Chemotherapy-treated Cancer Patients Research Articles

Evaluation of sleep quality among chemotherapy-treated cancer patients

Evaluation of sleep quality among chemotherapy-treated cancer patients

Complications of implanted port catheters and peripherally inserted central catheters in chemotherapy-treated cancer patients: A meta-analysis.

One of the most significant advancements in nursing technology for cancer patients has been the development of implantable port catheters and peripherally inserted central venous catheters. They create an essential, dependable route for subjects to receive chemotherapy, long-term infusions and nutritional care, and provide a site for regular blood draws. We performed a meta-analysis to evaluate the complications of implanted port catheters and peripherally inserted central catheters in chemotherapy-treated cancer patients. A systematic literature search up to April 2022 was performed and a total of 11,801 articles have been retrieved. Of these, 5017 concerned peripherally inserted central catheters and 6784 implanted port catheters to administer chemotherapy. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs) were calculated to assess the complications of implanted port catheters and peripherally inserted central catheters in chemotherapy-treated cancer patients using dichotomous and contentious methods with randomor fixed-effects models. Peripherally inserted central catheters had significantly higher incidence of occlusion complications (OR: 5.43, 95% CI: 3.46-8.52, p < 0.001), longer durations of local infection (OR: 2.94, 95% CI: 2.17-4.00, p < 0.001), higher incidence of catheter-related infection (OR: 2.13, 95% CI: 1.19-3.83, p = 0.01), higher rate of malposition (OR: 6.46, 95% CI: 2.93-14.27, p < 0.001), higher rates of catheter-related thrombosis (OR: 2.71, 95% CI: 1.90-3.87, p < 0.001), higher incidence of phlebitis complications (OR: 6.67, 95% CI: 2.94-15.11, p < 0.001), higher incidence of accidental removal (OR: 3.38, 95% CI: 1.97-5.81, p < 0.001), and a shorter catheter lifespan (MD: -233.16, 95% CI: -449.52--16.80, p = 0.03) in subjects undergoing chemotherapy compared to those in whom implanted port catheters were used. Implantable port catheter has advantages over peripherally inserted central catheter in decreasing cancer patients' complications. The outcomes provide evidence for practitioners to select which type of central venous catheters is better for cancer chemotherapy subject.

Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis.

Objective: Venous thromboembolism (VTE) is a life-threatening complication that may exacerbate cancer prognosis. Whilst some studies indicate an increased risk of VTE in cancer patients undergoing chemotherapy, the prevalence estimates on the pooled prevalence of VTE in cancer patients undergoing chemotherapy are not known. This study aims to calculate the pooled prevalence of VTE in chemotherapy-treated cancer patients. Methods: Studies on VTE occurrence in cancer patients undergoing chemotherapy were retrieved after database search. The terms used included "cancer", "chemotherapy", and "venous thromboembolism". A random-effects meta-analysis was conducted to obtain a pooled estimate of VTE prevalence in cancer patients undergoing chemotherapy. Results: A total of 102 eligible studies involving 30,671 patients (1773 with VTE, 28,898 without) were included in the meta-analysis. The pooled estimate of VTE prevalence was found to be 6%, ranging from 6% to 7% (ES 6%; 95% CI 6-7%; z = 18.53; p &lt; 0.001). Conclusions: The estimated pooled prevalence rate of VTEs was 6% in cancer patients undergoing CRT, which was higher than the overall crude prevalence rate (5.78%). Comprehensive cancer care should consider stratified VTE risk assessment based on cancer phenotype, given that certain phenotypes of cancer such as bladder, gastric and ovarian posing particularly high risks of VTE.

