bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a 1-day disease overview session on knowledge and preparedness for incoming hematology/oncology fellows.
Authors: Pywell Cameron , Gahagan Andrew , Paschal Rita Daniell
Published: July 2024

e21011

Background: The start of hematology/oncology fellowship involves an abrupt transition in disease management and a steep learning curve. Many fellowship programs have introductory lecture series over the first weeks or months, but fellows often need specialty knowledge prior to the completion of these. Methods: A 1-day session for incoming first year fellows at our institution was developed to provide brief overviews of common conditions in classical hematology, malignant hematology, and oncology, subdivided into a total of 12 topics. Fellows were surveyed before and after the session regarding their feelings of preparation for fellowship and having good disease frameworks for each of the 3 major content areas. Fellows also evaluated the content and length of each topic. Pre- and post-course knowledge assessments were conducted. Feedback was sought later in the year as well. Results: The session was well-received by fellows. Post-course assessments increased by a mean of 32% (SD 6%). The majority of topics were well-reviewed for length and content. Fellow responses to feelings of preparedness and disease frameworks were improved or unchanged from pre-course surveys. All fellows agreed that it was a good use of their time and would recommend it being a part of future orientation sessions. Fellows recommended splitting the session into 2 days. Conclusions: A 1-day introductory course for incoming hematology/oncology fellows is feasible and rapidly improves baseline knowledge to prepare fellows for clinics, consults, and being on call.
Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.
Authors: Lee Daniel , Yang Alexander , McNamara Madeline , Kluger Harriet M. , Tran Thuy , Olino Kelly , Clune James , Sznol Mario , Ishizuka Jeffrey Joseph
Published: July 2024

e21522

Background: Despite the drastic improvement in survival of patients with metastatic melanoma from immune checkpoint inhibitors (ICIs), almost half of patients still die from their disease. Factors surrounding death including mechanisms of death, sites of disease, and settings of death remain poorly described. A better understanding of these factors is paramount to optimize management for these patients. Methods: A retrospective observational cohort study was performed for patients age > 18 who died after treatment for advanced melanoma with anti-PD1 therapy or ipilimumab + nivolumab (Ipi/Nivo) at Yale Cancer Center (YCC) between 1/2009 and 6/2023. Primary outcome was cause of death. Statistical analyses were performed with Stata SE, version 15.0 (StataCorp, College Station, TX). This study was approved by the Yale Institutional Review Board (Protocol #2000034631). Results: Overall, 287 patients with melanoma who received ICIs were documented to be deceased; 183 met inclusion criteria. Median time from metastatic diagnosis to death was 16.1 mos (range 0.3 to 135.1 mos). Median age at death was 70 (range 22-101), 62.8% were male, and 90.2% were white. Most patients (52.5%) received Ipi/Nivo first line, and 79.8% of patients received both anti-PD1 and anti-CTLA4 treatment at some point. The median number of metastatic sites at death was 4 (range 0-13). The majority (90.1%) of patients with measurable disease had multi-system involvement of melanoma. Eleven patients had no evidence of disease at death and died due to non-melanoma causes. The most common sites of metastatic disease at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). In total, 80.3% (147/183) experienced hospitalization within 3 months prior to death or hospice enrollment. Most died in the hospital (31.7%) or while enrolled in hospice (31.2% inpatient vs. 29.4% home). Overall, 10.9% of patients had survival > 5 years after metastatic diagnosis; 76.2% of long-term survivors died due to melanoma. Of 174 patients with evaluable causes of death, 87.9% of deaths were due to melanoma (Table 1). Patients with pleural metastases were more likely to die of respiratory failure (p = 0.036, OR 2.41 95% CI 1.06-5.50). Conclusions: The majority of deaths were a consequence of metastatic melanoma, with the most common causes including FTT, respiratory failure, and infection. [Table: see text]
Correlation of previous local vaccination site “flares” during immunotherapy for metastatic melanoma with complete responses to therapy.
Authors: Loo Kimberly Leticia , Ma Barbara Ting-wen , Pavlick Anna C.
Published: July 2024

