bluuebunny/crossref_metadata_2025 huggingface dataset:
EVICTION study: ICT01, an anti-Butyrophilin 3A monoclonal antibody activating γ9δ2 T cells in combination with pembrolizumab in checkpoint inhibitor refractory melanoma.
Authors: Champiat Stephane , Wermke Martin , Vicier Cecile , De Bono Johann S. , Calvo Emiliano , Ramón Jorge , Hall Evan Thomas , Garralda Elena , Galvao Vladimir , Romano Emanuela , Italiano Antoine , Saada Esma , You Benoit , De Gassart Aude , Mairesse Maelle , Valentin Emmanuel , Brune Patrick , Olive Daniel , Lemmens Katrien , Frohna Paul ,   ASCO 24 authors
Published: July 2024

9534

Background: γ9δ2 T-cell tumor infiltration is associated with a favorable prognosis making these cells a new potential target for immunotherapy. The anti-BTN3A mAb ICT01 selectively activates γ9δ2 T cells and is being studied in the phase1/2a EVICTION Trial (NCT04243499). In preclinical studies, ICT01 induces upregulation of PD-1 on γ9δ2 T-cells and combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale to evaluate this combination. Here we present interim results from EVICTION of ICT01 in combination with pembrolizumab in patients with checkpoint inhibitor (CPI) refractory melanoma. Methods: EVICTION evaluated ICT01 (20 µg to 200 mg, Q3W) plus pembrolizumab (200mg IV Q3W) in a dose escalation solid tumor basket design that resulted in an ongoing expansion cohort of patients with CPI refractory melanoma (2 dose levels, 7 and 200 mg ICT01). Patients are selected based on higher baseline γ9δ2 T cells. Efficacy evaluations by i/RECIST 1.1 are conducted every 8 weeks. Disease Control Rate (DCR) as primary efficacy endpoint is defined as the sum of complete response (CR), partial response (PR) and stable disease (SD, minimum week 16). Baseline and on-treatment blood and biopsy specimens are collected for correlative translational work. Results: ICT01 plus pembrolizumab has a favorable safety profile with first-dose Grade 1/2 infusion related reactions (IRR) and cytokine release syndrome (CRS) as most common adverse events (in 38% and 19% of patients respectively, 5%and 2% Grade 3) among all doses and indications. To date, 35 CPI refractory melanoma patients have been enrolled, of which 65% have received 2+ prior lines of CPI. Currently 21 patients are evaluable at week 16 with a DCR of 42% (including 3 PR) and a 6-month progression free survival of 38%. In the circulation, full BTN3A receptor occupancy on immune cells was achieved at 7 mg dose, with down-modulation of BTN3A observed at doses greater than 20 mg. Clinical response was related to baseline tumoral BTN3A expression, sustained elevation of IFNg levels, and tumor microenvironment remodeling, including increased PD-L1 expression and CD8 T cells proliferation and activation. Conclusions: ICT01 in combination with pembrolizumab has a favorable safety profile and promising efficacy data. Patient selection based on BTN3A tumor expression will be further evaluated as an enrichment strategy. Clinical trial information: NCT04243499 .
Analyzing the gut microbiome in adolescent and young adult patients with melanoma receiving immune checkpoint blockade.
Authors: Afridi Faraz , Fallon Eleanor , Ayabe Reed I , Damania Ashish , Wargo Jennifer Ann , Roth Michael
Published: July 2024

9563

Background: Melanoma is the third most common cancer in adolescent and young adults (AYA), a unique cohort defined as patients between 15-39 years of age per the National Cancer Institute. Immune checkpoint inhibitors (ICI) have changed the landscape for advanced melanoma treatment, and the gut microbiota has been shown to remodel the tumor microenvironment to improve ICI efficacy. There is a paucity of research in this cohort, however studies show that AYA patients, in general, have historically not seen the same survival gains as other age groups. Furthermore, literature shows that survival was much worse for AYA's with stage IV melanoma than observed among older adults. Methods: The AYA cohort in this retrospective review is from the 2021 Science publication entitled "Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response". This cohort was matched on a 2:1 basis with older non-AYA patients 50-70 years of age. We controlled for sex, BMI, race, treatment naivety, stage of disease, as well as smoking, drug, and alcohol status. Results: Our AYA cohort of 23 patients is comprised of 15 females, 22 Caucasians, 20 with primary cutaneous melanoma, 12 with stage III at the start of treatment and 11 with stage IV, 17 were BRAF positive, 8 received combined immunotherapy, 20 were treatment naïve, and 11 were responders. We found no difference in alpha or beta diversity in AYA and older non-AYA patients, however alpha diversity increased with age. This is consistent with literature regarding aging gut microbiomes. Furthermore, we noted the most common microbes found between these groups varied considerably. Using differential analyses, we found, for example, a higher abundance of Ruminococcaceae, at the family level, in older non-AYA patients and a higher abundance of Bacteroides stercoris in AYA patients. Literature shows the relative abundance of Ruminococcaceae increased with age and was significantly higher in older patients. Furthermore, Bacteroides stercoris correlates positively with fiber, grain, and vegetable intake. Additionally, Blautia massiliensia, Blautia obeum, and Dorea longicatena were found to be significantly more prevalent (p=0.010, p=0.34, and p=0.035, respectively)) in older non-AYA patients. These species are all known to be obesity biomarkers. Conclusions: We found that the gut microbiota of AYA and older non-AYA melanoma patients differ. Older non-AYA patients have bacterial species associated with negative biomarkers which may be due to an aging gut microbiome. Establishing microbial features in the AYA population can help with microbiome modulation as a therapeutic strategy. Enriching modalities include fecal microbiota transplantation, probiotics, and improving diet as well as fiber intake. Further research should explore if the gut microbiome influences worse outcomes in AYA's with late stage melanoma.
Adjuvant BRAF/MEK versus anti-PD-1 in BRAF-mutant melanoma: Propensity score–matched recurrence-free, distant metastasis-free, and overall survival analysis.
Authors: Bloem Manja , de Meza Melissa Melanie , Aarts Maureen J.B. , Van Den Berkmortel Franchette , Blank Christian U. , Blokx Willeke , Boers-Sonderen Marye J. , Bonenkamp Han J. , de Groot Jan Willem , Haanen John , Hospers Geke , Kapiteijn Ellen , Piersma Djura , van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , van den Eertwegh Alfonsus Johannes Maria , Suijkerbuijk Karijn , Wouters Michel WJM
Published: July 2024