Abstract P4-07-28: Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients

Abstract RationaleNeoadjuvant chemotherapy (NAC) for the treatment of early and locally advanced breast cancer is shown to cause effective tumour shrinkage, allowing breast conserving surgery. However, rates of recurrence remain high following surgical excision of NAC-treated breast tumours. We investigated relapse-free survival (RFS) in NAC-treated breast cancer patients; the primary aim of this study was to estimate probability of early relapse (&amp;lt;5 years) and identify possible predictor variables. MethodsWe retrospectively reviewed NAC-treated breast cancer patients diagnosed between January 2013 and August 2018 at the Royal Cornwall Hospital, UK. Patients met inclusion criteria with &amp;gt;3 cycles of NAC, surgery and follow-up &amp;gt;1 year. Demographic, histopathological and surgical data were collected including age, TNM classification, tumour histology, breast cancer immunohistochemical marker receptor status (ER, PR, HER2), NAC dose, adjuvant radiotherapy, type of breast and nodal surgery, pathologic response to NAC, number of positive lymph nodes (LN) at surgical removal and lymph node ratio (LNR). Tumour histology was categorised by inflammatory versus non-inflammatory. TNM classification was used for tumour staging. TNM nodal classification was categorised as N0 or N1 according to axillary LN cytology. LN classification data was missing for patients with inconclusive LN status at diagnosis. LNR was calculated as the ratio of positive LN to total number of LN removed at surgery. NAC response was categorised as pathologic complete (pCR) or incomplete (no-pCR). Kaplan-Meier method was used to compare survival functions for categorical variables. The Cox proportional hazards model was used at univariate and multivariate analysis for predictor variables that satisfied the proportional hazards assumption, to calculate hazard ratios for RFS. p-values &amp;lt;0.05 were taken as statistically significant. Results165 of 190 women were eligible for analysis. Median (IQR) age at diagnosis was 51.7 years (45.5-60.3). 68 patients (41.2%) achieved pCR following NAC and 147 (89.1%) received adjuvant RT. 30 relapses (18.2%) were recorded during follow-up, of which 24 (80%) were distant metastases. The Kaplan-Meier survival function estimated a 25% (95% CI, 17-36) probability of relapse by year five post-surgery. At univariate Cox analysis, RFS was associated with fewer positive LN (p = 0.001), lower LNR (p &amp;lt; 0.001) and TNM node classification N0 at diagnosis (p &amp;lt; 0.001). Table 1 below shows the results of multivariate Cox proportional hazards regression. Small sample size might conceal statistical significance of some covariates. ConclusionsOver 1 in 4 NAC-treated breast cancer patients relapsed within 5 years of surgery, usually with distant metastases. At univariate analysis, relapse-free survival (RFS) was individually associated with decreased LNR, fewer positive LN and TNM node classification N0. LNR remained a significant predictor of RFS at multivariate analysis with risk of relapse for a LNR of 1, 9-fold higher than a LNR of 0. Age, tumour histology, HER2 receptor status, TNM tumour classification, NAC dose and response to NAC had no significant association with RFS in this sample size. Risk FactorSubjectsHazard Ratio (95% CI)p-valueAge1651.042 (0.998 - 1.088)0.064Tumour histology (inflammatory = 1, other = 0)1651.268 (0.302 - 5.331)0.746HER2 receptor status (HER2+ = 1, HER2- = 0)1651.217 (0.357 - 4.150)0.754TNM tumour classification (T3-4 = 1, T1-2 = 0)1650.852 (0.298 - 2.442)0.766TNM node classification (N1 = 1, N0 = 0)1021.684 (0.428 - 6.622)0.455NAC dose (full dose = 1, reduced dose = 0)1651.091 (0.393 - 3.028)0.866NAC response in breast (pCR = 1, no-pCR = 0)1650.696 (0.199 - 2.442)0.572Lymph node ratio1649.426 (2.061 - 43.099)0.004 Citation Format: Natalie Martin, Julia Pasztorova, Isabella Hibell, Duncan Wheatley. Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-28.

Efficacy of the mRNA-Based BNT162b2 COVID-19 Vaccine in Patients with Solid Malignancies Treated with Anti-Neoplastic Drugs.