e21534

Background: mRNA vaccines have been shown to stimulate T-cells targeting patient-specific tumor neoantigens. When combined with immune checkpoint inhibitors (ICI) in a randomized Phase II trial, mRNA vaccines demonstrated improvement in recurrence free survival and distant metastasis free survival compared to ICI alone. We retrospectively examined patients (pts) with advanced melanoma treated more than 5 years ago on clinical trials with adjuvant NYESO1 or mRNA vaccine therapies (VT) then ICI upon recurrence and analyzed biomarkers correlating with treatment response. Methods: This retrospective study examined 22 pts with advanced melanoma treated between 2004-2017 with adjuvant vaccine therapies (VT). 10 of the 22 pts subsequently developed recurrent disease and were treated with ICI. We evaluated disease free interval following ICI, sex, age, BRAF status, HLA type, site of primary and metastatic disease, initial vaccine treatment, vaccine toxicities, stage and sites of melanoma recurrence, ICI treatment, response and toxicities, vaccine site flares or cutaneous immune related adverse events (irAEs) following ICI. Results: Of the 22 patients (11 male, 11 female) treated with adjuvant VT, median age at first vaccine was 53 years old. HLA type was known for 11 pts. Stage at initial VT was IIB to IIIC. 14 pts recurred following adjuvant VT. Median time from vaccine initiation to melanoma recurrence was 3.2 years (range 6.5 months to 11 years). 10 pts received ICI for recurrent melanoma, 3 pts received ipilimumab, 2 anti-PD1 monotherapy, 4 ipilimumab and nivolumab, and 1 nivolumab/relatlimab. Stage at first ICI was IIIB to IV M1d. 9 pts experienced cutaneous irAEs. 7 pts experienced local vaccine site flare reactions following ICI treatment. Additionally, 2 pts experienced vitiligo, 2 with dermatologic flares (bullous pemphigoid and psoriatic rash), 2 with generalized rash that resolved with steroid cream. 1 pt did not experience rash, vaccine site flare, nor irAE dermatologic flare. Of the pts who recurred, 2 pts had BRAF V600E mutations, and 1 of these pts experienced vaccine flare, the other did not. 1 pt with a BRAF Q16L mutation did not have vaccine flare. 6 out of 7 BRAF wild type pts who recurred and received ICI experienced a localized vaccine site flare. Median disease-free interval following ICI treatment was 1.5 years (range 3 months to 9 years). All 10 pts are disease-free and off ICI being closely monitored. Conclusions: Evidence of prior localized vaccination “flare” may be a biomarker for a complete immunologic response in pts with metastatic disease treated with immunotherapy. ICI targeting CTLA-4 and/or PD-1 both triggered this localized vaccination site response, suggesting that T cell memory and immunologic activation against melanoma antigens translate into clinical responses.
Responses to immune checkpoint inhibitor therapy in NF1 mutated cutaneous melanoma.
Authors: Kroll Matthew Robert , Snow Anthony N , Loeffler Bradley T. , Milhem Mohammed M. , Javed Asad
Published: July 2024

e21535

Background: NF1 mutations occur in 14% of cutaneous melanoma. Less than 20% of advanced melanoma patients on Immune Checkpoint Inhibitor (ICI) therapy achieve radiographic Complete Response (CR). We present data on radiographic responses to ICI therapy in advanced melanoma patients with tumors harboring NF1 (Neurofibromatosis 1) mutations. Methods: Patients with metastatic or unresectable NF1 mutated melanoma were included in the analysis. Mutation status was identified via NGS and mutation pathogenic status was determined using Genome Oncology Software. All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions. Results: 26 metastatic or unresectable melanoma patients met criteria for inclusion. Of these, eight (30.8%) had CNS metastasis. ICI therapy included Ipilimumab-Nivolumab, Pembrolizumab, Nivolumab, or Relatlimab-Nivolumab (24/26 in front-line setting). The 12- and 24-month estimated cumulative incidence of CR were 43.9% and 60.6%, respectively. Altogether, 16 patients achieved CR as their best overall response. Four patients that achieved CR subsequently progressed. Four patients progressed without achieving CR. Six patients achieved a partial response by last follow-up without achieving CR or disease progression. Of the 8 patients with CNS metastasis, five (62.5%) had intra-cranial radiographic responses to ICI therapy, including 1 (12.5%) complete response. Five (62.5%) had multifocal ( > 2 sites of intracranial metastasis) intracranial disease. Five (62.5%) of these patients with intracranial disease received radiation, 2/8 (25.0%) received radiation and surgical resection, and one (12.5%) received neither radiation nor surgery. Three (37.5%) patients with CNS metastasis experienced disease progression while on ICI therapy. Conclusions: NF1 mutated melanoma appears to have high rates of radiographic responses to ICI therapy. Prospective validation of this finding, particularly in patients with CNS metastasis, is warranted.
Options for enhancing specific antitumor immunity in patients with melanoma.
Authors: Sultanbaev Alexander Valerievich , Kolyadina Irina Vladimirovna , Sultanbaev Mikhail , Musin Shamil , Menshikov Konstantin , Sultanbaeva Nadezda , Kudlay Dmitry , Tuzankina Irina
Published: July 2024

e21547

Background: The special interest in oncology is the research of the immune status of patients. Quantification of T-cell receptor excision rings (TREC) and B-cell receptor κ deletion elements (KREC) allows to evaluate a humoral and a cellular immunity. In melanoma, the effectiveness of the use of drugs to control immune points depends on the formation of specific antitumor immunity. Quantitative indicators of excision recombination rings reflect the formation of a different repertoire of T-cell receptors, which are an integral component in the formation of specific immunity. The understanding of changes in TREC levels in patients with melanoma during therapy with various drugs can improve the selection of patients for immunotherapy. The purpose of this study is to assess the dynamics of changes in quantitative indicators of the T-cell receptor during adjuvant therapy for melanoma. Methods: The study included 82 patients with melanoma. Among patients with melanoma, the proportion of male patients was 36.5% (30/82), female - 63.5% (52/82). The median age in the group of patients with cancer was 63 years [Q1-Q3: 52.8-75]. Results: From the results obtained, it follows that in cancer patients, a decrease in the number of TREC in the blood indicates the presence of immunodeficiency. The data obtained indicate significant changes in TREC in melanoma. Targeted therapy (dabrafenib + trametinib) and interferon therapy are accompanied by a significantly significant increase in the level of TREC, which indicates an increase in the formation of specific antitumor immunity. Conclusions: The results obtained demonstrate a significant decrease in TREC content in patients with melanoma compared to healthy individuals. Determination of TREC levels during adjuvant therapy demonstrated the effectiveness of dabrafenib in combination with trametinib and interferon α-2β, which is reflected in a significant increase in the T-cell receptor repertoire. The presented data indicate the possibility of using the method for determining the TREC level to predict the risk of cancer progression and the effectiveness of prescribed therapy.
Analysis of neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma using the SWOG S1801 event-free survival definition.
Authors: De Barros E Silva Milton Jose , Tavares Monique Celeste , Lima Joao Paulo S. N. , Garcia Daniel , Molina Andre , Lobo Matheus , Pinto Clovis Antonio Lopes , De Paula Rafaela Brito , Rinck Jr Jose Augusto , Duprat Neto João Pedreira
Published: July 2024

