 101 children (20%)). Hesitancy: At baseline, 351 adults (88%) and 56 children (55%) responded. The adult cohort was predominantly female (67.2%) with an average age of 53.8 years. Preliminary analysis showed similar levels of vaccination concerns between baseline (mean score = 18.4, SD = 5.1) and follow-up pre-3rd dose (mean score = 17.9, SD = 5.7) in adults. We will present results regarding whether self-reported COVID-19 vaccine toxicity after the first dose was related to change in hesitancy scores at follow-up, which may have implications for COVID-19 vaccine booster willingness. Patient toxicity surveys have been returned post dose 1 for 445/497 (91%), post dose 2 for 417/457 (91%) and post dose 3 for 280/334 (84%). Incidence of any AEs was high (77-100% depending on age and dose), however the incidence of severe AEs (patient reported) was low (0-10% depending on age and dose). Interruptions to cancer treatment after vaccination were uncommon (2-12%). Pain at the injection site was the most commonly reported AE for all ages and doses. Hospital admissions (any reason) were reported post dose 1 in 4/15 children aged 5-12, but were uncommon in older adolescents and adults. The most common systemic adverse effect was rigors in children 5-12, while adolescents and adults reported fatigue most frequently. Quality of life analysis is ongoing and will be presented at the meeting. Conclusions: It is feasible to collect detailed toxicity and quality of life data in a large cohort of cancer patients receiving COVID-19 vaccinations. Data to date are reassuring that severe adverse events and interruptions to cancer therapy are uncommon. Clinical trial information: ACTRN12621001004853.

16 Months Follow Up of Patients' Behavior and Mild COVID-19 Patterns in a Large Cohort of Cancer Patients During the Pandemic.

Background: Acute severe forms of COVID-19 infection are more likely in cancer patients and growing attention has been given to the persistent symptoms of the disease after severe COVID-19. However, mild illness is the dominant clinical presentation of COVID-19 infection. To investigate patients’ behavior and the short- and longer-term pattern of the disease in cancer patients with mild COVID infection, a longitudinal online survey was conducted for 16 months during the pandemic in a large cohort of cancer patients from a French COVID-19 hot spot. An online questionnaire was administered at three time points between the first wave of the pandemic in France and the fourth wave. The questionnaire was completed by 1415 to 2224 patients, which queried patients’ demographics, their behavior, and COVID infection patterns. Seventy percent of the patients were female, and 40% had a comorbid condition. More than one-third of the participants had breast cancer, and half were survivors. The rate of infection was 30% during wave 1 and 10% in wave 4; most patients had a mild COVID-19 infection. Twenty-five percent of infected patients during wave 4 did not seek medical advice. At wave 4, 87% of the patients received at least one dose of vaccine. Systematic compliance to shielding measures decreased over time. The short-term pattern of mild COVID changed between wave 1 and wave 4. Twenty-two percent of infected patients experienced persistent signs for more than 6 months with a negative impact on sleep, social behavior, and increased consumption of stress-relieving drugs. Our results showed a high prevalence of long-lasting symptoms in cancer patients with mild COVID-19 infection and inadequate behavior toward the disease and prevention measures among patients.

Veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe respiratory failure in adult cancer patients: a retrospective multicenter analysis

PurposeThe question of whether cancer patients with severe respiratory failure benefit from veno-venous extracorporeal membrane oxygenation (vv-ECMO) remains unanswered. We, therefore, analyzed clinical characteristics and outcomes of a large cohort of cancer patients treated with vv-ECMO with the aim to identify prognostic factors.Methods297 cancer patients from 19 German and Austrian hospitals who underwent vv-ECMO between 2009 and 2019 were retrospectively analyzed. A multivariable cox proportional hazards analysis for overall survival was performed. In addition, a propensity score-matched analysis and a latent class analysis were conducted.ResultsPatients had a median age of 56 (IQR 44–65) years and 214 (72%) were males. 159 (54%) had a solid tumor and 138 (47%) a hematologic malignancy. The 60-day overall survival rate was 26.8% (95% CI 22.1–32.4%). Low platelet count (HR 0.997, 95% CI 0.996–0.999; p = 0.0001 per 1000 platelets/µl), elevated lactate levels (HR 1.048, 95% CI 1.012–1.084; p = 0.0077), and disease status (progressive disease [HR 1.871, 95% CI 1.081–3.238; p = 0.0253], newly diagnosed [HR 1.571, 95% CI 1.044–2.364; p = 0.0304]) were independent adverse prognostic factors for overall survival. A propensity score-matched analysis with patients who did not receive ECMO treatment showed no significant survival advantage for treatment with ECMO.ConclusionThe overall survival of cancer patients who require vv-ECMO is poor. This study shows that the value of vv-ECMO in cancer patients with respiratory failure is still unclear and further research is needed. The risk factors identified in the present analysis may help to better select patients who may benefit from vv-ECMO.