Simple SummaryCancer patients undergoing active treatment may be more vulnerable to COVID-19 due to the effects of the malignant disease and the anti-cancer treatment. Assessing COVID-19 vaccine efficacy in protecting these patients from SARS-CoV-2 infection, is important due to the worldwide pandemic reaching an unprecedented third surge. Cancer patients on active neoplastic treatment had a reduced antibody response following immunization with the BNT162b2 vaccine, manifested as significantly more seronegative results and lower antibody levels compared with those of non-cancer individuals. The risk of a negative serological response was 7.35 times higher in patients on active anticancer treatment. This impaired serological response was mostly attributed to chemotherapy treatment. Cancer patients receiving non-chemotherapy treatments had a similar serologic response as those without cancer. Vaccinated cancer patients treated with chemotherapy might not be protected against SARS-CoV-2 infection and may need to continue exercising precautionary measures such as social distancing and facial masking.The BNT162b2 vaccine was shown to be highly effective in reducing the risk of COVID-19 infection in healthy individuals and patients with chronic disease. However, there are little data regarding its efficacy in patients treated for cancer. We analyzed the humoral response following vaccination with the second dose of BNT162b2 in 140 patients with solid malignancies who were receiving anti-cancer therapy at the time of vaccination and 215 participants who had not been diagnosed with cancer. Multivariate analysis was performed, followed by matching the two groups by age, gender and days from vaccination. The humoral response in the cancer patient group was significantly lower than in the non-cancer group: 20/140 seronegative (14.3%) vs. 3/215 (1.4%), p < 0.001; median IgG levels 2231 AU/mL (IQR 445-8023) vs. 4100 (IQR 2231-6774) p = 0.001 respectively. The odds ratio for negative serology results in cancer patients adjusted by age and gender was 7.35 compared to participants without cancer. This effect was observed only in chemotherapy treated patients: 17/73 seronegative (23.3%) vs. 3/215 (1.4%), p < 0.001; median IgG 1361 AU/mL vs. 4100, p < 0.001 but not in patients treated with non-chemotherapeutic drugs. Reduced immunogenicity to COVID-19 vaccine among chemotherapy-treated cancer patients, raises the need to continue exercising protective measures after vaccination in these patients.

Increased resting-state cerebellar-cortical connectivity in breast cancer survivors with cognitive complaints after chemotherapy

Cognitive complaints after chemotherapy are common in breast cancer patients, but the neural bases for these complaints remain unclear. This pilot study explored resting-state functional connectivity (FC) as a marker of subtle cognitive changes in breast cancer patients who experience cognitive complaints. Chemotherapy-treated (n = 20, at least 6 months off therapy) and untreated (n = 17, disease-control) female breast cancer patients with cognitive complaints and healthy controls (n = 20) were recruited. The FC of the right dorsolateral prefrontal cortex was calculated, and any correlations between this FC and neuropsychological assessments were determined. Chemotherapy-treated patients with cognitive complaints displayed increased FC between the right dorsolateral prefrontal cortex and both the contralateral cerebellar lobule VII and the cerebellar vermis XI, compared to the disease-control and healthy-control groups, despite unimpaired neuropsychological performance. The increased FC was negatively correlated with executive function and attention in breast cancer survivors with cognitive complaints. Our pilot study findings provide evidence that cerebellar-cortical FC changes may be a pathophysiological basis for chemotherapy-related cognitive complaints. In addition, the FC changes have the potential to reflect minor or compensated cognitive function impairment in breast cancer patients.

The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability.

Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

Barriers and facilitators to implementation of serial point-of-care hearing tests using a novel iPad-based audiometry in platinum chemotherapy-treated cancer patients (pts).

223 Background: Platinum-based chemotherapy agents cause significant hearing loss in 40-80% of treated cancer pts. Lack of follow-up serial testing has created gaps in knowledge regarding hearing loss onset, progression, and possible recovery between treatment cycles. This study aims to determine barriers and facilitators to implementation of a tablet-based point-of-care hearing test, as a serial screening tool to address these knowledge gaps. Methods: From Jul 2019 to Mar 2020, 53 pts receiving high dose platinum agents were recruited from three clinics (Thoracic, head and neck, and testicular cancer) at a comprehensive cancer centre, to undergo serial audiometry testing. Baseline hearing tests, mid cycles (3,6, and 9 weeks), and post treatment tests (3,6,9,12, 19 and 24 months) were completed during the pts’ clinic appointments. Clinical research coordinators (CRCs) collected feedback from physicians, nurses, and pts to identify barriers and facilitators of implementing serial point-of-care hearing tests in these clinics. An inductive and iterative approach was used to identify themes. Implementation was tailored and mapped to the CIHR Knowledge to Action Framework (KTA). Results: Barriers: Logistical barriers included: locating quiet and accessible rooms to administer the test; pts being distracted or interrupted while completing the test; presence of family members adding to noise levels; concerns over the serial testing during treatment; length of each test; and clinic staff burden. Facilitators: User-friendly self-administered tests; increasing healthcare staff education and pt management. Adapting to the local context: Logistical barriers were resolved by CRCs designating quiet spaces for the study to occur, and meeting pts upon arrival to utilize their wait time. A ‘hearing test in progress’ sign put on exam room doors prevented interruptions. CRCs utilized the test’s ‘assisted mode’ feature to keep pts attentive and/or accelerate the process. Low noise level was emphasized to obtain accurate test results. Pt engagement in their test results facilitated retention in the study. Test length may be shortened in the future by omitting low frequency testing. Conclusions: Participants and stakeholders expressed support for in-clinic hearing tests and identified personal and systemic barriers to implementation. These findings suggest that implementation should focus on addressing concerns related to accessible rooms, pt time investment and overall clinic flow.