e21563

Background: Perioperative pembrolizumab to advanced melanoma, as shown SWOG S1801 trial, was associated with a longer event-free survival (EFS) than those who received adjuvant pembrolizumab (EFS at 2y: 72% vs 49%, respectively). EFS, as defined in this trial, encompasses important factors related to neoadjuvant therapy in clinical practice. So far, there is no data of EFS rate for melanoma patients(pts.) treated with neoadjuvant nivolumab and ipilimumab, which is associated with more response rate but also more toxicity. Methods: We conducted a retrospective analysis of pts. with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1 mg/kg (N3+I1) for two cycles followed by surgery and adjuvant therapy at AC Camargo Cancer Center. We applied the SWOG S1801 EFS definition (which includes inability to receive surgery, to start adjuvant therapy, melanoma recurrence and death) to this cohort. Results: Between Jan 2019 and Jan 2024, 37 pts. with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), Stage AJCC 8th edition: IIIB = 23 (62%), IIIC = 12 (32%), IIID = 2(6%). G3/G4 immune-related adverse events (irAE): 11 patients (30%). Two out 37 pts. did not complete the programmed neoadjuvant cycles due to toxicity (1 = colitis, 1 = myositis). Three pts. (8%) were unable to receive surgery: irAE = 1, metastatic disease = 2. All pts. who underwent surgery (n = 35) achieved R0 resection and started adjuvant therapy within 84-days after the procedure. Major pathological response (MPR) = 23 pts(66%) and non-MPR = 12 pts.(34%). There were 4 melanoma relapses after starting adjuvant therapy (11%). The total number of events was 7 (19%). In a median follow-up of 16.1 months(range:13.9-25), the landmark analysis of EFS at 2 years was 73% (95%CI, 49 to 87). Relapse-free survival(RFS) for MPR at 2 years: 96%. Conclusions: Neoadjuvant N3+I1 seems to have similar EFS compared to SWOG S1801, but numerically more MPR rate and fewer events of progression, relapse and/or death. [Table: see text]
Real world experience of molecular landscape of uveal melanomas: Implications for personalized medicine strategies.
Authors: Crook Tim , Datta Vineet , Velicaria Eisa , Vijayan Poornima , Gosavi Rahul Ashok , Patil Darshana , Ajami Ramin
Published: July 2024

e21572

Background: In the realm of ocular oncology, Uveal Melanoma (UM) stands out as a rare and formidable malignancy, necessitating a deeper understanding of its molecular landscape to enhance treatment strategies. This abstract delves into the real-world experiences of unraveling the molecular intricacies of UM and explores the implications for personalized medicine strategies. Methods: In this study, we conducted a comprehensive genomic analysis of tissue samples from 7 UM cases to identify key genetic alterations and molecular features, elucidating the heterogeneity of this ocular malignancy. Results: Consistent with other studies, 57% (4/7) of our cohort harbored a driver mutation in either the GNAQ or GNA11 genes. GNAQ Q209 codon mutations (Q209L or Q209P), were the most frequent variants identified. GNAQ/GNA11 mutations are known to activate the MAPK/ERK signaling pathway, contributing to uncontrolled cell proliferation; its presence qualifies for entry into clinical trial testing DYP688 in metastatic UM. Concurrent mutations were identified in EIF1AX (n = 1), SF3B1 genes (n = 1) and BAP1 (n = 1), highlighting the molecular diversity. EIF1AX, SF3B1, and BAP1 inactivating mutations indicate varying risks for distant metastasis, categorized as low, medium, and high risk, respectively. Notably, homologous recombination repair (HRR) pathway gene mutations were identified in 28% (2/7) of cases. Additionally, SF3B1 mutations have been proposed to induce a BRCA-like phenotype, resulting in synthetic lethality to PARP inhibitors (PARPi). These findings provide opportunities to explore additional targeted therapy (off label) options with PARPi. In a case where gene expression profiling (GEP) was performed, an upregulation in PRAME gene expression (PRAME+) was observed. This finding potentially indicates an increased metastatic risk and a shorter time to metastasis, given that PRAME+ status has been established as an independent risk modifier for metastasis, regardless of the GEP-derived UM class (Class 1 or 2). TMB ranged from 2 to 21 muts/mb, with 5 out of 7 specimens showing low TMB ( < 10 mutations/Mb) and two sample with high TMB (15 and 21muts/mb). This case with TMB of 21 muts/mb showed Deficient Mismatch Repair (dMMR) status. All samples evaluated for PD-L1 expression (n = 4) in our cohort showed < 1% PD-L1 expression in tumor cells, including the dMMR tumor. Conclusions: These findings underscore the need for a comprehensive genomic approach in guiding therapeutic decisions, understanding prognostic implications and advancing personalized medicine strategies for UM patients. Our study provides an overview of the molecular landscape of UMs with delineation of key molecular features, thereby enhancing our understanding of UM biology and setting the stage for the development of targeted therapies tailored to the unique genomic profile of each patient.
Median Breslow thickness during, post and pre-COVID-19 lockdown and correlation with socioeconomic factors.
Authors: Marusca Georgiana , Dlugas Hunter , Kim Seongho , Ruterbusch Julie J. , Duque Diana , Neill Daniel , Mehregan Darius , Daveluy Steven , Kim Steve , Sukari Ammar , Flaherty Lawrence E. , Shao Yusra F.
Published: July 2024