Current Screening Methods for the Risk or Presence of Malnutrition in Cancer Patients.

Malnutrition is highly common among cancer patients and is associated with a poor quality of life, increased treatment toxicities and decreased survival. The screening of malnutrition should be performed in an early stage of cancer disease and should be rapid, not expensive and highly sensitive to identify the risk of developing malnutrition. Importantly, international clinical guidelines suggest to perform screening for malnutrition in all cancer patients and if the risk is present, they recommend to perform a full nutritional assessment. During the screening phase, different nutritional parameters are considered including the loss of appetite, low food intake, body weight loss and burden of the disease. These items are present in several screening tools, such as the Nutrition Risk Screening (NRS)-2002, the Malnutrition Universal Screening Tool (MUST) and the Mini Nutritional Assessment (MNA) which represent the most widely used tools to screen for an altered nutritional status in cancer patients. Recently, the Global Leadership Initiative on Malnutrition (GLIM) developed an assessment tool for the diagnosis of malnutrition taking into account the presence of i) involuntary body weight loss, ii) body mass index, iii) low muscle mass, iv) low food intake and disease burden/inflammation; in particular, body weight loss, decreased body mass index (BMI), and low muscle mass are considered as phenotypic criteria, whereas reduced food intake, disease burden and inflammation are defined as etiologic criteria. To perform the diagnosis of malnutrition, GLIM consensus considered the presence of at least one phenotypic and one etiologic criterion. The above-mentioned screening tools were validated in different clinical settings and suggesting the use of one tool vs another is challenging considering, among others, different factors including the type and stage of cancer and the setting (i.e., inpatient or outpatient care). Recent data obtained among large cohorts of cancer patients indicate that personalized nutritional therapy reduced mortality risk and ameliorated quality of life and functionality among cancer patients with high nutritional risk, supporting the urgent need for implementing screening and diagnosis of malnutrition in this context.

TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells.

ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.

SARS-CoV-2 Infection in Cancer Patients: A Population-Based Study.

AimIn a consecutive series of cancer patients tested for SARS-CoV-2 infection, this retrospective population-based study investigates the risks of viral infection and death.MethodsMalignancies were distinguished as incident or prevalent (active or inactive). Cancer management and vital status were retrieved from institutional regional databases. Comorbidities were recorded, based on Adjusted Clinical Groups (ACG). Six Resource Utilization Bands (RUBs) were also considered. Independent risk factors for SARS-CoV-2 infection and death were identified using multivariable logistic regression, considering sex, age, comorbidities and RUBs, cancer status (active versus prevalent), primary cancer site, and treatments (chemotherapy and/or radiotherapy).ResultsAmong 34,929 cancer patients, 1,090 (3.1%) tested positive for SARS-CoV-2 infection (CoV2+ve). The risk of infection was associated with age (OR per 1-year increase=1.012; 95%CI=1.007-1.017), prevalent-inactive disease, hematologic malignancies (OR=1.33; 95%CI=1.03-1.72) and RUB (OR per 1-level increase=1.14; 95%CI=1.05-1.24). Among CoV2+ve cancer patients, the risk of death was doubled for males, and increased with age (OR per 1-year increase=1.07; 95%CI=1.06-1.09) and comorbidities (renal [OR=3.18; 95%CI=1.58-6.49], hematological [OR=3.08; 95%CI=1.49-6.50], respiratory [OR=2.87; 95%CI=1.61-5.14], endocrine [OR=2.09; 95%CI=1.25-3.51]). Lung and blood malignancies raised the mortality risk (OR=3.55; 95%CI=1.56-8.33, and OR=1.81; 95%CI=1.01-3.25 respectively). Incident or prevalent-active disease and recent chemotherapy and radiotherapy (OR=4.34; 95%CI=1.85-10.50) increased the risk of death.ConclusionIn a large cohort of cancer patients, the risk of SARS-CoV-2 infection was higher for those with inactive disease than in incident or prevalent-active cases. Among CoV2+ve cancer patients, active malignancies and recent multimodal therapy both significantly raised the risk of death, which increased particularly for lung cancer.