End of an era of administering erythropoiesis stimulating agents among Veterans Administration cancer patients with chemotherapy-induced anemia.

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003–2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010–2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.

599 PPARg signaling modulation protects from hair follicle bulge stem cell damage and cyclophosphamide-induced hair follicle cytotoxicity

In oncology, permanent chemotherapy-induced alopecia (pCIA) remains an unfulfilled clinical need. Irreversible hair loss may result from permanent damage of hair follicle bulge epithelial stem cells (HFeSCs), some of which may undergo epithelial-mesenchymal transition (EMT). To prove our hypothesis, we treated ex vivo full-length HFs with 4HC, a cyclophosphamide metabolite 4HC, which routinely induces reversible CIA and sometimes pCIA. PPARγ signaling is known to have a protective role in eSCs biology. Therefore, we additionally tested whether NAC-GED-0507-Levo (NACGED), a PPARγ modulator, may protect HFs from 4HC-induced damage. Ex vivo, treatment with 4HC (3μM, 30μM) induced HF cytotoxicity and promoted dystrophic catagen development. Moreover, 4HC caused reduction of CK15+ bulge cells number, mainly by inducing apoptosis. Interestingly, 4HC also induced EMT in the bulge epithelium, as indicated by decreased E-cadherin expression, upregulation of fibronectin and appearance of vimentin+ intra-bulge cells. HFs pretreatment with 0.01-1mM NACGED before addition of 4HC provided relative protection from induction of cytotoxicity without preventing catagen development. Finally, NACGED treatment also antagonized CIA-induced intra-bulge EMT by counteracting both E-cadherin expression reduction and increased vimentin+ cells number. Our data suggest that pCIA irreversibility may indeed result from apoptosis and/or EMT-mediated destruction of CK15+bulge eSCs. Modulation of PPARγ signaling could provide an effective strategy for managing permanent hair loss in chemotherapy-treated cancer patients.

Pharmaceutical interventions to improve safety of chemotherapy-treated cancer patients: A cross-sectional study.

Cancer chemotherapy is a high-risk process. To improve patient safety, a systematic pharmaceutical analysis of chemotherapy prescriptions is performed in our institution. The aim of this study was to assess the impact of pharmaceutical interventions (PIs) on the safety of patient chemotherapy prescriptions. This prospective cross-sectional study was conducted in an 800-bed university hospital with oncology departments. All chemotherapy prescriptions were included and PIs were collected prospectively during one month. The clinical impact of PIs was scored by an expert panel of oncologists and pharmacists, using the Hatoum scale. Univariate and multivariate analysis were conducted to identify factors associated with a higher frequency of PIs. Of 1346 prescriptions included, 129 required a PI (9.6% (95% CI: 8.1-11.4)). Most PIs were scored as having at least a significant impact for patient safety (69.8% (95% CI: 60.4-76.9)). The frequency of PIs was significantly associated with tumour site (p = 0.04) and weekday of prescription (p = 0.005). Multivariate analysis identified factors independently associated with PI performance, including pancreas and biliary tract cancers (odds ratio = 2.8 (95% CI: 1.4-5.3)), ovary cancers (odds ratio = 2.4 (95% CI: 1.2-4.8)) and head and neck cancers (odds ratio = 2.4 (95% CI: 1.1-5.1)) and the day 1 of the protocol with a cytotoxic agent (odds ratio = 3.7 (95% CI: 1.1-11.1)). Oncology pharmacists have a critical role in the safety of chemotherapy prescriptions. The coordination between healthcare professionals and access to patient data seem essential to improve the PIs' relevance and their clinical impact on patient safety.