e21574

Background: Access to routine cancer care during COVID-19 pandemic was greatly affected. The impact of this on melanoma care is unknown. Breslow thickness (BT) was seen to decrease and then increase during and post-COVID-19 lockdown in Italy. Here, we aim to study the impact of COVID-19 lockdown on melanoma care in the United States. Methods: Patients diagnosed with cutaneous melanoma (CM) pre (September 15th 2019-March 14th 2020), during (March 15th-June 14th 2020), and post-lockdown (June 15th-December 14th 2020) were retrospectively studied using Metropolitan Detroit Cancer Surveillance System (MDCSS) database. Patients without an identifiable primary lesion, or with ocular, mucosal, or acral melanoma were excluded. Demographic and clinical characteristics were reviewed. The primary endpoint was median BT during and post vs pre-lockdown. Fisher's exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, to compare groups. Interaction in subgroup analyses was assessed using likelihood ratio tests. Linear regression analyses were performed with Box-Cox transformed BT. Cox proportional hazards regression analyses were performed for overall survival. Covariates for multivariable analysis were selected using LASSO-based penalized regression models. Results: 802 patients were included (pre N = 347, during N = 87, post N = 368). Patients diagnosed with CM post-lockdown were younger (age < 50 years pre = 14%, during = 13%, post = 23%). More patients diagnosed pre-lockdown carried government-issued insurance (pre = 48%, during = 39%, post = 38%). No difference (diff) in median BT was seen between periods (median = 0.6mm for pre, during, and pos). Married status was associated with a lower BT vs unmarried (diff = -0.19, 95% CI -0.36 to -0.014, p = 0.034) and higher census tract poverty level was associated with a higher BT (5%-10% diff = 0.17, 95% CI 0.004 to 0.33, p = 0.045; 10%-100% diff = 0.27, 95% CI 0.093 to 0.45, p = 0.003) vs 0-5% poverty on univariable analysis. Male gender was associated with a lower BT on multivariable analysis (diff = -0.12, 95% CI -0.20 to -0.04, p = 0.005) and lower risk of death on univariable analysis (HR = 0.50, 95% CI 0.31 to 0.82, p = 0.006). Conclusions: We found no difference in median BT during and post- vs pre-lockdown. We also identified at-risk populations (female, unmarried, and living in greater poverty areas) who could benefit from proactive melanoma care. Time to surgery from initial diagnosis during and post vs pre-lockdown would be of interest to study further.
Can vitamin D deficiency be considered a risk factor be considered a risk factor in luminal breast cancer?
Authors: Fernández Madrigal Laura , Garcés María Yeray Rodríguez , Castaño López Miguel Angel , Bayo Calero Juan Lucas
Published: July 2024

e24122

Background: The relationship of vitamin D (VD) with cancer is controversial. Its antiproliferative function by inhibiting the cell cycle has been described, as well as its characteristics as an inhibitor of angiogenesis, inducer of apoptosis and its ability to reduce inflammation, invasion and metastasis. Deficiency of this vitamin is very prevalent, affecting 40% of the population under 65 years of age, and there are some studies that relate it to the increase in the incidence of breast cancer (BC), colon or prostate cancer. VD deficiency is defined as a serum level of 25-hydroxy VD < 20 ng/mL. We analyzed whether VD deficiency can be considered a risk factor for BC, given that it is the most frequent tumor in the world. Methods: A single-center, retrospective, descriptive and analytical study of female patients diagnosed with localized luminal BC (stage I-II and III) in the year 2023 and a control group of healthy women. Baseline VD levels were determined in both groups. Statistical analysis (IBM SPSS Statistics 22) of demographic and clinical characteristics and multivariate analysis using a logistic regression model for the study of VD deficiency, according to the variables age, menopausal status and previous chemotherapy. Results: We analyzed 231 patients (p) with luminal BC and a control group of 324 healthy women. In the BC group the median age was 62 years (range 34 - 88 years), 72% (168 p) in postmenopausal stage. 52% (121 p) had stage I, 37% (86 p) stage II, and 11% stage III. 59.7 % (138 p) had luminal A phenotype and 40.2 % luminal B phenotype. 27.7 % (64 p) had received chemotherapy. In the control group the median age was 65 years (range 45 - 78 years), 90% (287 women) in postmenopausal state. VD deficiency was present in 50.6 % of the BC group with a mean VD value of 21 ng / ml. In the control group the deficit was 33 % with a mean VD value of 24 ng / ml. Therefore, this deficit is significantly higher in breast cancer patients than in healthy patients, with OR of 2.08 with 95% CI (1.4 - 2.7). In the overall multivariate analysis postmenopausal women have 5.1 more risk of presenting VD deficit, with p = 0.04. The variable age did not reach statistical significance. Logistic regression was performed to determine the effects of age, menopausal status, and having received previous chemotherapy, on the probability of BC patients presenting a VD deficit, without reaching statistical significance. Conclusions: VD deficiency is more prevalent in women with BC than the normal population, which is consistent with previous studies. Further well-designed studies are needed to assess the effect of VD supplementation in the female population as prevention of BC.
External validation of a bleeding risk assessment model developed with natural language processing and machine learning (PREDICT-AI study) in patients with anticoagulated cancer with venous thromboembolism in the TESEO international prospective registry.
Authors: Muñoz Martín Andrés J. , Viñuela Benéitez María Carmen , Iglesias Pérez Claudia , Sánchez-Cánovas Manuel , Rubio Jaime , Martínez Maria Purificacion , Garcia de Herreros Marta , De Castro Eva Martinez , Fernández Isaura , García Escobar Ignacio , Porta Rut , Brozos Elena , Quintanar Maria Teresa , Garcia Adrian Silvia , Guirao Sánchez Sara , Covela Marta , Santiago Crespo José , Pelegrín Francisco , Carmona-Bayonas Alberto , Jimenez-Fonseca Paula ,   Cancer and Thrombosis Section, Spanish Society of Medical Oncology (SEOM)
Published: July 2024