9573

Background: Adjuvant BRAF/MEK inhibitors (BRAF/MEKi) and immunotherapy with anti-PD-1 have become the standard of care for resected high-risk stage III and IV melanoma, but a head-to-head comparison is lacking. In our earlier study, we compared adjuvant BRAF/MEKi and anti-PD-1 in a nationwide cohort in the Netherlands. However, the follow-up was too limited for overall survival (OS) analysis. We present an updated analysis including OS with extended follow-up. Methods: We included all resected high-risk stage III melanoma patients treated with first-line adjuvant BRAF/MEKi and anti-PD-1 from the Dutch Melanoma Treatment Registry from 2018-2023. We performed a propensity score matched outcome analysis of 1- and 2-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and OS. Grade ≥ 3 toxicity rates and discontinuation rates due to toxicity were described. Results: In total, 225 BRAF/MEKi-treated patients and 729 anti-PD-1-treated patients were included. BRAF/MEKi-treated patients had lower disease stages (16.4% versus 10.2% stage IIIA disease; p=0.01) and more comorbidities (76.0% versus 63.8%; p<0.01) than anti-PD-1-treated patients. Median follow-up duration was 20.9 months. Two similar groups of 213 patients each were created by propensity score matching. Before matching, RFS and DMFS were significantly shorter in the anti-PD-1 treated patients, OS was not (Table). After matching, the 1- and 2-year RFS, DMFS and OS rates were not significantly different (Table). Toxicity data will be presented at the meeting. Conclusions: Our results suggest no significant differences in outcomes between adjuvant BRAF/MEKi and anti-PD-1 treatment in stage III melanoma.[Table: see text]
Use of early circulating tumour DNA dynamics in patients with stage III melanoma receiving neoadjuvant combination immunotherapy.
Authors: Chan Wei Yen , Lee Jenny , Stewart Ashleigh , Diefenbach Russell J. , Gonzalez Maria , Menzies Alexander M. , Blank Christian U. , Scolyer Richard A , Long Georgina V. , Rizos Helen
Published: July 2024

9577

Background: Neoadjuvant therapy in resectable stage III cutaneous melanoma improves relapse-free survival compared to adjuvant therapy alone and is now a standard of care.While pathological response can help predict recurrence risk and the need for further treatment, more biomarkers are required. We investigated circulating tumour DNA (ctDNA) as a predictive biomarker for recurrence in stage IIIB/C melanoma patients following neoadjuvant immunotherapy and surgery. Methods: We retrospectively analysed plasma samples collected at baseline and six weeks post-surgery from 30 patients enrolled in the OpACIN-neo and PRADO clinical trials, who received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent pre-amplification followed by tumour-informed mutation detection analysis using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system. BRAF mutations were identified in 60% of patients through tumour tissue sequencing. Following neoadjuvant therapy, 7/30 (23%) achieved complete pathological response (pCR), 5/30 (17%) near pCR, 4/30 (13%) partial response, and 14/30 (47%) non-response (pNR). Results: Baseline ctDNA was detectable in 15/30 (50%) patients using the pre-amplification ddPCR method. At median follow-up of 47 months, 9/30 (30%) patients recurred, with a median time to recurrence of 8 months (range 6 to 29 months). Post-surgery, ctDNA was detectable in 4/9 patients who recurred; all four were pathological non-responders and recurred with distant, unresectable disease. Among the 15 ctDNA-positive patients at baseline, 13/15 (87%) patients achieved ctDNA clearance while 2/15 (13%) remained persistently ctDNA-positive; with a subsequent relapse rate of 0% and 100% respectively. ctDNA detection post-surgery predicted patients at higher risk of disease recurrence [relapse-free survival (RFS) hazard ratio (HR) 7.83, 95%CI 0.82-74.48; p=0.0002] and poorer melanoma-specific survival (MSS) [HR 6.35, 95% CI 0.36-110.70; p=0.0337]. Conclusions: Post-surgery ctDNA positivity can signal imminent recurrence, thus offering a window for personalised adjuvant therapy modification.
Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC).
Authors: Brohl Andrew Scott , Silk Ann W. , Thomas Jacob Stephen , Eroglu Zeynep , Tarhini Ahmad A. , De-Aquino Deanryan B. , Abraham Edith , Khushalani Nikhil I. , Markowitz Joseph , Tsai Kenneth Yee
Published: July 2024