A longitudinal mixed methods study on changes in body weight, body composition, and lifestyle in breast cancer patients during chemotherapy and in a comparison group of women without cancer: study protocol

BackgroundMore than 60% of women diagnosed with early stage breast cancer receive (neo)adjuvant chemotherapy. Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect body weight and body composition. Changes in body weight and body composition may detrimentally affect their quality of life, and could potentially increase the risk of disease recurrence, cardiovascular disease and diabetes. To date, from existing single method (quantitative or qualitative) studies is not clear whether changes in body weight and body composition in breast cancer patients are treatment related because previous studies have not included a control group of women without breast cancer.MethodsWe therefore developed the COBRA-study (Change Of Body composition in BReast cancer: All-in Assessment-study) to assess changes in body weight, body composition and related lifestyle factors such as changes in physical activity, dietary intake and other behaviours. Important and unique features of the COBRA-study is that it used I) a “Mixed Methods Design”, in order to quantitatively assess changes in body weight, body composition and lifestyle factors and, to qualitatively assess how perceptions of women may have influenced these measured changes pre-, during and post-chemotherapy, and II) a control group of non-cancer women for comparison. Descriptive statistics on individual quantitative data were combined with results from a thematic analysis on the interviews- and focus group data to understand patients’ experiences before, during and after chemotherapy.DiscussionThe findings of our mixed methods study, on chemotherapy treated cancer patients and a comparison group, can enable healthcare researchers and professionals to develop tailored intervention schemes to help breast cancer patients prevent or handle the physical and mental changes they experience as a result of their chemotherapy. This will ultimately improve their quality of life and could potentially reduce their risk for other co-morbidity health issues such as cardiovascular disease and diabetes.

The evaluation of changes in peripheral neuropathy and quality-of-life using low-frequency electrostimulation in patients treated with chemotherapy for breast cancer: a study protocol

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a progressive, enduring, and sometimes irreversible neurotoxic symptom that occurs in 30–40% of chemotherapy-treated cancer patients. CIPN negatively affects both the patient’s abilities to perform daily activities and their health-related quality of life (HRQOL) after chemotherapy treatment. Although this neuropathy has been treated with duloxetine and/or gabapentin, limited therapeutic benefits have been reported, thereby necessitating the development of an integrated approach that combines pharmacological management and complementary methods such as acupuncture and electric nerve stimulation. Therefore, this study is designed to examine the effect of a portable, low-frequency electrostimulation (ES) device on CIPN symptoms and HRQOL of female patients diagnosed with CIPN immediately after chemotherapy for breast cancer.MethodsThis study is a single-center, randomized, placebo-controlled trial with two parallel groups and a 2-week follow-up. We will enroll 80 breast cancer patients who are newly diagnosed with CIPN after chemotherapy. Duloxetine or pregabalin will be prescribed to all participants from the initial assessment. Half of the patients will be assigned into the experimental group and the other half to the control group. The CarebandR (Piomed Inc., Seoul, Korea), a wearable wristband that generates low-frequency electrostimulation, will be administered only to the experimental group. Electrostimulation will be administered on the unilateral PC6 acupoint. A numerical rating scale will be used to assess the overall intensity of CIPN symptoms. The key secondary outcome variables include patient-reported CIPN symptom distress tested by a self-rated questionnaire, physician-rated symptom severity assessed by the Total Neuropathy Score, and HRQOL.DiscussionIt is expected that the combination of a low-frequency electrostimulation device and pharmacological intervention (duloxetine or pregabalin) will produce synergistic effects in breast cancer patients with CIPN after treatment. To our knowledge, this is the first study to investigate the beneficial effect of a new integrated approach for CIPN management after breast cancer treatment. The study findings can expand our knowledge and understanding of the occurrence of CIPN and the efficacy of integrated intervention efforts to ameliorate CIPN symptoms.Trial registrationClinical Research Information Service (CRIS), Republic of Korea, ID: KCT0002357. Registered retrospectively on 13 June 2017.

Increased Plasma Nitrite and von Willebrand Factor Indicates Early Diagnosis of Vascular Diseases in Chemotherapy Treated Cancer Patients.