e24123

Background: The risk factors for bleeding during anticoagulation in patients with cancer-associated thrombosis (CAT) remain largely unexplored. The recently developed PredictAI model ( Muñoz Martín AJ et al. JCO 40, e18744-e18744(2022) was aimed to predict major bleeding (MB) in anticoagulant-treated cancer patients within the first 6 months following venous thromboembolism (VTE) diagnosis. The goal was to validate the PredictAI model using an independent cohort of patients from the TESEO international, observational, prospective registry. Methods: The performance of the three predictive models developed in PredictAI were assessed in terms of accuracy, precision, recall, F1-score, and the receiver operating characteristic (ROC) area under the curve (AUC): PredictAI decision tree classifier ROC-AUC 0.66 (confidence interval 95% [CI 95%], 0.63-0.69; P < .0001), random forest classifier ROC-AUC 0.61 (CI 95%, 0.58-0.64; P < .0001), and logistic regression ROC-AUC 0.70 (CI 95%, 0.67-0.73; P < .0001). The outcome was MB within 6 months following VTE diagnosis, whereas the analyzed predictors for MB at baseline comprised those from PredictAI, namely patient’s age, presence of metastasis, hemoglobin levels, platelet count, leukocyte count, and serum creatinine levels. Results: The TESEO cohort used for the external validation comprised 2,179 patients (51.9% male, mean age = 64.72 ± 11.34 years) with active cancer and VTE under anticoagulant treatment. The median (Q1, Q3) follow-up duration across patients was 6 (2, 14) months. Considering the ROC-AUC values for the three tested models (table 1), the results confirm a statistically significant validation and best performance of the logistic regression (ROC-AUC = 0.59; 95% CI = 0.53, 0.65; P = .002) approach. Conclusions: Our results support the first external validation of a risk assessment model of bleeding specifically developed for CAT. This model may guide objective decisions regarding the extension and dosing of anticoagulant therapy in this population. Future steps should involve further validation of the present model in other patient cohorts and the generation of a clinical tool to facilitate its use in healthcare settings. [Table: see text]
Increase in blood pressure in patients with metastatic kidney cancer treated with combination checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.
Authors: Lin Rick Y. , Patel Neil Jigish , Chatzkel Jonathan Alexander , Benidir Tarik , O'Malley Padraic , Crispen Paul , Ramnaraign Brian Hemendra
Published: July 2024

e24128

Background: The combination therapy of an immune checkpoint inhibitor (ICI) with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) is considered a first line treatment option for patients with metastatic clear cell renal cell carcinoma (ccRCC). TKI-induced hypertension is a well-known potential side effect with VEGFR-TKIs however little is known about the real-world increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with and without underlying hypertension treated with this combination therapy. Methods: A retrospective study was performed that included patients with metastatic ccRCC who were treated at the University of Florida Health Cancer Center between June 2019 and September 2022 who received treatment with the combination of an ICI and VEGFR-TKI. The data collected included history of hypertension, patients use of anti-hypertensive therapy at baseline, SBP and DBP prior to initiation of therapy and at approximately one month after initiation of treatment. Results: We identified a total of 29 patients who met the inclusion criteria for our study. The median age was 68 years old (IQR 61-72) while 25 patients (86%) were male and 4 (14%) were females. There were 27 patients (93%) who were treated with axitinib with pembrolizumab, while 1 (3%) was treated with cabozantinib with nivolumab, and 1 (3%) was treated with lenvatinib with pembrolizumab. Out of the 29 patients, 11 (38%) did not have hypertension prior to therapy while 18 (62%) did have baseline hypertension and were receiving at least one anti-hypertensive treatment. In those patients without baseline hypertension, the median baseline SBP was 113 and the median SBP after one month of treatment was 144 (p = 0.01). Conversely, those patients with baseline hypertension, the median baseline SBP was 122 and median SBP after one month of treatment was 148 (p = 0.003). In those without hypertension at baseline, the mean SBP increase after one month was 27.3% while in those with baseline hypertension the mean increase in SBP of 17.0%. Conclusions: Our study demonstrates that in a real-world population of patients with metastatic ccRCC there is a statistically significant elevation of both SBP and DBP when treated with the combination of an ICI and VEGFR-TKI and that in those patients without baseline hypertension and not on anti-hypertensive therapy at baseline, there is a more pronounced increase in blood pressure. This data should reinforce the need to have close monitoring of SBP and DBP during therapy, regardless of whether the patient has underlying hypertension or not, and may help guide anti-hypertensive therapy during kidney cancer treatment.
Trilaciclib use for prevention of hematological adverse events in chemotherapy: A meta-analysis of real-world studies and clinical trials.
Authors: Batra Nitya , Khosla Atulya Aman , Shrestha Abhigan Babu , Jaiswal Vikash , Alnabulsi Zaid , Kiryakoza Morgan , Chisti Mohammad Muhsin
Published: July 2024