VTE Recurrence and Safety of Anticoagulants Among Patients with Cancer Treated for Venous Thromboembolism

Introduction:Anticoagulation (AC) is effective for the treatment of venous thromboembolism (VTE) in cancer patients, but is associated with an increased risk of bleeding. Currently, LMWH monotherapy is the recommended treatment for cancer patients with VTE; however, emerging data from Medicare patients suggests that rivaroxaban had a significantly lower risk of VTE recurrence and similar risk of major bleeding compared to LMWH or warfarin. In this study, we compared the effectiveness and risk of major bleeding associated with these anticoagulants in a younger cohort of patients from a commercial claims database.Methods: Truven Health Analytics MarketScan databases were used to find patients aged ≥18 newly diagnosed with cancer who then had their first VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE); excluding upper VTE) between 1/1/2013 - 9/30/2016 and AC start ≤ 7 days. Patients were categorized into LMWH, warfarin, or rivaroxaban cohorts based on index AC. The warfarin cohort included patients who started LMWH and warfarin ≤ 7 days of their first VTE. Inverse probability of treatment weights based on propensity score were used to adjust for treatment differences in the comparison of LMWH vs. rivaroxaban, warfarin vs. rivaroxaban, and LMWH vs. warfarin. Patients were observed until the earliest of end of eligibility or data end. VTE recurrences were defined conservatively as hospitalizations with a primary diagnosis of VTE ≥7 days after the first VTE. Major bleeding events were identified using validated criteria (Cunningham et al., 2011) and evaluated while patients were on treatment. Kaplan-Meier rates at 6 and 12 months were used to compare VTE recurrence between cohorts. Time on treatment was approximately 30-50% of total eligibility time, so rates at 3 and 6 months were used to compare major bleeding between cohorts. Cox proportional hazard models were used to compare VTE recurrence and major bleeding risk between cohorts.Results: A total of 12,457 patients (LMWH: N=4,313; warfarin; N=4,774; rivaroxaban: N=3,370) were included. After weighting the cohorts, baseline demographic and clinical characteristics were well balanced. Mean patient age ranged from 61.3 to 63.6 years. Median observation time with LMWH was shorter than with rivaroxaban (6.8 vs. 8.3 months, p<0.001) and with warfarin (7.4 vs. 9.8 months, p<0.001). Time on treatment was significantly shorter as well (Figures 1A-1C). VTE recurrence rates were significantly lower with rivaroxaban than with LMWH users at 6 months (8.7% vs. 11.7%; p=0.003) and 12 months (11.9% vs.14.7%; p=0.006), respectively, with a hazard ratio (HR [95%CI]) of 0.83 (0.73-0.96; p=0.010; Figure 1A). Major bleeding rates for rivaroxaban and LMWH users were similar at 3 months (3.2% vs. 3.5%; p=0.592) and 6 months (4.4% vs. 4.9%; p=0.438), respectively [HR 0.91 (0.71-1.17; p=0.455]. VTE recurrence rates for rivaroxaban and warfarin users were similar at 6 months (8.2% vs 8.8%; p=0.530) and 12 months (11.3% vs 11.6%; p=0.675), respectively [HR 0.95 (0.83-1.09; p=0.456; Figure 1B)]. Major bleeding rates for rivaroxaban and warfarin users were also similar at 3 months (3.2% vs. 2.8%; p=0.199) and 6 months (4.2% vs. 3.8%; p=0.362), respectively [HR 1.08 (0.86-1.37; p=0.500)]. Recurrence rates were significantly lower for warfarin users than for LMWH users at 6 months (10.2% vs. 12.4%; p=0.006) and 12 months (13.3% vs. 15.3%; p=0.011), respectively, but the rate of recurrence over the entire follow up was not significantly different between the two cohorts [HR of 0.91 (0.81-1.02; p=0.103; Figure 1C)]. Major bleeding rates for warfarin and LMWH users were similar at 3 months (3.1% vs. 3.7%; p=0.114) and 6 months (4.3% vs. 5.1%; p=0.109), respectively [HR of 0.86 (0.68-1.08; p=0.187)].Conclusion: In this large cohort of cancer patients treated for VTE, time on treatment was shorter for patients treated with LMWH than oral agents. Rivaroxaban was associated with a significantly lower rate of VTE recurrence than LMWH and a similar rate of VTE recurrence to warfarin; major bleed rates were similar for all. While LMWH has been associated with greater reductions in recurrent VTE compared to warfarin in trials, poor persistence on LMWH in real world settings may explain its lack of comparative effectiveness in this analysis. [Display omitted] DisclosuresKhorana:Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Halozyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Milentijevic:Janssen Scientific Affairs, LLC: Employment, Equity Ownership. McCormick:Janssen Scientific Affairs, LLC: Research Funding. Laliberté:Janssen Scientific Affairs, LLC: Research Funding. Crivera:Janssen Scientific Affairs, LLC: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs, LLC: Research Funding. Lejeune:Janssen Scientific Affairs, LLC: Research Funding. Rozjabek:Janssen Scientific Affairs, LLC: Other: Fellowship supported by Janssen Scientific Affairs, LLC. Schein:Janssen Scientific Affairs, LLC: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Streiff:Roche: Research Funding; CSL Behring: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Portola: Research Funding.

Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

BackgroundThe aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies.MethodsWe conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens.ResultsPlasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall.ConclusionA dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

Frequency of longitudinal changes in TP53 mutation status from gene sequencing of serial tumor biopsies from a large cohort of cancer patients.

3124 Background: The p53 pathway is one of the most important in cancer biology, with mutation of the TP53 gene that encodes the p53 tumor suppressor protein observed in ≈50% of all cancers. We evaluated the frequency of changes in TP53 mutation status in a large cohort of serial tumor biopsies. Methods: From a database of &gt;200,000 next-generation gene sequencing results we identified 16,592 samples arising from repeat biopsies from 7840 patients (pts), average 2.12 per pt, 1007 pts with ≥3, max 11; over an interval up to 234 months (mos), average 11.0 mos. TP53 mutations with known or unknown significance in successive biopsies and changes in assignment from TP53-Wild-Type (WT) to Mutant (Mut), or Mut to WT, were evaluated vs. cancer type and time between biopsies. Results: Table: N (%) of samples vs. change in TP53 status from previous biopsy vs. mos from initial biopsy in all samples (7840 initial + 8752 successive, 46% TP53-Mut) and the three most represented cancers: non-small cell lung cancer (NSCLC, 1189 initial + 1268 successive, 60% Mut), breast (947 initial + 993 successive, 55% Mut), multiple myeloma (MM, 578 initial + 981 successive, 18% Mut). Conclusions: Changes in TP53 status were rare (&lt;10% of samples). Differences may occur in serial biopsy samples for pathophysiological reasons, e.g., a mutant clone becoming dominant and/or heterogeneity at different tumor biopsy sites, or analytical differences in biopsy tumor content or assay sensitivity between samples. In this analysis, WT-to-Mut changes were more frequent (5.9%) than Mut-to-WT changes (3.3%), suggesting a small selection pressure for TP53 alterations later in oncogenesis and indicating that these alterations are truncal. Mut-to-WT changes are not readily explained physiologically and may suggest these infrequent changes are mostly due to sampling or analytical variability, and genuine changes in TP53 mutation status are quite rare.[Table: see text]

Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes

Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels. In some tumor types, especially in gastrointestinal cancers, expression of ACE2 and TMPRSS2 is highly correlated. Furthermore, we found infiltration with T-cell and natural killer (NK) cell infiltration to be particularly pronounced in ACE2-high tumors. These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibly promote the frequently detrimental hyper-immune response in patients infected with this virus.

Improving tumor budding reporting in colorectal cancer: a Delphi consensus study

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.

Genomic and clinical characteristics of MET exon14 alterations in a large cohort of Chinese cancer patients revealed distinct features and a novel resistance mechanism for crizotinib

Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers. Patients with METex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients.Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients by next-generation sequencing (NGS), and the clinicopathologic and molecular characteristics were reviewed.Results: Compared to Western population (~3%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and lung cancer patients (1.1%, n=175). Seventy-eight distinct METex14 alterations, including several novel alteration types were detected. Concurrent MET copy gain and non-exon14 MET mutations were also found. EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern. Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01). Co-amplification of CDK4 and MDM2, CDK6 and EGFR were identified, which indicated cell cycle dysregulation and EGFR alteration are important co-occurring features in patients with METex 14 alteration. Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, which is comparable to other types of tumor. In 14 crizotinib-treated patients, the median progression free survival (mPFS) was 7 months. Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism.Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients. Patients with METex14 alterations showed distinct molecular characteristics and the representative case study showed responses to MET tyrosine kinase inhibitor (TKI).

Measurement of body mass by bioelectrical impedance analysis and computed tomography in cancer patients with malnutrition - a cross-sectional observational study.