Chemotherapy induced cardiotoxicity leads to development of hypertension, conduction abnormalities, and congestive heart failure. However, there is no simple test to detect and assess cardiovascular risk in a chemotherapy treated cancer patient. The aim of the present study on cancer patients treated with (n = 66) and without (n = 66) chemotherapy is to identify indicators from plasma for vascular injury. The levels of plasma nitrite, asymmetric dimethyl arginine (ADMA), von Willebrand factor (vWF), cardiac troponins, lipid peroxidation (MDA), and lactate dehydrogenase (LDH) were estimated. An R package, namely, Optimal Cutpoints, and a machine learning method-support vector machine (SVM) were applied for identifying the indicators for cardiovascular damage. We observed a significant increase in nitrite (p < 0.001) and vWF (p < 0.001) level in chemotherapy treated patients compared to untreated cancer patients and healthy controls. An increased MDA and LDH activity from plasma in chemotherapy treated cancer patients was found. The R package analysis and SVM model developed using three indicators, namely, nitrite, vWF, and MDA, can distinguish cancer patients before and after chemotherapy with an accuracy of 87.8% and AUC value of 0.915. Serum collected from chemotherapy treated patients attenuates angiogenesis in chick embryo angiogenesis (CEA) assay and inhibits migration of human endothelial cells. Our work suggests that measurement of nitrite along with traditional endothelial marker vWF could be used as a diagnostic strategy for identifying susceptible patients to develop cardiovascular dysfunctions. The results of the present study offer clues for early diagnosis of subclinical vascular toxicity with minimally invasive procedure. Schematic representation of chemotherapy induced elevated plasma nitrite level in cancer patients.

Machine learning for tackling microbiota data and infection complications in immunocompromised patients with cancer.

Machine learning for tackling microbiota data and infection complications in immunocompromised patients with cancer.

Abstract P2-01-01: Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study

Abstract Little is known about the dynamics of CTCs during treatment and its clinical significance. We examined the predictive utility of serial CTC analysis in ER+HER2- MBC patients (pts) treated with chemotherapy in the CALGB 40502/NCCTG N063H study, a randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-paclitaxel or ixabepilone +/- bevacizumab as first-line therapy (ClinicalTrials.gov Identifier: NCT00785291, Support: U10CA180821, U10CA180882). Methods: Of the 783 pts treated, 469 had ≥3 serial blood samples (including baseline) successfully analyzed for CTCs by CellSearch® and were included in this analysis (n=2,202). Samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC+. The prognostic and predictive performance of baseline CTCs (bCTC) and CTC status from baseline to cycle 2 (b2CTC) were compared to a novel latent mixture model classification based on trajectory of CTCs (tCTC). Akaike Information Criterion (AIC) was used to select the model (bCTC vs b2CTC vs tCTC) that best predicts overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). Results: 53% of the pts were CTC+ at baseline. b2CTC status changed in 36% of the pts, most of whom were CTC+CTC- (35%), and very few CTC-CTC+ (1%); the rest of the pts did not experience a change in b2CTC status (46% CTC-CTC- and 19% CTC+CTC+). Mixture model analysis revealed 4 groups of pts that show distinct tCTC patterns over the course of treatment: consitently very low/undectectable CTCs (tCTCneg, 56%), low (tCTClo, 24%), intermediate (tCTCmid, 15%), or high (tCTChi, 5%). bCTC, b2CTC, and tCTC were significantly correlated with tumor subtype (all p &amp;lt;0.0022) and presence of bone metastasis (all p &amp;lt;0.0001). Multivariate analysis showed that pts who were CTC+ at baseline, and those whose b2CTC status remained positive (CTC+CTC+) had significantly reduced OS, PFS and TTF. OSPFSTTFModelsHR (95% CI)p-valueHR (95% CI)p-valueHR (95% CI)p-valuebCTC (vs CTC-) → CTC+2.5(1.8-3.3)&amp;lt;0.00011.6(1.3-2.0)&amp;lt;0.00011.3(1.1-1.6)0.0046b2CTC (vs CTC+CTC-) → CTC-CTC+1.6(0.5-5.4)0.41491.6(0.6-4.5)0.39051.6(0.6-4.3)0.3961→ CTC+CTC+2.7(1.9-3.8)&amp;lt;0.00011.8(1.4-2.5)&amp;lt;0.00011.8(1.3-2.4)&amp;lt;0.0001→ CTC-CTC-0.5(0.4-0.8)0.00020.8(0.6-0.9)0.01600.9(0.7-1.1)0.2771tCTC (vs tCTCneg) → tCTClo2.6(1.9-3.7)&amp;lt;0.00011.9(1.4-2.4)&amp;lt;0.00010.9(0.7-1.1)0.0033→ tCTCmid5.3(3.6-8.0)&amp;lt;0.00012.5(1.8-3.4)&amp;lt;0.00011.8(1.4-2.5)0.0001→ tCTChi10.8(6.1-19)&amp;lt;0.00013.0(1.8-5.0)&amp;lt;0.00012.3(1.4-3.7)0.0009CTC- (&amp;lt;5 CTCs per 7.5 mLs); CTC+ (≥5 CTCs per 7.5 mLs) Pts with tCTClo, tCTCmid and tCTChi had significantly shorter OS, PFS and TTF compared to those with tCTCneg. After adjustment for potential confounders, AIC analysis revealed that the tCTC model best predicts OS and PFS, while b2CTC best predicts TTF. AIC Score*ModelsOSPFSTTFbCTC243240514199b2CTC240540384186tCTC237940264188*The lowest AIC score indicates the best model. Conclusions: Analysis of CTC trajectory patterns identified pts with poor outcome who could potentially benefit from more effective treatment. Validation in independent cohorts is warranted to confirm the findings in this study. Citation Format: Magbanua MJ, Hendrix L, Hyslop T, Barry WT, Winer EP, Hudis C, Toppmeyer D, Burnstein H, Qadir M, Ma C, Scott JH, Park JW, Rugo HS. Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-01.