e24130

Background: Trilaciclib, a cyclin-dependent kinase (CDK)-4 and -6 inhibitor, is the only FDA-approved agent that preemptively protects hematopoietic stem cells from chemotherapy-induced myelosuppression (CIM) without compromising efficacy. It transiently arrests hematopoietic stem cells in the G1 phase, thus temporarily blocking progression through the cell cycle and protecting progenitor cells from cytotoxicity. It has been approved for use in extensive-stage small-cell lung cancer (SCLC). Limited real-world evidence of its efficacy exists owing to its recent approval. We sought to enhance our understanding and evaluate the preventive effect of trilaciclib through a combined meta-analysis of clinical trials and retrospective studies. Methods: A systematic literature search was performed on PubMed, Embase, Cochrane, and Scopus from inception until December 2023. Retrospective cohort studies and randomized-controlled trials with trilaciclib and non-trilaciclib arms were included. The primary outcomes of interest were CIM-related grade ≥3 hematological adverse events, and secondary outcomes included supportive care interventions to remedy CIM. Quantitative meta-analyses were conducted using the random-effects model on STATA v17. Results: The meta-analysis comprised seven studies, including four clinical trials and three real-world retrospective studies, including 6537 patients with extensive SCLC or locally recurrent or metastatic breast cancer. Chemotherapy regimens in SCLC patients included the combination of etoposide/platinum (E/P), E/P/PD-L1 inhibitors, or topotecan, and gemcitabine/carboplatin in patients with breast cancer. The mean age of the patients was 63.28 ± 5.31 years, and 49.21% were males. Administration of trilaciclib led to a reduction in the incidence of febrile neutropenia (2.41% vs. 7.56% OR = 0.35), severe neutropenia (21.76% vs. 41.91% OR = 0.57), anemia (18.02% vs. 32.41% OR = 0.51), and thrombocytopenia (20.06% vs. 31.25% OR = 0.62). Utilization of cytopenia-supportive therapies, including granulocyte colony-stimulating factor use (40.47% vs. 81.01% OR = 0.61) and RBC transfusions (16.66% vs. 18.25% OR = 0.59) were significantly lower in the trilaciclib cohort as compared to control. The overall response rate (mean difference = 1.09,95% CI = 0.74–1.60) and overall survival (OR = -0.02 95% CI = -0.95-0.92) were similar, and progression-free survival was noted to be longer in the trilaciclib group (mean difference = 1.75, 95% CI = 0.75-2.75). Conclusions: Trilaciclib use consistently demonstrated efficacy in reducing CIM, thus lowering cytopenia-related healthcare utilization without compromising treatment efficacy in trials and real-world settings. Its novel mechanism of action offers great promise, and further studies with larger sample sizes on various cancers will corroborate existing evidence.
A phase II randomized double-blind placebo-controlled study of fisetin to improve physical function in frail older breast cancer survivors (TROFFi).
Authors: Ji Jingran , Bae Marie , Wong Florence Lennie , Crespi Catherine M , Yee Lisa D , Sedrak Mina S.
Published: July 2024