9592

Background: MCC and cSCC have limited treatment options when refractory to immune checkpoint inhibitor (ICI) therapy. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intra-tumoral (IT) injection. In this Phase 1b study, we evaluated the safety and efficacy of different schedules of IT IFx in patients (pts) with advanced MCC or cSCC. Methods: In the first trial stage (n=9), IT IFx was administered in up to 3 lesions on 3 schedules following a 3+3 exposure escalation schema; weekly x 1, 2, or 3. In the second trial expansion stage (n=11), IT IFx was administered weekly x 3. The primary objective of the study was to establish safety and feasibility of repeated IT administrations of the investigational agent. ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge. Results: We treated 22 pts (MCC, 13; cSCC, 9). All pts had received prior anti-PD(L)1 based treatment with disease progression being the reason for ICI discontinuation in all patients but one. Two pts did not complete planned study therapy due to rapid clinical progression and were replaced but included in the safety analysis. IT IFx was well tolerated at all dose schedules evaluated with 1 high-grade toxicity deemed possibly treatment related (G3 hepatitis in a patient recently treated with ICI). The study therefore met predefined study endpoints for safety and efficacy. After protocol specified IT therapy, 11 MCC pts and 6 cSCC pts were treated with anti-PD(L)1 based therapy as the immediate post-protocol treatment. Five of 9 (56%) evaluable MCC patients and 1 of 7 (14%) cSCC patients experienced an objective response to this ICI rechallenge, with duration of response ongoing in 4 patients (6+, 19+, 21+, 23+ months) and the two other responses lasting 23 and 33 months. The two remaining MCC patients were not evaluable for response from IO rechallenge due to radiation administered to the only measurable disease site(s), but both remain progression free at 11+ and 13+ months with previously progressive disease. Conclusions: IT IFx-Hu2.0 is safe and feasible to administer at weekly dosing repeated up to 3 weeks. An unplanned exploratory analysis revealed frequent (56%) and durable responses in advanced MCC to ICI re-challenge despite prior resistance to this class of drug, suggesting that IFx induced an immune priming effect. Preliminary biomarker analyses to investigate this phenomenon are ongoing and will be presented. Clinical trial information: NCT04160065 .
The impact of adjuvant radiation therapy on disease-specific survival in stage I and II Merkel cell carcinoma: A SEER database analysis.
Authors: Curlin Marcus , McEvoy Aubriana , Ansstas George
Published: July 2024

9593

Background: Merkel Cell Carcinoma (MCC) is a rare, cutaneous neuroendocrine tumor associated with poor prognosis. Adjuvant radiation therapy (RT) is commonly used for the treatment of locoregional disease, but the impact on survival remains controversial. Previous studies from the Survival, Epidemiology, and End Results (SEER) database have shown an overall survival benefit to adjuvant RT without controlling for important prognostic differences in comparison groups such as age. To better control for these variables, we examined the impact of postoperative adjuvant radiation therapy on stage I and II disease-specific survival using the SEER database. Methods: SEERStat was used to obtain and analyze the outcomes of 2423 histologically confirmed MCC patients treated with surgery monotherapy or surgery with postoperative radiation therapy between 2004 and 2020 in the 17-registry (November 2021) SEER database. We compared the 5-year disease-specific survival (DSS) between the surgery monotherapy and adjuvant RT groups for stage I (n=1697) and stage II (n=726) MCC patients. Results: Patients treated with surgery and adjuvant RT were younger than those who received surgery monotherapy (median age 72 versus 77, respectively). Adjuvant RT was not associated with an increase in disease-specific survival. In contrast, adjuvant RT was associated with a statistically significant decrease in 5-year DSS among stage I patients (82.8% for those treated with RT versus 87.5% for those treated with surgery monotherapy, p = 0.023). Additionally, RT was not associated with a significant increase in DSS among stage II patients (77.0% versus 74.4% for patients treated with surgery monotherapy, p=0.490). Conclusions: This study demonstrates that there is no statistically significant disease-specific survival benefit from adjuvant radiation therapy for stage I and II MCC in the SEER database. Interestingly, in stage I patients we find a significant negative association between adjuvant RT and DSS. Younger patients are more likely to receive adjuvant RT, which likely contributes to higher overall survival previously reported from the SEER database, but the explanation for decreased DSS in patients who received RT remains unclear. Further studies regarding the effect of radiation therapy on local disease control and tumor microenvironment are needed to establish the appropriate role of RT in stage I-II MCC patients. [Table: see text]
Factors that impact aromatase inhibitor adherence in early-stage hormone receptor positive breast cancer.
Authors: Yang Angela , Baldwin Elena , Casasanta Nicole , Tiersten Amy , Kier Melanie Wain
Published: July 2024