1564P - Random optimization interactive system based on Kernel learning (RISK) for venous thromboembolism risk assessment in chemotherapy-treated cancer patients

Background: Using a combined approach of Kernel machine-learning (ML) and random optimization (RO) techniques we recently developed a set of predictors (ML-ROs) for VTE risk assessment. Aim of this study was to validate a model incorporating the two best ML-ROs to devise a web-based graphical interface for VTE risk stratification. Methods: Pre-chemotherapy age, sex, tumor site and stage, hematological attributes, fasting blood lipids, glycemic indexes, liver and kidney function, BMI, ECOG, supportive and anti-cancer drugs of 608 cancer outpatients were entered in the model, with numerical attributes analyzed as continuous values. Variables were clustered into groups according to clinical significance, and RO was used to devise their relative weight in final prediction. Results: VTE occurred in 7.1% of patients. Overall, 6% were at high-risk for VTE, as per current guidelines (Khorana Score (KS) ≥3), 11% of which had VTE during treatment. 42% and 52% were at intermediate (KS 1/2) or low-risk (KS = 0), with VTE rates of 9% and 5%, respectively. Accordingly, the performance of KS, despite a 94% specificity, was characterized by a 9% sensitivity with an area under the ROC curve (AUROC) of 0.589, translating into non-significant positive (+LR) [1.58 (0.48-4.30)] or negative likelihood ratio (-LR) [0.96 (0.83-1.04)]. Conversely, the VTE risk prediction performance of the combined ML model showed a 0.716 AUROC, which was significantly higher than that observed with KS (difference between areas: 0.127, p = 0.0044). At a criterion >1 (risk estimate achieved by both predictors) this combined approach showed significant +LR [2.30 (1.70-2.82)] and -LR [0.46 (0.28-0.69)] and a 4.9 Hazard Ratio (95%CI: 2.5-9.4) with a 6-month VTE rate of 3.4% in the low-risk, compared with 14.9% in the high-risk category. Conclusions: These results demonstrate that a ML approach, optimizing the relative weight (by RO) of groups of clinical attributes, is of clinical value for VTE risk prediction, performing better than KS. We are now finalizing the architecture of a web service with a graphical interface helping oncologists in the critical phase of decision making. Legal entity responsible for the study: RISK Research Group Funding: European Social Fund PON03PE_00146_1/10 BIBIOFAR Disclosure: All authors have declared no conflicts of interest.

Abstract 3319: Elevating adipokine adiponectin level can induce cytotoxic autophagy in breast cancer cells and potentiate the efficacy of chemotherapeutic regimens: preclinical studies

Abstract Adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that adiponectin induces a robust accumulation of autophagosomes, increases LC3II and decreases p62/SQSTM1 in breast cancer cells. Adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. Lysotracker-Red-staining and tandem-mCherry-GFP-LC3 assay show that autophagosomes/lysosomes fusion is augmented upon adiponectin treatment. Adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by autophagy, which is integral for adiponectin-mediated cell death. Accordingly, blunting autophagosomes-formation, blocking autophagosomes-autolysosome fusion or genetic-knockout of BECN1/Beclin1/ATG7 effectively impedes adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that adiponectin reduces intracellular ATP levels and increases AMPK phosphorylation leading to ATG1 activation. AMPK-inhibition abrogates adiponectin-induced ATG1-activation, LC3II-turnover and p62-degradation while AMPK-activation potentiates adiponectin’s effects. Further, adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase LKB1, which is a key node in anti-tumor function of adiponectin as LKB1-knockout abrogates adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. Adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of adiponectin receptor, adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that adiponectin induces autophagic cell death in breast cancer and provide in vitroa and in vivo evidence for the integral role of LKB1-AMPK-ATG1 axis in adiponectin-mediated cytotoxic-autophagy. Citation Format: Seung J Chung, Ganji Purnachandra Nagaraju, Arumugam Nagalingam, Nethaji Muniraj, Panjamurthy Kuppusamy, Alyssa Walker, Juhyung woo, Balázs Győrffy, Edward Gabrielson, Neeraj K. Saxena, Dipali Sharma. Elevating adipokine adiponectin level can induce cytotoxic autophagy in breast cancer cells and potentiate the efficacy of chemotherapeutic regimens: preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2017-3319

Model-based prediction of myelosuppression and recovery based on frequent neutrophil monitoring

PurposeTo investigate whether a more frequent monitoring of the absolute neutrophil counts (ANC) during myelosuppressive chemotherapy, together with model-based predictions, can improve therapy management, compared to the limited clinical monitoring typically applied today.MethodsDaily ANC in chemotherapy-treated cancer patients were simulated from a previously published population model describing docetaxel-induced myelosuppression. The simulated values were used to generate predictions of the individual ANC time-courses, given the myelosuppression model. The accuracy of the predicted ANC was evaluated under a range of conditions with reduced amount of ANC measurements.ResultsThe predictions were most accurate when more data were available for generating the predictions and when making short forecasts. The inaccuracy of ANC predictions was highest around nadir, although a high sensitivity (≥90%) was demonstrated to forecast Grade 4 neutropenia before it occurred. The time for a patient to recover to baseline could be well forecasted 6 days (±1 day) before the typical value occurred on day 17.ConclusionsDaily monitoring of the ANC, together with model-based predictions, could improve anticancer drug treatment by identifying patients at risk for severe neutropenia and predicting when the next cycle could be initiated.

Association of Interleukin-6 and Other Cytokines with Self-Reported Pain in Prostate Cancer Patients Receiving Chemotherapy.

Pain is a common and dose-limiting side effect of many potentially curative cancer chemotherapeutic agents. This chemotherapy-induced pain (CIP) affects the quality of life of cancer patients and survivors and hampers the optimal clinical management of chemotherapy in cancer patients. The underlying mechanisms remain largely unknown, but changes in levels of cytokines/chemokines may contribute to the pathophysiology of CIP. This retrospective study was aimed at examining whether plasma levels of various cytokines change in prostate cancer patients after chemotherapy treatment and whether such changes (if any) are associated with their pain intensity. Using a Luminex assay, plasma levels of 27 cytokines/chemokines were measured in 78 men: 30 patients with metastatic prostate cancer who received chemotherapy (Docetaxel, 75 mg/m2 intravenously), 29 untreated patients with nonmetastatic prostate cancer, and 19 healthy controls. Subjective pain was assessed in chemotherapy-treated cancer patients using the 11-point numeric rating scale (NRS) pain scores. Chemotherapy-treated patients with pain (NRS ≥ 3) exhibited significantly increased levels of the pro-inflammatory cytokines (IL-6, IL-8) and chemokines (Eotaxin, VEGF, and IP-10) compared with untreated cancer patients or with patients without pain (NRS = 0). Of the 27 cytokines examined, only IL-6 was positively correlated with pain intensity in the chemotherapy-treated patients with pain. These findings suggest that the cytokines, particularly IL-6, whose levels were elevated in the chemotherapy-treated patients may be involved in the pathophysiology of CIP, and that they might be potential new targets for pain control in cancer patients receiving chemotherapy.