TPS1645

Background: Among postmenopausal breast cancer survivors treated with chemotherapy, one-third experience a persistent decline in physical function even 12 months after completing treatment. This decline has been associated with loss of independence, disability, and death. One mechanism that is thought to drive chemotherapy-related decline in physical function is cellular senescence, a state of terminal growth arrest. Chemotherapy increases the burden of senescent cells (Sncs), which develop a senescence-associated secretory phenotype (SASP) that over time leads to functional decline. Preclinical mouse studies have demonstrated that eliminating chemotherapy-induced Sncs in mice led to reductions in SASP and improved physical activity. In patients with stage I-III breast cancer treated with chemotherapy, expression of p16INK4a (p16), a known Snc marker, rapidly increased after chemotherapy and persisted over time. Higher levels of pretreatment p16 have also been associated with increased frailty in older breast cancer survivors. Novel senolytic agents have been developed to eliminate Sncs. Among existing senolytics, fisetin is a natural dietary supplement with a favorable safety profile and preclinical efficacy to reduce Snc burden and alleviate frailty in mice. There are multiple ongoing studies of this plant flavonoid in humans, but few are studying the effects of fisetin on chemotherapy-related functional decline in breast cancer survivors. Therefore, we hypothesize that targeting Sncs with fisetin after chemotherapy will improve physical function in frail older breast cancer survivors by reducing systemic Snc burden. Methods: This phase II randomized, placebo-controlled study will enroll 88 postmenopausal women with stage I-III breast cancer who experience physical functional decline after completing neo/adjuvant chemotherapy. Key eligibility criteria include being postmenopausal and within 12 months of completing neo/adjuvant chemotherapy at the time of enrollment. All participants must have evidence of physical functional decline, as measured by a 6-minute walk distance (6MWD) <400 meters, prior to enrollment. Participants will be randomized 1:1 to either placebo or oral fisetin (20mg/kg) on days 1-3 of 14-day cycles for a total of 4 cycles. The primary objective is to determine the effect of fisetin on physical function, as assessed by the change in 6MWD from baseline to end of treatment. Secondary objectives include studying the effect of fisetin on quality of life and additional measures of function including fatigue, cognition, and neuropathy. We will also determine the effect of fisetin on biomarkers of aging, including circulating markers of senescence, as well as the safety of and adherence to fisetin. Enrolment on this study began March 2023 and is currently ongoing. Clinical trial information: NCT05595499 .
Linking in with advice and supports for men impacted by metastatic cancer: The LIAM Mc trial (NCT05946993).
Authors: Gleeson Jack , Cahill Anita , Johnston Katie E , Corkery Stephanie , Medved Katarina , Cusack Anne Marie , Raigal Laia Aran , Hegarty Josephine , Connolly Roisin M. , Saab Mohamad M. , Bambury Richard Martin , Noonan Brendan
Published: July 2024

TPS1646

Background: Multidisciplinary supportive care interventions are key to preventing and managing adverse effects of cancer and its treatment for patients, reducing symptom and psychological burdens and enhancing quality of life (QoL). However, the optimal composition of these interventions for men with genitourinary (GU) cancers is poorly understood. The LIAM Mc Trial is an enhanced supportive care programme, funded by the Irish Cancer Society and designed with the input of patient representatives who highlighted the unmet needs of cancer survivors. An important aspect of the trial is to demonstrate how to improve the survivorship supports and services for underserved communities of men who experience disparities in cancer incidence, prognosis, outcome and QoL, and have not traditionally been the focus of such initiatives. Methods: Using an embedded mixed-method process evaluation this prospective trial aims to assess the feasibility and impact of a holistic 12-week survivorship programme amongst men with advanced GU cancers at an Irish Cancer Centre. The programme involves twice-weekly sessions with input from a dedicated physiotherapist, dietitian, and nurse specialist, along with education sessions from medical social worker and psycho-oncology specialists, and programme oversight provided by medical oncologists. Outcomes are measured at three timepoints; pre-intervention, immediately post-intervention and at 6 months post intervention, and will include EORTC QoL; muscle strength; body composition through bioelectrical impedance analysis and ultrasound; diet quality; cancer related symptom control; cancer related fatigue scores; feasibility outcomes, qualitative interviews and a process evaluation. Any man with a locally advanced or metastatic GU cancer who has recently completed a course of treatment or is stable on active anti-cancer treatment is eligible for the programme. Over the two-year study period the sample size target is 72 participants. The primary endpoint of the study is to evaluate the feasibility of introducing an enhanced supportive care programme as part of routine management for male cancer patients with metastatic disease. Acceptability, satisfaction with the programme and QoL changes are key secondary endpoints. Barriers to participation are also a key outcome under investigation. The study was activated in May 2023 with the first participants enrolled in June 2023. To date 17 men have enrolled with accrual completion anticipated in June 2025. Clinical trial information: NCT05946993 .
A phase I/II open label study to assess safety and preliminary evidence of a therapeutic effect of azeliragon in patients refractory to first-line treatment of metastatic pancreatic cancer.
Authors: Hendifar Andrew Eugene , Marcus Stephen Garrett , Brenner Warren S. , Uemura Marc Isamu , Chung Ki Y. , Richards Donald A. , Bahary Nathan
Published: July 2024