e12524

Background: Despite efficacy of aromatase inhibitors (AI) in improving survival for patients with hormone receptor positive (HR+) breast cancer, adherence to AI remains suboptimal. The aim of this study is to evaluate factors that may affect patient adherence to first-line AI. Methods: We retrospectively reviewed records of 195 female patients with HR+, HER2 negative early-stage breast cancer who were started on first-line adjuvant AI between 2011-2020 at our academic institution. We collected information on recurrence risk (defined by Oncotype score, with low risk ≤ 15, moderate risk 16-25, high risk ≥ 26), AI-related side effects, supportive therapy use for side effects, and socioeconomic demographics (i.e. income, insurance type, and race). We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. The primary end point was the rate of first-line AI adherence at 4 years. The Kruskal-Wallis rank sum test, Fisher’s exact test, and Pearson’s chi-squared test were used to compare AI adherence when varying patient profiles. Results: In our cohort, 50% (n=98) were adherent to first-line AI at 4 years, 9% (n=17) were still taking first-line AI but have not yet reached 4 years, and 41% (n=80) discontinued first-line AI early. Of those who discontinued first-line AI early, 68% (n=54) switched to an alternate endocrine treatment due to side effects, 4% (n=3) stopped all endocrine treatment, and 28% (n=23) were lost to follow up. AI-related side effects were common; 83% (n=162) reported AI-related side effects, yet only 27% of those patients received supportive therapy. Supportive therapy use was not significantly different when varying patients’ recurrence risk and socioeconomic demographics. In addition, adherence did not differ based on side effect frequency or supportive therapy use. The population’s Oncotypes included 36% (n=70) low risk, 36% (n=70) moderate risk and 12% (n=24) high risk; the remaining had no Oncotype sent. There was no significant difference in adherence among the risk groups. In evaluating demographics, the cohort’s median age was 62 and it included 9% Asian, 13% Black, 5% Hispanic, 54% White, and 19% Other/Unknown. The majority (62%) of patients were of middle income ($52,000-145,000), followed by 29% in upper and 9% in lower income. The minority (22%) of patients were on Medicaid. Those with a lower discontinuation rate were older (64 vs. 61, p=0.019), while there was no significant difference based on race, income, or insurance. Conclusions: Despite the small sample, it is reassuring that at our institution, long term adherence to first-line AI and supportive therapy use did not vary among socioeconomic demographics. However, a gap persists between the prevalence of AI-related side effects and usage of proven supportive treatments. Further study on strategies to enhance AI tolerance and adherence is needed.
Effects of a pilot 12-week exercise program on breast cancer survivors’ quality of life.
Authors: Imai Lauren , Baron Kirsten , Toyama Matthew , Pagano Ian , Yamada Paulette , Teranishi-Hashimoto Cheri , Fukui Jami Aya
Published: July 2024

e12525

Background: Previous studies have demonstrated that breast cancer survivors commonly experience a decrease in quality of life including an increased risk of depression, insomnia, cancer-related fatigue, and negative body image. Several studies have shown that exercise interventions, such as yoga, Pilates, water aerobics, and strengthening exercises can improve survivors’ quality of life. We implemented a 12-week exercise program in breast cancer survivors and evaluated quality of life changes. Here we discuss our findings evaluating 13 quality of life questionnaires. Methods: We evaluated 46 participants who completed a baseline and post 12-week questionnaire assessment. All participants underwent an exercise program 3 times/week for 90 minutes/session. We calculated differences in baseline and post 12-week quality of life through 13 questionnaires: Functional Assessment of Cancer Therapy - General (FACT-G) Physical, Social/Family, Emotional, and Functional, Social Support, Insomnia Severity Index, Brief Fatigue Inventory, Patient Health Questionnaire, and Body Image after Breast Cancer (BIBCQ) Vulnerability Scale (VS), Body Stigma Scale (BSS), Limitations Scale (LS), Body Concerns Scale (BCS), Transparency Scale (TS), and Arm Concerns Scale (ACS) and assessed the intervention's efficacy by comparing the baseline and post 12-week scores using paired t-tests. Results: The difference between baseline and post 12-week quality of life are presented in the Table. 7/13 questionnaires showed statistical significance: FACT-G Physical and Functional, Insomnia Severity Index, Brief Fatigue Inventory, Patient Health Questionnaire, and BIBCQ LS and BCS. Conclusions: Our study showed improvement in metrics evaluated in breast cancer survivors who underwent the personalized exercise program. Specifically, body image was improved with exercise which further exemplifies the impact of lifestyle changes on quality of life measures and is an important adjunct to future cancer survivorship studies. Clinical trial information: NCT04013568 . [Table: see text]
Impact of comorbidity on surgical management of breast cancer in elderly patients.
Authors: Shivilov Evgenii , Anichkina Kristina , Arslanov Khalil , Kvetenadze Gurami , Zhukova Lyudmila
Published: July 2024

e12596

Background: More than half of breast cancers are diagnosed above the age of 60 years, a quarter of which diagnosed with invasive breast cancer among those over 75 years of age. Treatment of breast cancer (BC) at this age remains a complex problem. Elderly patients often have various comorbidities that impose increased risks of complications with antitumor treatment. This leads to both excessive and insufficient treatment of BC. In patients over 75 years of age, an individual approach to treatment is recommended, taking into account their general health and life expectancy, the risk of death from breast cancer compared to other causes, as well as the advantages and disadvantages of treatment methods. Objective: To evaluate the influence of comorbidity on the risks of complications (early and delay) after surgical treatment in elderly and senile patients (pts). Methods: A retrospective analysis of the results of breast cancer treatment in 292 pts over 75 years of age, who underwent surgical treatment at the first stage in SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM from 2016 to 2019. The initial stages of breast cancer (I and IIA) were diagnosed in 257 (88.0%) pts, 35 pts (12.0%) has IIB and IIIA clinical stages. Radical mastectomy was performed in 171 (58.6%) cases, breast-conserving surgery was performed in the remaining 121 (41.4%). Forty-six (15.8%) patients had diabetes mellitus, 121 (41.4%) had cardiovascular disease, 36 (12.3%) had heart rhythm disorders, 38 (13.0%) had chronic cerebral ischemia, and the risk of grade 3 and 4 cardiovascular complications was found in 251 (86.0%) cases. Results: In the early postoperative period severe complications occurred in 1 (1.7%) patient (acute coronary syndrome) leading to death. No local recurrences were detected. The overall 3-year survival rate was 86.3% and the recurrence-free survival rate was 89.7%. In 10 (3.4%) cases, death was due to progression of RRMS, 30 (10.3%) patients died from other causes (acute cardiovascular failure, stroke, COVID-19). Conclusions: Comorbid conditions in elderly patients after surgery did not affect the development of complications in the early postoperative period. Preliminary preoperative preparation of elderly patients (correction and selection of drug therapy for concomitant chronic diseases) reduces the risk of early postoperative complications.
Single institution analysis of glioblastoma multiforme (GBM) outcomes based on year of diagnosis: A 17 year review.
Authors: Mustafa Yazan Hani , Keogh Rachel J , Barry Simon , O'Reilly Seamus , Gleeson Jack , Bambury Richard Martin
Published: July 2024

e14023

Background: GBM is the most common brain tumour in adults. The latest WHO classification excludes IDH mutated tumours, acknowledging their favourable prognosis. MGMT methylation is a prognostic biomarker and predicts level of benefit from Temozolomide. The standard of care management includes maximal surgical resection followed by radiotherapy with concurrent and adjuvant Temozolomide. This has remained largely unchanged for nearly 20 years. We analysed 17 years of newly diagnosed GBM cases attending Medical Oncology at our institution to assess outcome advancements. Methods: Demographic information, clinicopathological characteristics, surgery, radiotherapy and systemic anti-cancer treatment data were collected from the charts of patients diagnosed with GBM and seen by the Medical Oncology department at Cork University Hospital between 2005-2021. The study population was divided into 2 time periods: 2005-2016 and 2017-2021. Overall survival was recorded. Baseline characteristics was compared across time periods using the Chi-Square test. Univariate and multivariate analysis was performed to assess impact of different variables on overall survival. Results: The analysis comprised 306 patients, with 142 and 164 diagnosed between 2005-2016 and 2017-2021 respectively. Median age was 62 years (range 17-86) and patients were predominantly male (65%). Patients in the earlier time period were more likely to have ECOG performance status 0-1 (80% vs 65% p = 0.011) and were more likely to commence treatment on Stupp protocol (99% vs 80% p = <0.001). IDH and MGMT testing were less prevalent in the earlier time period. Median overall survival (mOS) for the entire cohort was 11.6 months. Univariate analysis revealed correlations between overall survival and time period of diagnosis, age >65, MGMT status, ECOG performance status, steroid use, surgery, re-resection, and completion of adjuvant chemoradiation protocols. The mOS was 12.3 months in the earlier time period and 10.4 months in the later time period (HR = 1.35 p = 0.012). Time period of diagnosis remained an independent prognostic factor for poor outcome on multivariate analysis. Notably, mOS during the COVID-19 pandemic (2020-2021) was 10.6 months, showing no difference from other time periods. Conclusions: Despite advances in our knowledge regarding the molecular biology of GBM, prognosis remains poor. Our institution’s 17 year survival data indicates no improvement over time emphasising the urgent need for new treatment strategies. Notably, the more recent time period had an increased number of frailer patients who were too unwell to commence any adjuvant treatment, possibly indicating a lower referral threshold which may have negatively impacted mOS in that cohort. Additionally, the absence of IDH status assessment in the earlier era means some IDH mutant patients were likely included, thereby inflating the mOS for that cohort.
Personalized neoantigen-pulsed autologous dendritic cells vaccine as an adjuvant treatment for patients with newly-diagnosed glioblastoma multiforme: A phase I trial.
Authors: Zhang Yang , Chi Xiaohan , Cheng Xudong , Zhang Yu , Zhang Kangna , Huang Na , Ji Nan
Published: July 2024

e14025

Background: Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain malignancy in adults. We herein report a phase I trial using personalized neoantigen-pulsed autologous dendritic cells (nDC) vaccine as an adjuvant treatment for patients with newly-diagnosed GBM. Methods: It is a single-center, single-arm phase I trial, enrolling patients aged 18-75 years old, with newly-diagnosed GBM and tumor resection extent ≥90%. Tumor specimens were sequenced for identification of personalized neoantigens. A total of 3-10 neoantigen peptides were loaded into DC to generate the nDC vaccine. The vaccine was administered subcutaneously for 5-6 doses at 1×10^7 cells following concomitant radiotherapy plus temozolomide. The primary objective is safety. Secondary objectives include survival outcomes and T cell immune response against the neoantigens. Results: As of Dec. 31, 2023, eleven patients completed at least one dose of vaccination and were included in the safety analysis; eight patients completed planned doses and were included in the efficacy analysis. All the patients reported Treatment-emergent adverse events (TEAEs). Most TEAEs were grade 1 or 2. One patient reported two grade 3 TEAEs: decreased white blood cell count and decreased lymphocyte count. Pyrexia was considered as treatment-related adverse event (TRAE) that was reported in two (18.2%) patients. No treatment-related deaths occurred. Among eight efficacy-assessable patients, seven (87.5%) patients kept progression-free for at least 5.4-27.3 months; one patient progressed at 10.2 months after surgery and achieved complete remission after receiving anti-PD1 plus bevacizumab therapy; compared to the baseline level, a median 15-fold (3 to 506-fold) increase of neoantigen-specific cytotoxic T cells was detected in their peripheral blood samples post-vaccination, indicating strong anti-tumor T cell responses elicited by the nDC vaccine. Conclusions: The nDC vaccine, combined with the standard treatments for GBM, was well tolerated. Initial results from this ongoing study have exhibited encouraging survival outcome of the nDC vaccine for patients with newly-diagnosed GBMs. Clinical trial information: NCT04968366 . [Table: see text]
Co-treatment of human GBM cell lines with imipridone ONC206 and tumor treating fields: Effect on on cell death and p-AKT.
Authors: Tajiknia Vida , El-Deiry Wafik S. , Schwermann Maximilian , MacDonald William J. , Stubbs Nolan
Published: July 2024

e14033

Background: Glioblastoma (GBM) is the most common primary brain malignancy with dismal prognosis. Tumor Treating Fields (TTFields) therapy is available for the treatment of both newly diagnosed and recurrent glioblastoma and represents a new category of treatment modalities in oncologic therapy. Despite decades of study, few FDA approved modalities are available for GBM and provide limited survival improvements for patients. AKT functions as a key serine/threonine kinase in the RTK/PTEN/PI3K pathway, and extensive genomic analysis of GBM has revealed that this pathway is mutated in a significant majority of GBM cases. Activation of this pathway ultimately leads to the activation of AKT, and phospho-AKT levels are elevated in the majority of GBM tumor samples and cell lines. Studies have shown that increased p-AKT levels contribute to uncontrolled growth, resistance to apoptosis, and enhanced invasive capabilities of glioma cells, which are characteristics of tumor progression in GBM. AKT serves as a critical hub in this pathway, enabling the amplification of growth signals, thereby making the inhibition of AKT an appealing and promising therapeutic target for treating GBM. Imipridone ONC206 is under clinical development for treatment of pediatric and adult patients with primary brain tumors (NCT04732065 and NCT04541082). Here we show inhibition of p-AKT as well as upregulation of cleaved PARP following cotreatment of ONC206 and TTFields. Methods: We investigated the effect of ONC206 at IC50s plus TTFields in LN229, U138, U251 and T98G human GBM cell lines at different time points. Effect of treatment on cPARP, BCL-2, CHOP, caspase-10, and p-AKT were investigated using western blot. Results: Treatment with ONC206 at the IC50 in T98G cells with TTFields at 24h showed synergistic upregulation of cPARP as well as inhibition of BCL-2. At 96hour time point, inhibition of p-AKT was observed following all treatments (ONC206, TTFields, and co-application compared to control. In U251 cells, following treatment of ONC206 and TTFields, inhibition of BCL-2 was observed at 24h time point. Upregulation of CHOP and Casapse-10 at 96h time point was seen, as well as inhibition of p-AKT. Spheroid models showed structure disruption and growth arrest following combination treatment. At 72 h time point co treatment with ONC206 and TTFields resulted in synergistic upregulation of cleaved PARP. Conclusions: Here we showed cotreatment with TTFields and ONC206 results in inhibition of p-AKT, the key node in GBM growth pathway. This is the first report of cleaved PARP upregulation following TTFields and ONC206 in Human GBM cell line. Further studies to investigate the in vivo efficacy of TTField treatment in GBM with ONC206 are warranted. More studies are needed to understand the exact mechanism of synergy.
Exploring the diagnostic potential of cerebrospinal fluid (CSF) IL-10:IL-6 ratio in patients with primary central nervous system lymphoma (PCNSL).
Authors: Singh Sofia , Kapila Aastha Takkar , Prakash Gaurav , Lal Vivek , Gupta Vishali , Minz Ranjana Walker , Mahesh karthik Vinay
Published: July 2024

e14041

Background: Primary Central Nervous System Lymphomas (PCNSL) present significant diagnostic challenges due to their aggressive nature. Current diagnostic methods include neuroimaging, CSF cytology, FDG-PET scans, and biopsies. Building upon the success of the IL-10:IL-6 ratio as a diagnostic biomarker in intraocular lymphoma, this study investigates its potential in PCNSL diagnosis. CSF IL-10:IL-6 ratio emerges as a promising, easily accessible biomarker for early PCNSL detection. Methods: Fifteen histopathologically confirmed PCNSL patients were compared with fifteen CNS inflammatory condition patients and ten patients with other CNS malignancies. Detailed clinical assessments were conducted, and IL-10:IL-6 levels were measured in serum and CSF using Flow cytometry. Results: The CSF IL-10:IL-6 Ratio was elevated (> 1) compared to serum levels in PCNSL patients in contrast to other control groups. The mean age ± SD of PCNSL patients was 55.47 ± 17.29, with a male-to-female ratio of 8:7. The mean (SD) for CSF IL-10:IL-6 ratio in PCNSL was 3.35 (3.88), while the mean (SD) for serum IL-10:IL-6 ratio was 0.438 (1.54). The statistical analysis revealed a significant difference (P = 0.0058 < 0.05). Conversely, comparing the CSF IL-10:IL-6 ratio with serum levels in controls with CNS inflammatory conditions and CNS malignancies showed no statistical significance (P > 0.05). Conclusions: Elevated CSF IL-10 and CSF IL-10/IL-6 ratios suggest their potential as early diagnostic markers for large B cell PCNSL. The IL-10:IL-6 ratio holds promise as a novel, easily accessible biomarker in readily available body fluids for PCNSL diagnosis.
Combined NF2/PTEN mutations as predictors of meningioma aggressiveness.
Authors: Gandhi Om H. , Ajmera Sonia , Tarbay Antonio Corral , Patel Saawan , Mannam Sneha Sai , Karsalia Ritesh , Jackson Christina
Published: July 2024

e14044

Background: In meningiomas, loss of the NF2 tumor suppressor gene function leads to dysregulation of cell proliferation and tumor formation. PTEN, another tumor suppressor gene correlated with worse prognosis in tumors like gliomas, has also been reported in meningiomas, but the impact of its mutation alone or in conjunction with NF2 loss on outcomes in these tumors is unexplored. We aimed to evaluate whether dual NF2/PTEN mutations comprise a more aggressive meningioma phenotype compared to tumors with only NF2 mutations. Identifying this high-risk genetic profile could allow for preventative and individualized treatment of these aggressive meningiomas. Methods: We reviewed patients who underwent meningioma resection at our institution from January 2018 through October 2022. Demographic information, tumor characteristics, pre- and post-operative clinical characteristics, and outcomes were collected. Meningioma specimens were analyzed by immunohistochemistry for WHO grading and Ki67 proliferation index and by sequencing for genomic alterations. We performed multivariable logistic regression analyses to identify clinical outcomes associated with proliferation index and genetic mutations. Results: We identified NF2 mutations in 24 meningiomas and dual NF2/PTEN mutations in 7 meningiomas. Mutation rates did not significantly differ based on demographic factors including sex, age, race, socioeconomic status, or prior cranial radiation status (p>0.05). The majority of tumors with these mutations (93%) were in non-skull base regions (i.e. convexity, parafalcine). Tumors with both NF2 and PTEN mutations were more likely to be WHO grade III tumors than those with the NF2 mutation alone (29% versus 9%). Tumors with dual mutations had higher likelihood of having Ki67 proliferation indices ≥ 10% (OR 5.98, p<0.01). While higher Ki67 index was significantly associated with features of more aggressive tumors including higher WHO grade and recurrence rates, dual mutation in NF2 and PTEN is associated with higher rate of recurrence (OR 13.13, p<0.001) and mortality (OR 5.14, p<0.05) compared to NF2 irrespective of Ki67 index. Notably, patients with mutations in NF2 alone or both NF2/PTEN did not differ in preoperative Karnofsky performance score, Simpson resection grade, or presence of post operative residual tumor. Conclusions: Our results demonstrated that concomitant NF2 and PTEN mutations in meningiomas were associated with higher WHO grades, tumor proliferation indices, recurrence rates, and mortality rates. This finding suggests that NF2/PTEN mutated meningiomas represent a distinct subset of tumors that demonstrate a more aggressive clinical and histopathological phenotype that may require more aggressive treatment and closer surveillance. Further investigation is warranted to confirm the prognostic relevance of NF2/PTEN mutations in meningioma and elucidate their underlying molecular mechanisms.
Epigenetic silencing of LDHB to promote hepatocellular carcinoma by remodeling the tumor microenvironment.
Authors: Zhang Peng , Zhang Chengsheng
Published: July 2024

e16220

Background: Hepatocellular carcinoma (HCC) is a deadly disease with limited therapeutic options. Low expression of the LDHB has been associated with poor prognosis of HCC patients, but the role and underlying mechanism remains unclear. Methods: The HCC dada from The Cancer Genome Atlas (TCGA) and GEO were obtained to analyze the LDHB expression and DNA methylation levels. Next, the correlation between LDHB and Hallmark gene sets was analyzed by GO and KEGG. RNA-seq, Western blotting, Immunohistochemistry, and Bisulfite DNA sequencing were performed to explore the relationship between DNA methylation and LDHB expression. CCK8 and colony formation assay were used to evaluate the effect of overexpression of LDHB on the proliferation of hepatocellular carcinoma cells in vitro. Finally, the role of LDHB in HCC tumor immunity was assessed in multiple mouse models in vivo. Results: Here, we found that down-regulation of LDHB was coupled with the promoter hypermethylation and knocking down the DNMT 3A restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Notably, HCC patients with high LDHB expression responded better to immune checkpoint inhibitors. Finally, we demonstrated that there was no difference in the tumor growth rate between the LDHB-expressing tumors and the control tumors in immunodeficient BALB/c nude mice. However, the LDHB-expressing tumors were significantly inhibited in immunocompetent C57BL/6 mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Moreover, as compared with the LDHB+/+ mice, LDHB-/- mice showed promoted tumor growth in an NRAS/shp53 plasmid-induced primary liver tumor model. Conclusions: Overall, our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and target for HCC immunotherapy.
Immunotherapy responses in viral hepatitis-induced hepatocellular carcinoma: A meta-analysis.
Authors: Anwar Junaid , Arslan Hafiz Muhammad , Sarfraz Zouina , Abdelhakeem Ahmed , Zafar Maha , Saeed Anwaar
Published: July 2024

e16223

Background: The advent of immunotherapy has ushered in a paradigm shift in the management of advanced hepatocellular carcinoma (HCC). The distinctive etiological profiles of HCC, characterized by HBV predominance in Asia and HCV/nonviral prevalence in the West, may impart intricacies in the immunological milieu, thereby influencing treatment outcomes. This meta analysis delves into the immunotherapeutic outcomes in patients with hepatitis-induced HCC. Methods: A systematic search was conducted by applying the Boolean logic (and/or) in PubMed (MEDLINE), Embase and Cochrane Library until February 3, 2024. This study investigates the outcomes of patients with HCC complicated by hepatic infection, focusing on overall survival (OS) and progression-free survival (PFS). A meta-analysis was conducted, combining data from 6 studies for OS and 5 studies for PFS. Statistical analyses were conducted using R (v.4.3.2., Vienna). Results: A total of 6 clinical trials pooling in 2958 patients were included in this meta analysis. For OS, the random effects model estimated the cumulative survival across the studies to be 18.3950 months (95% CI [16.3869; 20.4032]). Quantifying heterogeneity revealed a tau-squared value of 5.1789 and Higgins I-squared of 72.7% [41.2%; 87.3%]. The test of heterogeneity indicated significant variability among the studies (Q = 21.99, df = 6, p = 0.0012). For PFS, the random effects model estimated the combined progression-free survival to be 5.9906 months (95% CI [4.2889; 7.6923]). Quantifying heterogeneity revealed a tau-squared value of 3.4995 and Higgins I-squared of 95.4% [91.9%; 97.4%]. The test of heterogeneity indicated significant variability among the studies (Q = 87.66, df = 4, p < 0.0001). Conclusions: The intricate relationship between HCC, hepatic infection, and treatment outcomes necessitates tailored therapeutic strategies for this patient population. Unveiling the heterogeneity in our analysis prompts a comprehensive exploration of potential factors, spanning both biological variances and clinical parameters. This inquiry fuels scientific discourse, urging an in-depth investigation into the immunological nuances influencing therapeutic responses in hepatitis-induced HCC. By addressing these complexities, we can optimize patient care and advance our understanding of effective treatment modalities for this challenging disease.
Differential IDH1 and IDH2 mutation-related landscape in intrahepatic cholangiocarcinoma.
Authors: Xu Shuaishuai , Qu Wenxin , Shen Yifei , Ruan Jian
Published: July 2024

e16224

Background: Patients with intrahepatic cholangiocarcinoma (ICC) are prone to recurrence and poor survival. Targeted therapy related to isocitrate dehydrogenase (IDH) is an extremely important treatment. IDH1 and IDH2 mutations are generally thought to have similar effects on the tumor landscape. However, it is doubtful whether these two mutations have exactly the same effects on tumor cells and the tumor microenvironment. Methods: All collected tumor samples were subjected to simultaneous whole-exon sequencing and proteome sequencing. Results: IDH1 mutations accounted for 12.2%, and IDH2 mutations accounted for 5.5%, all missense mutations. Tumors with IDH mutations had lower proportions of KRAS and TP53 mutations. Mutated genes were obviously enriched in the kinase pathway in the tumors with IDH2 mutations. The signaling pathways were mainly enriched in the activation of cellular metabolic activities and an increase of inhibitory immune cells in the tumors with IDH mutations. Moreover, tumors had unique enrichment in DNA repair in IDH1 mutants and secretion of biological molecules in IDH2 mutants. Inhibitory immune cells might be more prominent in IDH2 mutants, and the expression of immune checkpoints PVR and HLA-DQB1 were more prominent in IDH1 mutants. IDH mutations were more related to metabolism-related and inflammation-immune response clusters, and some belonged to the DNA replication cluster. Conclusions: These results revealed the differential IDH1 and IDH2 mutation-related landscapes, and we have provided an important reference database to guide ICC treatment.
Postoperative adjuvant hepatic arterial infusion chemotherapy combined with donafenib in hepatocellular carcinoma with solitary large tumor and microvascular invasion: A multicenter, prospective, single-arm, phase II trial.
Authors: Long Yin , Huang Ziqi , He Xiaodong , Huang Jue , Liao Jianguo , Zeng Yongyi , Tang Yunqiang , Zhang Lei
Published: July 2024

e16227

Background: Hepatocellular carcinoma (HCC) with solitary large tumor (≥ 5 cm) and microvascular invasion (MVI) was associated with high 5-year recurrence rate and poor survival prognosis. Postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) was found to improve the recurrence-free survival (RFS) with acceptable safety profiles in HCC patients with MVI. However, the prognosis of HCC who received adjuvant HAIC after hepatectomy still remain far from satisfactory. Several studies have shown that the combination of HAIC and tyrosine kinase inhibitors (TKIs) could exhibit a synergistic anticancer effect and improve the survival outcomes of advanced HCC. Thus, the present study was conducted to explore the efficacy and safety of adjuvant HAIC plus the novel multikinase inhibitor donafenib in HCC with solitary tumor ≥ 5 cm and MVI. Methods: This prospective, single-arm phase II study was conducted in three medical centers in China. HCC patients with both solitary tumor ≥ 5 cm and MVI, no evidence of recurrence at radiological follow-up at 4-8 weeks after hepatectomy, no previous treatment for HCC other than hepatectomy, Child-Pugh score A or B7 were enrolled. Eligible patients received one cycle of HAIC with oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX4), and followed by donafenib (200 mg orally twice daily) for up to 1 year until disease recurrence or unacceptable toxicity. The primary endpoint was 1-year recurrence-free survival rate (1-year RFS rate). Secondary endpoints included RFS, overall survival (OS) and safety. Results: A total of 18 patients were included for analysis. The median age was 59 years (range, 28–75), the median maximum tumor size was 7.0 cm (interquartile range [IQR], 6.2–7.8), 88.9% had low-risk MVI, 61.1% had Edmondson-Steiner grade III-IV and 44.4% had incomplete tumour capsule. As of November 27, 2023, 4 of 18 patients (22.2%) recurrenced and no deaths occurred with a median follow-up of 15.0 months (95% confidence interval [CI], 5.1–19.1). The 1-year RFS rate was 64.9% (95%CI, 39.2%–100%), and current immature median RFS was 14.3 months (95%CI, not available [NA], 11.2–NA). The most common treatment-related adverse events (TRAEs) were hand-foot skin reaction (72.2%), diarrhea (38.9%), decreased platelet count (22.2%), hypoalbuminemia (22.2%), and alopecia (22.2%). Grade 3 TRAEs occurred in 6 patients (33.3%), and no grade 4 or 5 TRAEs occurred. Conclusions: In this prospective study, the preliminary data indicated that HAIC combined with donafenib is an encouraging adjuvant therapy with well-tolerated safety profiles for HCC patients with solitary tumor ≥ 5 cm and MVI. Clinical trial information: NCT04962958 .