Malnutrition and cachexia affects the majority of cancer patients and significantly worsens their quality of life and prognosis. However, the diagnostic criteria of malnutrition and cachexia remain a topic under constant debate. To overcome this hurdle, diagnostic tools to objectively detect and quantify the loss of muscle and fat mass are needed. Computed tomography (CT)-based measurement is currently considered the golden standard. Bioelectrical impedance analysis (BIA) is an economical, non-invasive tool but it is seen controversial in patients with cancer and malnutrition because of possible estimation errors.BIA and CT-based analysis of body mass compartments were performed 172 times in 118 cancer patients, within the nutrition program of our institution. Prevalence of malnutrition was determined according to the global leadership initiative on malnutrition criteria. Data obtained for muscle and fat mass from both BIA and CT were correlated using Pearson's ρ. All analyses were performed with an explorative significance level of 5%.45.7% of the cohort were classified as “malnourished.” No significant differences were observed between the 2 groups regarding demographic data. Median body mass index, Karnofsky performance status, and nutritional risk score were lower in the malnourished group. Values for muscle and fat mass by BIA and CT were significantly lower in malnourished patients. Correlation of the measured parameters were highly significant between CT-based and BIA measurement. In the overall cohort, correlation of measured muscle mass values by CT and BIA was significant with Pearson's ρ = 0.794 (P < .01). Looking at patients without malnutrition only, Pearson's ρ was 0.754 (P < .01). The correlation of measured fat mass values was equally significant, with Pearson's ρ of 0.748 (P < .01) in the overall cohort and 0.771 (P < .01) in patients with malnutrition.To our knowledge, this is the first study comparing BIA to CT-based body mass analysis in a large cohort of cancer patients with malnutrition. The results suggest that BIA is a valid diagnostic tool for the assessment of muscle and fat mass, even in patients with malnutrition, and could be implemented for the early detection and short-term follow-up of malnutrition and cachexia.

Outpatient Resource Utilization Of Medicare Cancer Patients With Malnutrition Diagnosis

Rationale: Malnutrition or its risk affects up to 85% of cancer patients either during or after their treatments. Such patients experience poorer health and economic outcomes resulting from prolonged hospitalizations and higher healthcare resource utilization. We assessed the prevalence of diagnosed malnutrition and outpatient resource utilization and associated costs among a large cohort of cancer patients with malnutrition as compared to counterparts without malnutrition diagnosis.

1708P Online survey on SARS-CoV-2 infections in cancer patients during a nationwide lockdown in France

The COVID 19 pandemic outbreak caused 143427 cases and more than 28000 deaths in France. To contain this highly contagious and potentially deadly disease, the French government decided an unprecedented nationwide lockdown. We investigated in a large cohort of cancer patients from Hauts-de-France, the third French region most stricken by COVID-19, the frequency of symptoms, how cancer navigated the health care system during these very difficult circumstances, and their feelings.

Abstract 1324: Genomic and clinical characteristics of MET exon14 alterations in 26,391 Chinese cancer patients

Abstract Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers, and suggested to cause enhanced MET activity and oncogenesis. Clinical evidences suggested that patients with METex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients. Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients, and the clinicopathologic and molecular characteristics of the cohort were reviewed. PD-L1 immunohistochemistry and the treatment response to MET inhibitors were also analyzed for cases with such information available. Results: Compared to Western cancer population (3~7%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and in Chinese lung cancer patients (1.1%, n=175). Seventy-eight distinct METex14 alterations were detected, with majority of alterations are base substitutions at splice donor site (42%) and insertion/deletions (indels) in intron 13 (28%). Concurrent MET copy gain and non-exon14 MET mutations were found in 4% and 11% of cases, respectively. Other driver alterations, such as EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern. In 71 patients sequenced by 425-gene panel, gene copy gains were prevalent in MDM2 (24%), CDK4 (14%), MCL1 (13%), TERT (13%), MYC (11%), CD274 (7%) and CDK6 (6%). Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01). Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, indicating the option for immunotherapy. In 14 patients who received crizotinib-treatment, the median progression free survival (mPFS) was 7 months with the longest PFS of 17 months. Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism to crizotinib treatment. Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients, and these patients can be potentially treated by immunotherapy and crizotinib. Citation Format: Sisi Liu, Danni Song, Xiaoling Tong, Xue Wu, Xiaonan Wang, Yang Washington Shao. Genomic and clinical characteristics of MET exon14 alterations in 26,391 Chinese cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1324.