TPS4212

Background: Azeliragon is an orally administered small molecule, administered once daily, that inhibits RAGE interactions with its natural ligands, including HMGB1 and S100 proteins. Azeliragon was previously under development for Alzheimer’s disease and failed to show efficacy in phase 3 trials. Clinical safety data from these trials, with over 1500 individuals dosed for periods up to 18 months, indicated that azeliragon has a high level of safety and tolerability, virtually indistinguishable from placebo. RAGE, the receptor for advanced glycation end products, is highly expressed in pancreatic ductal adenocarcinoma (PDAC). RAGE interaction with its ligands, including S100 proteins and HMGB1 released from PDAC cells, promotes PDAC invasion, metastasis, and resistance to 5 FU and Gemcitabine. PDAC-secreted S100 proteins can also stimulate fibroblasts surrounding PDAC cells since RAGE is positively expressed in fibroblasts, promoting the desmoplastic response. RAGE has also been implicated in the muscle wasting associated with cancer and with aging, as well as in neuropathic pain, suggesting a potential supportive role in PDAC treatment. Methods: This is an open label study to determine the safety and preliminary evidence of a therapeutic effect of azeliragon in patients refractory to the standard of care treatment of metastatic pancreatic cancer. Azeliragon is administered at three dose levels in a rolling dose escalation strategy with 6 patients at each dose level: 5 mg/day (level 1), 10 mg/day (level 2) and 20 mg/day (level 3). These dose levels have an initial loading dose for 6 days at 15 mg daily, 15 mg twice a day and 30 mg twice a day, respectively. The primary objective is to determine the RP2D, defined as the dose for which <33% patients experience a dose limiting toxicity (DLT) within 28 days from initiation of dosing. Secondary endpoints include disease control, overall survival, changes in pain as determined by the Brief Pain Inventory, and changes in ECOG performance status, weight, and serum albumin. The study received regulatory approval and accrual started in June 2023. Clinical trial information: NCT05766748 .
EFFECT-neo: A phase 3 study of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinoma.
Authors: Zhang Yang , Guo Wei , Zhang Wenchao , Wang Zhenyu , Yu Kai , Li Li , Wang Yan , Huang Zhigang
Published: July 2024

TPS6123

Background: There is still a huge need for treatment of operable locally advanced head and neck squamous cell carcinoma (LA HNSCC). Multiple phase 2 studies have shown that PD-1 combined with chemotherapy has good short-term efficacy, especially the pathological complete response (pCR) rate exceeds 30%, which is also considered to be an important factor in the survival benefit that neoadjuvant immune therapy may bring. The randomized, open-label, phase 3 EFFECT-neo study (NCT06102395) will evaluate efficacy and safety of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable LA HNSCC. Methods: Patients with untreated LA HNSCC who met the inclusion criteria will be randomly assigned 1:1 to two treatment arms. Experimental group will be given 2 cycles of pembrolizumab (200mg d1, Q3W) + chemotherapy (perfer TPF regimens) . Control group will undergo 2 cycles of chemotherapy. Both two arms should finish imaging evaluation, and If the result is CR after neoadjuvant treatment, radiotherapy (RT) (60-70Gy) ± chemotherapy (investigator's choice) will be given as adjuvant treatment; if the result are PR or SD, surgery (within 2 weeks) will be performed, and then RT ± chemotherapy will be given. If the imaging evaluation is PD, patients will be received standard treatment. Enrolled patients must closely monitor the adverse reactions of chemotherapy and record the time, grade, treatment measures, outcomes, etc. All patients will be reviewed every 3 months for 1 year; after 1 year, they were reviewed every 6 months for 3 years; patient recurrence and survival data were recorded. Eligibility criteria will include age ≥18 years; untreated with immunotherapy, resectable, stage III/IVB HNSCC (AJCC Cancer Staging Manual, 8th edition); ECOG performance status 0-2; and the investigators believe that patients can safely receive pembrolizumab combined with chemotherapy in neoadjuvant chemotherapy. Randomization treatment will continue until disease progression, unacceptable toxicity, or decision to withdraw. Primary end points is pCR, defined as the absence of residual invasive squamous cell carcinoma within the primary tumor specimen on resection/needle biopsy (Patients with CR imaging results will undergo multi-point biopsy). Secondary end points include objective response rate, 1-year and 2-year event-free survival rates, 2-year overall survival rate, functional preservation rate, safety and Karnofsky performance status. Recruitment is ongoing and will continue until 272 patients are enrolled. Clinical trial information: NCT06102395 .
Proportional relations between the wave number and amplitude of spiral waves near Neimark-Sacker bifurcations
Authors: Xu Bin , Gao Jian , Shen Chuansheng
Published: July 2024

The spatiotemporal distribution patterns of interacting populations are broadly accepted as a pivotal factor in sustaining species diversity. Spiral waves represent common spatiotemporal patterns observed in ecosystems and biological systems, encompassing both continuous-time and discrete-time systems. The study of the dynamics and regulation of spiral waves in continuous-time systems, often observed in the vicinity of Hopf bifurcations, has been comprehensively examined. However, the dynamical characteristics and rules governing spiral waves near Hopf bifurcations in discrete-time systems, also named Neimark-Sacker bifurcations, are still not fully understood. Here, we investigate spiral waves in a discrete-time predator-pest model caused by a Neimark-Sacker bifurcation. Our results suggest a linear relationship between the amplitude and wave number of spiral waves near the Neimark-Sacker bifurcation. At last, we propose a model that can describe the behaviors of spiral waves in discrete-time systems near Neimark-Sacker bifurcations. Our findings illuminate the process of pattern formation in discrete-time systems, offering potential insights for forecasting and managing pest distribution.
From promoter motif to cardiac function: a single DPE motif affects transcription regulation and organ function in vivo
Authors: Sloutskin Anna , Itzhak Dekel , Vogler Georg , Pozeilov Hadar , Ideses Diana , Alter Hadar , Adato Orit , Shachar Hadar , Doniger Tirza , Shohat-Ophir Galit , Frasch Manfred , Bodmer Rolf , Duttke Sascha H. , Juven-Gershon Tamar
Published: July 2024

Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach using both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7 bp substitution mutation results in massive perturbation of the Tinman regulatory network that orchestrates dorsal musculature, which is manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features, and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation.