bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of recombinant human endostatin combined with whole-brain radiotherapy in patients with brain metastases from NSCLC.
Authors: Chen Lingjuan , Tong Fan , Peng Ling , Huang Yu , Yin Ping , Feng Yue , Cheng Shishi , Wang Jing , Dong Xiaorong
Published: June 2022

e21158

Background: Brain metastasis (BM) is the first cause of poor prognosis in non-small cell lung cancer (NSCLC) patients. To date, localized whole-brain radiotherapy (WBRT) is still the therapeutic option for patients with extensive BM. However, effectiveness is currently unsatisfactory. This study aimed to investigate the effects of Rh-endostatin combined with WBRT on NSCLC patients with BMs. Methods: 43 NSCLC patients with BMs were divided into two groups randomly. Rh-endostatin combination group (n = 19) received WBRT combined with Rh-endostatin, and radiation group (n = 24) received WBRT alone. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints were intracranial progression free survival (iPFS), overall survival (OS), objective response rate (ORR) and the change of cerebral blood volume (CBV), cerebral blood flow (CBF) of the contrast medium pre- and one month post-radiation. Results: Median progression-free survival (PFS) was 8.1 months in the Rh-endostatin combination group versus 4.9 months in the radiation group (95%CI: 0.2612-0.9583, p= 0·0428). Besides, median iPFS was 11.6 months in Rh-endostatin combination group versus 4.8 months in the radiation group (95%CI：0.2530-0.9504, p= 0·0437). Overall survival (OS) was 14.2 months in the Rh-endostatin combination group versus 6.4 months in the radiation group (95%CI：0.2508-1.026, p= 0·0688). Compared with radiotherapy alone, CBV and CBF in the Rh-endostatin combination group increased more significantly than before radiotherapy, indicating that Rh-endostatin may improve local blood supply and microcirculation. Conclusions: Rh-endostatin showed better survival and a safety profile, improved cerebral perfusion and increased the quality of life of NSCLC patients with BMs. Clinical trial information: NCT03614065.
Real-world assessment of clinical outcomes in NSCLC patients with MET exon 14 skipping mutation and brain metastases (BM) treated with capmatinib.
Authors: Paik Paul K. , Goyal Ravi K. , Cai Beilei , Price Mark , Davis Keith , Derrien Ansquer Valerie , Caro Nydia , Saliba Teddy Rassem
Published: June 2022

e21171

Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 NSCLC in the US in 2020 based on the GEOMETRY mono-1 trial data. Subgroup analyses from that study showed intracranial (IC) efficacy in pts with BM. However, there were no data on the effectiveness of capmatinib in pts with BM in the real-world setting; IC effectiveness is particularly challenging to study as many pts are also treated with radiation therapy (RT) to the brain. The current study examined real-world clinical outcomes of pts with NSCLC with MET exon 14 skipping mutation and BM who were treated with capmatinib, including those who were RT-naïve. Methods: A retrospective medical record review was performed by panel-based oncologists recruited nationwide in the US. Eligible pts were aged ≥ 18 years, had confirmed BM diagnosis and MET exon 14 skipping mutated NSCLC, started capmatinib therapy in any line following BM diagnosis (with ≥ 1 IC lesion ≥ 10 mm), and had a follow up of ≥ 6 months after starting capmatinib (except death). Modified (pseudo) RECIST and RANO-BM criteria were used for response assessments. Key outcomes were IC and systemic real-world best overall response rate (rwORR), disease control rate (rwDCR), progression-free survival (rwPFS), and time-to-treatment discontinuation (TTD) assessed separately for first-line (1L) capmatinib and immunotherapy (IO)-containing regimens alone or in combination with chemotherapy (CT). The analyses are descriptive in nature. Outcomes were also analyzed in RT-naïve pts (no prior/concurrent BM RT). Results: A total of 68 eligible pt charts were abstracted (median age at BM diagnosis, 64.3 years; 60.3% male; 72.1% treated in academic setting; 83.8% de novo metastatic). For the 1L therapy after BM diagnosis, 80.9% (n = 55) received capmatinib, 16.2% (n = 11) received IO-containing regimens, and 2.9% received CT alone; 29 pts were RT-naive. The IC rwORR in RT-naïve pts was 85.0% for capmatinib 1L and 11.1% for IO 1L (Table). In the overall cohort, the IC rwORR was 87.3% (rwDCR 96.4%) for capmatinib 1L and 27.3% (rwDCR 45.5%) for IO 1L. Median systemic rwPFS was 14.1 months for capmatinib 1L and 5.1 months for IO 1L. The 1-year systemic rwPFS rate was 70.8% for capmatinib 1L and 18.2% for IO 1L. TTD was 13.2 months for capmatinib 1L and 5.1 months IO 1L. Conclusions: This study shows a substantial systemic and IC effectiveness associated with capmatinib 1L use in pts with NSCLC with MET exon 14 and BM in the real-world setting. These findings remain true in RT-naïve pts.[Table: see text]
Overall survival of patients with chronic obstructive pulmonary disease receiving immunotherapy for non-small cell lung cancer: A population-based analysis in Ontario, Canada.
Authors: Chan Sze Wah Samuel , Goffin John R. , Pond Gregory Russell
Published: June 2022

e21172

Background: Outside of clinical trial eligibility criteria, there is limited data to guide the selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) therapy. Chronic obstructive pulmonary disease (COPD) and lung cancer are associated, independent of smoking history, with a common background of chronic inflammation. Previous studies have demonstrated that COPD is a negative prognostic marker for NSCLC, but the clinical benefit of ICI in patients with NSCLC and COPD is unknown. Methods: A population-level administrative data analysis of Ontario patients was performed through the Institute of Clinical Evaluative Sciences (ICES) Data Analytic Services. All patients with NSCLC diagnosed between Jan 2010 and Dec 2020 and treated with immune-checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) were included. Demographics, comorbidity and marginalization scores, and COPD status were extracted along with outcome information. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared between patients with or without COPD using Cox proportional hazards regression. The frequency of patients requiring hospitalization and duration of treatment was also estimated and compared using the chi-square and Wilcoxon rank-sum test. Results: 73331 NSCLC patients were identified, of which 4.5% (n = 3285) patients received ICI. COPD patients were less likely to receive immunotherapy (3.8% vs. 5.1%, p < 0.001). Among those receiving an ICI, 41% (n = 1362) of patients had a diagnosis of COPD prior to NSCLC diagnosis. Median (95% CI) OS was 17.3 (16.6 to 18.2) months for patients with COPD and 16.9 (16.2 to 17.8) for patients with no known COPD, which was not significantly different in univariate (hazard ratio = 0.96, 95% CI = 0.89 to 1.04, p = 0.35) or multivariate analysis (HR = 0.96, 95% CI = 0.89 to 1.05, p = 0.40). The 5-year survival was also similar between both groups (6.7% vs. 6.5%). The rate of hospitalization within 6 months (18.4% vs 18.0%, p = 0.82) and the duration of immunotherapy treatment (median = 80 vs 71 days p = 0.23) did not differ for the COPD vs. non-COPD groups. Conclusions: Despite an expectation of frailty, our data suggest that NSCLC patients with COPD receiving ICI maintained similar durations of treatment and similar rates of hospitalization, with no significant difference in survival time, compared with those without COPD. While a treatment selection bias cannot be excluded in this non-randomized dataset, our data suggest that a diagnosis of COPD itself should not be considered a contraindication to immune checkpoint inhibitor use in NSCLC.
LAG3-PD1 or CTLA4-PD1 inhibition in advanced melanoma: Indirect cross comparisons of the CheckMate-067 and relativity-047 trials.
Authors: Nie Run-Cong , Wang Yun , Yuan Shu-Qiang , Chen Yingbo , Zhou Zhiwei
Published: June 2022

e21511

Background: There remain unmet needs to identify novel immune checkpoint inhibitors to improve the benefit-risk profile of immunotherapy for advanced melanoma. The comparison between LAG3-PD1 inhibition and CTLA4-PD1 inhibition was lacked. To compare the inhibition of lymphocyte-activation gene 3 (LAG3) plus programmed cell death 1 (PD-1) versus the inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) plus PD-1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) data were extracted from the KM plots using a graphical reconstructive algorithm through eligible. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. The primary endpoint was progression-free survival. Results: The CheckMate-067 (N = 630) and RELATIVITY-047 (N = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab-relatlimab (LAG3 inhibitor) versus nivolumab-ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab-relatlimab versus nivolumab alone was 2.35 (95% CI 0.77 to 3.94) months, compared with 1.87 (95% CI 0.25-3.49) months for nivolumab-ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab-relatlimab had earlier PFS benefits than those with nivolumab-ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab-relatlimab and 55.0% of patients using nivolumab-ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and that LAG3-PD1 inhibition tended to exhibit earlier survival benefit and lesser TRAEs.
The role of surgery (metastasectomy) in advanced BRAF positive melanoma during modern therapy.
Authors: Orlova Kristina V. , Ledin Evgeny , Zhukova Natalia V. , Orlova Rashida , Protsenko Svetlana , Novik Alexey , Moiseenko Fedor Vladimirovich , Naskhletashvili David , Demidov Lev V.
Published: June 2022

e21512

Background: Improved overall survival in patients undergoing metаstasectomy for melanoma have been reported in several retrospective studies before era of modern therapy in melanoma. Rapid progress in BRAF and MEK targeted therapy (TT) and immunotherapy (IT) has led to significant improvements in objective response rates and survival rates in advanced melanoma patients. Unfortunately, part of patients have a resistance to modern therapy in one or more lesions. In 2019 Nelson DW et al published data when surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%, p = 0.049). But data about modern therapy in BRAF + advanced melanoma with metastasectomy during therapy are limited. Methods: We conducted an observational retrospective chart review study and evaluated a subset of patients which underwent surgery (metastasectomy) with V600 BRAF-mutant advanced melanoma, who received therapy in a real-world setting in Russia. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Results: The observed population included 382 patients in Russia. The date of the first enrollment after all approvals was 8 October 2018, and the date of the last completed register was 27 April 2019. Among 382 patients, 107 (28%) patients received surgical treatment for advanced melanoma during modern therapy (removal of metastases from the brain, lungs, soft tissues and other organs). Surgery during first line therapy was performed in 60pts (56%), as second – in 25pts (23.4%) and third or higher line in 22pts (20.6%). Comparison of overall survival curves for all patients depending on the surgical treatment showed that the survival in the subgroup of patients with the presence of surgical treatment was higher than among patients who did not undergo metastasectomy: 24-months OS was 76.7 (95%CI, 65.6 – 84.6) and 53.7% (95%CI, 46.4-60.4), p = 0,0027). Conclusions: Our findings suggest that resection of distant metastases associated with improved overall survival despite all limitations in retrospective nature of the study. While modern systemic therapy have improved outcomes in advanced melanoma, metastasectomy remains associated with favorable survival. Surgery have to be a part of multidisciplinary care for patients with advanced melanoma.
A phase Ia/Ib study evaluating the safety and efficacy of intratumorally administrated OH2, an oncolytic herpes simplex virus 2, in unresected stage IIIC to IV melanoma patients.
Authors: Wang Xuan , Cui Chuanliang , Lian Bin , Si Lu , Chi Zhihong , Sheng Xinan , Kong Yan , Hu Han , Gu Xiangyong , Li Caili , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Liu Binlei , Guo Jun
Published: June 2022

e21537

Background: OH2 is a herpes simplex virus type 2-derived oncolytic virus. It was engineered to selectively replicate within tumors and express granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance tumor-specific immune responses. We conducted a phase Ia/Ib clinical trial to evaluate the safety and preliminary efficacy in unresected stage IIIC to IV melanoma patients (pts). Methods: In this phase Ia/Ib trial, we enrolled pts aged between 18-75 with histologically confirmed unresectable stage III or distant metastatic melanoma failed with prior therapies. In phase Ia, nine pts were in the single-dose group, where 3 dose levels (106, 107, and 108 CCID50/mL) of OH2 were assessed. And six pts were in the multi-dose group testing multiple administration regimens. The recommended doses were then expanded in phase Ib. The primary objective was the safety and tolerability of OH2 injection as defined by the dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in phase Ia. Antitumor activity was assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase Ib. The clinical trial information: NCT04386967. Results: 35 pts were enrolled between November, 2018 and December, 2021. Among this, 37.1% were stageIVM1b-M1c; 88.6% had received of previous treatments: In the phase Ia study, OH2 was well-tolerated, neither serious AEs (SAEs) nor death were reported. No patient experienced TEAE leading to early withdrawal. Most TRAEs were Grade 1 in severity. There were no Grade 3 or above TRAEs. No DLTs were recorded, and the most frequent TRAEs were pyrexia (80%), Skin depigmentation (26.7), Oedema peripheral (26.7%), which were similar in three different doses of the single-dose group. The one-year survival rate was 93.3 % with median overall survival (mOS) being 20.8 months (still ongoing). In the phase Ib study, five pts achieved immune-partial response/partial response. The overall response rate (ORR) was 25.0 % and the five pts had ongoing responses. Six pts experienced stable disease (SD) with a disease control rate (DCR) being 55 %. The durable response rate (partial or complete response for ≥ 6 months) was 60 %. There were seven III-IV1a pts prior treated with anti-PD-1 antibodies. Three of the seven pts achieved iPR/PR (42.9 %), with DCR being 85.7 %. Conclusions: OH2 oncolytic virotherapy showed a favorable safety profile with no DLTs. And exhibited durable antitumor activity in pts. It warrants further investigation for the treatment of pts with unresectable melanoma. Clinical trial information: NCT04386967.
Validation of the 31-gene expression profile test to stratify melanoma-specific survival in an unselected, prospectively tested cohort of patients with stage IIB-III cutaneous melanoma.
Authors: Hong Young , Kurley Sarah J. , Bailey Christine N. , Martin Brian , Goldberg Matthew S. , Petkov Valentina I. , Covington Kyle R. , Zakharia Yousef
Published: June 2022

e21538

Background: Given recent FDA extended approval of Pembrolizumab for stage IIB-IIC cutaneous melanoma (CM) patients, it is critical to risk-stratify patients to balance potential benefits versus toxicities of adjuvant therapy. The 31-gene expression profile (31-GEP) is a validated test for CM for risk of recurrence or metastasis prognosis in patients with stage I-III CM. A low-risk (Class 1A) 31-GEP result is associated with lower recurrence risk and higher melanoma-specific survival than an intermediate (Class 1B/2A) or high-risk (Class 2B) result. To validate the 31-GEP’s ability to stratify patients’ risk in an unselected, prospectively tested cohort of therapy-eligible CM patients, we collaborated with the National Cancer Institute and the Surveillance, Epidemiology, and End Results (SEER) program. Methods: A linkage was conducted between SEER registries’ CM cases diagnosed 2012-2018, and 31-GEP tested patients between 2013-2020. A de-identified dataset was used for the analysis. Kaplan-Meier analysis with log-rank test was used to analyze patient melanoma-specific survival (MSS) in the overall cohort and the subset of patients with potential adjuvant therapy access: stage IIB-III melanoma (n = 615). Results: In the overall cohort of patients (N = 5,225), those with a 31-GEP Class 1A result had higher 3-year MSS than patients with a Class 2B result (99.7% vs. 90.4%, p < 0.001). In multivariable Cox regression analysis, a Class 2B result was an independent significant predictor of MSS (HR = 5.71, p = 0.01), as were age (HR = 1.05, p < 0.001), SLN positivity (HR = 2.42, p = 0.02), and T2b (HR = 8.29, p = 0.025) and T4b (HR = 11.99, p = 0.009) tumors. In the subset of patients with stage IIB-III melanoma, those with a 31-GEP Class 1A result had higher 3-year MSS (98.8% vs. 82.4%, p = 0.02) than patients with a Class 2B result. Patients with a Class 2B result had a five and a half times higher event rate than those with a Class 1A result for MSS (5.5% [21/382] vs. 1.0% [1/105]). Conclusions: In a large, unselected, prospectively tested cohort of patients with stage I-III CM, the 31-GEP stratified patient risk of dying from melanoma, validating previous studies. While the 31-GEP identified a subgroup (Class 1A) of traditionally high-risk patients (stage IIB-III CM) who had a > 98% MSS over three years, it can also facilitate identifying patients who could warrant earlier adjuvant therapy with a higher 31-GEP class designation.
Cemiplimab in advanced cutaneous squamous cell carcinoma: A real-world experience of outcomes and safety.
Authors: Badami Sunil , Mazloom Anita , Howard John Harrison , Liles J. Spencer , Alkharabsheh Omar , Persing Brian Edward , Cameron Daniel , Huddleston Adam , Gilbert Robert , Venkatesh Kshithi , Prodduturvar Pranitha
Published: June 2022

e21545

Background: Nearly 1.5 million cases of cutaneous squamous cell cancer (cSCC) are diagnosed annually in the United States. Approximately 1% of cases are in the advanced unresectable stage. The standard of care in unresectable advanced disease is immunotherapy with anti-PD-1 agents. Cemiplimab, an anti-PD-1 antibody, was approved by the Food and Drug Administration in 2018. We present real-world clinical data from a single institution on outcomes and safety for patients treated with cemiplimab for metastatic and unresectable cSCC. Methods: We conducted a retrospective cohort analysis of patients treated with cemiplimab (350 mg every 3 weeks) for advanced cSCC from September 2018 until December 2021. Data included patient demographics, tumor characteristics, and treatment course. Patients who received at least 1 dose of cemiplimab and one clinic follow-up were included for analysis. Clinical response and adverse events (AE) were evaluated. Results: Of the 26 patients treated, 84% were male (n = 22), and 16% were female (n = 4) with a median age of 74 years (39-94). Twenty-three (23) patients were included in the final analysis as 3 patients transferred care to an outside facility and were not available for follow-up. Nineteen (19) patients (73%) had locally advanced disease and 7 (27%) had metastatic disease. The most common site of the primary tumor was head/neck (85%, n = 22) with all remaining cases on the trunk/extremities (15%, n = 4). Patients received a median of 7 doses of cemiplimab (range 1- 46). The median time to first response was 1.7 months which required a median of 2.5 doses. An objective clinical response defined as complete response (CR) or partial response (PR) was seen in 18/23 (78%) patients, of whom 8/23(35%) were CR and 10/23 (44%) PR. The ongoing response was noted in 6/23 (27%) with continued treatment. Treatment was well-tolerated with 6/23 (26%) adverse events (AE) all of which were grade 1 or 2: 1 (4%) grade 1 pruritus, 5 (21.7%) grade 2. Of the 5 grade 2 AEs, 1 was infusion-related, 2 hypothyroidism, 1 dermatitis, 1 rheumatoid arthritis flare. No grade 3-5 AEs were noted. Conclusions: To the best of our knowledge, this is the first real-world outcomes study of advanced cSCC patients treated with cemiplimab in the United States. The overall efficacy, response rate, and safety profile were better in comparison to the results of the EMPOWER-CSCC-1 trial.[Table: see text]
Long-term toxicities with immune checkpoint inhibitor (ICI) in melanoma patients.
Authors: Tong Justin , Kartolo B. Adi , Yeung Cynthia , Hopman Wilma M. , Baetz Tara D.
Published: June 2022

e21549

Background: The incorporation of ICI into the treatment of melanoma has greatly improved patient outcomes, but this benefit has come at the cost of exposing patients to immune-related adverse events (irAEs). A wide spectrum of irAE types has been described, and severity is known to vary from minor to life-threatening; however, the literature to date on the chronicity of irAEs is limited. Objectives: To characterize the long-term and permanent irAEs associated with ICI treatment in patients with melanoma, the treatment of irAEs and the association with survival outcomes. Methods: We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥6 months), transient (resolution over a period < 6 months), or no irAEs. Overall survival was evaluated for those patients that were treated in the metastatic setting with PD1 inhibitor monotherapy. Results: Thirty-eight patients were treated in the adjuvant setting and 123 patients were treated in the metastatic setting. A total of 279 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, 15 (9.3%) experienced long-term irAEs as their longest-lasting toxicity, 34 (21.1%) developed transient irAEs only, and 46 (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (35.5%) or skin-related (32.7%). Grade ≥3 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still on treatment for long-term or permanent irAEs 6 months or more following completion of ICI therapy, including 23 patients on thyroid replacement and 22 on oral steroids. ICI treatment was temporarily interrupted for 63 (22.6%) irAEs and permanently discontinued due to irAE in 38 (13.6%) patients. Subgroup analysis of patients who received single-agent ICI in the first-line palliative setting reveals that those with longer-duration irAEs had a significantly longer median overall survival. Conclusions: Despite the significant benefits, treatment with ICIs in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients. The risk of long-term toxicity should therefore be discussed when obtaining consent for treatment. As these treatments are being used more commonly in the adjuvant setting, the impact of survivorship and the long-term management of these toxicities is increasingly important.
Melanoma: Morphological essays of energetic tumor death under the influence of live mitochondria.
Authors: Shikhlyarova Alla I. , Frantsiyants Elena M. , Kaplieva Irina V. , Neskubina Irina V. , Cheryarina Natalia D. , Trepitaki Lidia K. , Surikova Ekaterina I. , Bandovkina Valeria A. , Przhedetskiy Yuriy V. , Pozdnyakova Viktoria V. , Przhedetskaya Viktoria Yu , Zakharova Natalia A. , Khokhlova Olga , Kit Oleg I.
Published: June 2022

e21561

Background: Global trials form a new mitochondrial paradigm for suppressing the growth of malignant tumors. The unique role of mitochondria (MC) in the processes of metabolism, proliferation, and cell death was proven by the establishment of signaling pathways and critical conditions for the self-organization and degradation of MC. There are still many unsolved problems in the development of a new strategy, including the absence of an integral picture of morphological changes in the tumor under the influence of mitochondrial therapy (MCT), and this determined the purpose of the study. Methods: The study included male and female Balb/c Nude mice weighing 21-22 g. B16/F10 melanoma was transplanted to mice subcutaneously, and suspension of live liver MC was injected intraperitoneally. MC were isolated by differential centrifugation (Avanti J-E high-speed centrifuge, BECKMAN COULTER, USA). After an MCT cycle, the melanoma structure was examined with hematoxylin and eosin staining and light microscopy (LEICA DM LS2). Results: Control samples of melanoma (without MCT) showed abundant vascularization with dense growth of epithelial-like cells with branched cytoplasm, an eccentric nucleus and a moderate content of melanin pigment. Massive hypoxic death, autolysis and autoxidation of tumor cells were registered in male mice after MCT, as well as matrix hyalinosis, pronounced subcutaneous tissue edema with segregation and necrotization of fat accumulations. The formation of a large cavity filled with detritus indicated signs of total tumor necrosis and ischemia. The accumulation of hyperchromic granules indicated the activation of granulocytic and phagocytic elements in the mechanism of tumor regression. Female mice showed rare small areas of necrosis, as well as pronounced fragmentation of nuclei and cytoplasm of cells in most fields of view induced by bioenergetic hypoxia, with the formation of apoptotic bodies. Along the edge of the cells subjected to autophagocytosis, melanin accumulated as it left the cells and accumulated as large granules, while small ones filled the space of the vessels. The process of melanoma regression was confirmed by a significant increase in free fibrous areas, where only faint cell shadows remained. Conclusions: The initial state of melanoma degrades under the influence of MCT inducing bioenergetic hypoxia in male and female Balb/c Nude mice in different ways. Gender, in fact, hormonal differences determine the dominance of different ways of cell death, necrosis (in males) and apoptosis (in females), while maintaining the MCT access to the processes of preventing tumor growth.
Mitochondrial therapy can inhibit melanoma development.
Authors: Frantsiyants Elena M. , Neskubina Irina V. , Shikhlyarova Alla I. , Cheryarina Natalia D. , Surikova Ekaterina I. , Bandovkina Valeria A. , Nemashkalova Ludmila A. , Kaplieva Irina V. , Trepitaki Lidia K. , Kachesova Polina S. , Kuchkina Ludmila P. , Volkova Viktoriya L. , Engibaryan Marina A. , Ulianova Yulia V. , Kit Oleg I.
Published: June 2022

e21571

Background: Mitochondria of tumor cells undergo adaptive changes for even more active reproduction of tumor cells in the acidic and hypoxic microenvironment of tumor tissue. The purpose of this study was to evaluate antitumor effect of mitochondrial therapy in BALB/c Nude mice of both genders with B16/F10 melanoma growth. Methods: Male (n = 10) and female (n = 10) BALB/c Nude mice were injected subcutaneously with 0.5 ml of a suspension of B16/F10 mouse melanoma tumor cells in saline at a dilution of 1:20. Mitochondria (MC) were isolated from rat liver. 24 hours after subcutaneous transplantation of B16/F10 melanoma, mice were intraperitoneally injected with freshly isolated mitochondria (3.3 mg of protein per animal in 0.3 ml of saline). Further, mitochondrial therapy (MC therapy) was carried out according to the scheme on days 3, 5, 9, 13, 16, 19, 21. Male BALB/c Nude mice with subcutaneous inoculation of B16/F10 melanoma receiving intraperitoneal injections with 0.3 ml of saline served as controls. Results: Subcutaneous tumors in mice of both genders could be determined on the 5th day from the moment of tumor transplantation. In males, the regressive effect of MC therapy was recorded from the 8th day of tumor growth. The average tumor volume in males with MC therapy on day 8 was 3.0 times less than in the control group. On days 12 and 15, the regressive difference in tumor volumes between the groups was 1.8 times (p < 0.05) (MC therapy). On day 19, a slower tumor growth was recorded in the group with MC therapy, where the tumor volume was 2 times lower compared to the control volumes. At the end of the experiment on day 22, the difference in the average tumor volumes was 3.2 times, i.e. a significant inhibition of tumor growth was determined in males treated with MC therapy. A sizeable tumor node in females treated with MC therapy formed longer than in males, remaining as a flat tumor spot for up to 8 days. The inhibition of the growth of a large tumor node was determined on day 12 of melanoma growth, and the difference with the control values was 1.8 times (p < 0.05). On day 15, the tumor volumes in females with MC therapy decreased by 2.2 times compared with the control values, on day 19 - by 2.1 times. As a result, by the end of the experiment (day 22), the difference with the control group was 2.7 times. Conclusions: MC therapy inhibits the growth of B16/F10 melanoma in male and female BALB/c Nude mice. Formation of a sizeable tumor node and the start the tumor growth inhibition differs in time depending on the gender of experimental animals.
Evaluation of treatment patterns in patients with BRAF-mutant cutaneous melanoma in adjuvant setting in real practice.
Authors: Samoylenko Igor , Stroganova Anna , Shakhray Ekaterina , Orlova Kristina V. , Akhmetianova Angelina , Demidov Lev V.
Published: June 2022

e21573

Background: Mutation in BRAF is a crucial biomarker for treatment choice in patient with locally advanced or metastatic melanoma. In patient with BRAF wild-type (WT) melanoma aPD1 is the preferred treatment regimen. In patients with BRAF V600 mutant melanoma combined targeted therapy (cTT) could also be chosen as adjuvant treatment, which significantly improves OS. Methods: We conducted a retrospective continuous study of all melanoma patients, who were tested for BRAF mutation by RT-PCR in 2020 (COIVD-19 pandemic year) in our institution and analyzed adjuvant therapy options they received. Patient demographics, mutational status, disease stage, treatment regimens and treatment outcomes were collected from electronic medical records. Results: Between January 2020 and December 2020, tumor samples from 297 pts were tested for BRAF mutations. The mean pts age was 58.2 years (95% CI 51.2 to 60.3) and 130 (43.7%) were male. BRAF mutations were detected in 147 (49.5%) patients. Most common mutation was V600E (140 out of 147 samples, 88.4%) and V600K (13 out of 147, 8.84%). We also found K601N, K601E, L597R and V600M mutations (in one sample each). Among 150 BRAF wild type samples 44 were also tested for NRAS mutations and in 13 (29.54%) pts NRAS mutations were detected: Q61R – in 6 (46.15%) pts, Q61L – in 2 (15.38%) pts, Q61K – in 3 (23.08%) pts, G12E – in 1 (7.69%) pt, and G12D - in 1 (7.69%) pt . Also among 150 BRAF wild type samples 56 were tested for KIT mutations and only one sample were found to harbour D186V mutation . Among BRAF-positive pts at time of the genetic test performed stage I CM had 11 (7.48%) out of 147 pts, stage II - 13 (8.84%) pts, stage III - 67 (45.57%) pts, and stage IV - 43 (29.25%) pts. In 13 (8.84%) pts stage could not be clearly identified. In most cases (32 out of 67, 47.76%) monotherapy with aPD1 was given as adjuvant treatment in stage III pts where as only 6 (8.95%) patients received cTT, 7 pts (10.41%) received IFN-alfa and 22 pts (32.84%) received no or were given with other treatment (Table). Median DFS did not differ significantly between treatment cohorts. Conclusions: In our retrospective study we found that among stage III BRAF-mutant patients monotherapy with aPD1 was the most common adjuvant treatment regimen. In some patients with stage III disease IFN-alfa is still given. More studies are needed to define best adjuvant treatment for BRAF mutant stage III melanoma pts.[Table: see text]
A single arm phase 2 study of talimogene laherparepvec in patients with low-risk invasive cutaneous squamous cell cancer. interim analysis.
Authors: Curiel Clara N , Stratton Delaney , Cui Haiyan , Roe Denise , Arif Tiwari Hina , Sundararajan Srinath
Published: June 2022

e21583

Background: A compromised immune-surveillance plays an important role in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). Talimogene laherparepvec (TVEC) is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells, and induces production of GM-CSF to enhance systemic antitumor immune recognition. This proposed mechanism of action supports the innovative approach to implement TVEC in the management of cSCC. Methods: Immunocompetent patients > 18 years of age and diagnosed with at least one > 0.5 cm to < 5.0 cm, primary and histologically confirmed well-moderate differentiated cSCC, without evidence of perineural or vascular invasion were eligible to participate. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions include target injected lesions (TILs) and target non-injected lesions (TNILs). A total of up to 5 TILs were selected per subject. If feasible, target non-injected lesions (TNILs) were also selected in eligible participants to evaluate for abscopal effect. Every TIL was injected up to 4 times based lesion diameter according to current TVEC approved protocol administration and followed for 1yr after the 1st injection. The primary endpoint of the study was to evaluate the overall response rate (ORR), defined as the proportion of subjects who achieved complete response (CR) and partial response (PR) in the TILs. Safety and adverse effect profile (AEs), duration of ORR, time to response (TTR), durable response rate, and time to progression, were the secondary endpoints included. A Simon 2 stage design was used. Total sample size was calculated to be 20 subjects. Seven subjects were recruited for stage 1 with a plan to recruit an additional 13 patients if five or more subjects met the primary endpoint in stage 1. Results: The interim analysis was conducted after the 7th participant completed Visit 8 (352-266 days from study initiation). For the primary endpoint, all 7 participants achieved an overall complete response (100%; 95% CI: 59.0-100%). NCI CTCAE (v. 4.0) was used to assess the safety and adverse effect profile. All AEs ranged from grades 1-2, and most commonly experienced transient fatigue (n = 3/7), flu like symptoms (n = 2/7) and headaches (n = 2/7). The mean time to response was 43.4 (SD 31.6) days and for duration of ORR 190.0 days (SD 39.3) at the time of analysis. The 2 TNILs evaluated in the interim analysis also demonstrated 100% CR (95% CI: 15.8-100%). Conclusions: TVEC showed extremely impressive ORR for patients with cSCC with a 100% CR in stage 1 of our pilot study. AE profile of TVEC was mild and was well tolerated. Completion of the study will further assess this high response rate. Clinical trial information: 03714828.
Age associated mutations in cutaneous squamous cell carcinomas (CSCC).
Authors: Kumar Priyanka , Brazel Danielle , Doan Hung , Moyers Justin Tyler
Published: June 2022

e21592

Background: Cutaneous squamous cell carcinoma is the second most common skin cancer globally. However, advanced or metastatic disease is rare and is primarily a disease of the elderly or immunocompromised. The relationship between age and the presence and frequency of poor prognostic indicators (TP53 or TERT promoter mutations) and therapeutic targets (ERBB4) is unknown. Methods: We queried the American Association for Cancer Research (AACR) Project GENIE for cutaneous squamous carcinomas accessed through cBioPortal. We gathered genomic alterations and demographic data by age groups at time of tumor sequencing (< 65years, 66-80 years, > 81 years). Genomic alterations were assessed for function by OncoKB. Descriptive variables were presented as frequencies and compared by Chi squared method. Results: Among 1,025 non-melanoma skin cancer samples, 285 total CSCC samples were identified within the database. By age groups, 104 (36%) samples were from those 65 or younger, 127 (45%) in those 66-80 years, and 54 (19%) in those older than 80 years. Prevalence of TP53 mutations increased with age, 72% in < 65, 88% in 66-80, and 93% in > 80 (p < 0.001). Nearly all TP53 mutations were functional (96%; 228/237). ROS1 mutations also significantly increased in prevalence with older age, 27% in those < 65, 37% in 66-80, and 48% in > 80, respectively (p = 0.03). However, all ROS1 alterations were variants of unknown significance (VUS). TERT alterations also increased in frequency with more advanced age, with 32% in those < 65, 45% in 66-80, and 46% in > 80 (p = 0.078). ERBB4 alterations also increased in prevalence with age, 28% in those < 65, 30% in 66-80, 33% in > 80 groups (p = 0.71), however only 9/130 (6.9%) were known oncogenic alterations. Conclusions: Tumor suppressor genes (such as TP53, TERT, KMT2D, NOTCH1, NOTCH2, and FAT1) were frequently altered in CSCC among the AACR GENIE population, while actionable mutations and gain of function driver mutations (such as ERBB4) were infrequent.
Overall survival (OS) in metastatic uveal melanoma: A summary of recent prospective trials.
Authors: Piulats Josep M. , Shoushtari Alexander Noor , Ochsenreither Sebastian , Abdullah Shaad Essa , Holland Chris , McCully Michelle L. , Baurain Jean-Francois
Published: June 2022

e21598

Background: Metastatic uveal melanoma (mUM) historically has a poor prognosis where chemotherapy and checkpoint blockade, including combination, has had no impact on OS. Tebentafusp (tebe), a TCR bispecific (gp100 x CD3), is the first therapy to demonstrate an OS benefit in a mUM randomized trial (IMCgp100-202) against pembrolizumab (pembro), ipilimumab (ipi) or dacarbazine. Here we present a summary of OS from recent prospective trials in mUM in both previously untreated (1L) and previously treated (2L+) mUM including cross trial comparison with checkpoint blockade combination. Methods: A literature review of prospective Ph2/3 clinical trials of systemic therapies in mUM published recently (2019-2021) identified 8 trials: in 1L mUM (n = 2) a randomized Ph3 of tebe (N = 252) vs investigator’s choice (IC; N = 126) of pembro, ipi or dacarbazine (IMCgp100-202) and a single arm Ph2 of nivolumab (nivo) + ipi (N = 52; Piulats, 2021) (Table); in 2L+ mUM (n = 1) a single arm Ph2 of tebe (N = 127; IMCgp100-102); and in mixed line mUM (n = 5) a randomized Ph2 of cabozantinib (N = 31) vs chemotherapy (N = 15; Luke, 2019), a single arm Ph2 of nivo + ipi (N = 35; Pelster, 2021), a single arm Ph2 of pembro + entinostat (N = 29; Ny, 2021), a single arm Ph2 of glembatumumab (N = 37; Hasanov, 2020), and a single arm Ph2 of IMC-A12 (IGF-1 receptor inhibitor; N = 18; Mattei, 2020). The PUMMA (Khoja, 2019; N = 912) and Rantala, 2019 (N = 2494; n = 510 1L pts) meta-analyses were included to provide historical benchmarks for OS. Results: In previously untreated mUM, 1-yr and median OS were 73% and 21.7 months for tebe, 59% and 15.7 months for pembro, 52% and 12.7 months for nivo + ipi and 45% and 11.3 months for conventional chemotherapy. In previously treated mUM, 1-yr and median OS were 61% and 16.8 months for tebe, 34% and 7.0 months for checkpoint inhibitors, and 43% and 10.5 months for conventional chemotherapy. In mixed line (1L+) mUM, 1-yr and median OS were 56% and 19.1 months for nivo + ipi and 59% and 13.4 months for pembro + entinostat, 13.8 months for IMC-A12, 11.9 months for glembatumumab and 6.4 months for cabozantinib. Related AEs (any grade) leading to discontinuation and death for tebe were 2% and 0% vs 5% and 0% for IC control, and 23% and 3.8% for nivo + ipi in 1L pts. Conclusions: Tebe is the only therapy demonstrated to prolong OS in mUM. The 1-yr OS for tebe in 1L and 2L+ is superior to all recent published studies, including nivo + ipi. Both tebe and checkpoint combination therapy have high rate of any grade AEs, although checkpoint combination has a higher rate of treatment related discontinuations and deaths.[Table: see text]
Systemic bevacizumab for aggressive recurrent respiratory papillomatosis: A single center experience of five cases.
Authors: Liu Zengjun , Xiao Yang , Xu Jing , Zhu Dongyuan
Published: June 2022

e22005

Background: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven benign neoplasm, affecting larynx, trachea, and even lung, leading to voice disorders, airway obstruction, and post-obstructive pneumonia. Currently, there is no curative therapy for RRP.Patients require frequent debulking operations for symptomatic palliation. However, several case reports documented promising results on inhibition of vascular endothelial growth factor (VEGF) by systemic administration of bevacizumab. Methods: We retrospectively analyzed clinical, radiological, and bronchoscopy data of aggressive RRP patients treated with systemic bevacizumab since January 2021. Results: 5 consecutive patients were included. Median age (range) was 8 (4-30), 60% (3/5) were male. The locations of RRP were as follows: localized in the major airway (including vocal cords, larynx, trachea, and main bronchus), n = 1; extensive from major airway to lung parenchyma, n = 4. The median number (range) of local interventions was 8 (2-17) throughout the 12 months prior to bevacizumab treatment. The administration of systemic therapeutic agents, such as HPV vaccine and interferon had been tried in two patients. Bevacizumab was administered at a dose of 5 mg/kg (n = 4) or 7.5 mg/kg (n = 1) intravenously. Treatment intervals were initiated every 2-3 weeks and subsequently extended after achieving the maximum response. The patients received median 6 cycles of bevacizumab (range 4-7). The bevacizumab was given as adjuvant therapy in 2 patients on the 3rd and 5th day after laser operation, and as salvage therapy in the other 3 patients. All patients with major airway RRP displayed improvement in disease burden. No patients required surgery during a medain 7 (range 3-8) months follow up periods after initiating bevacizumab treatment. A rapid response was demonstrated in a patient with long-standing extensive pulmonary disease. Except from mild and transit abdominal pain and hemoptysis in 2 patients, systemic treatment with bevacizumab was well tolerated. Conclusions: Inhibition of VEGF by systemic bevacizumab seems to be a well tolerated and effective treatment option for localized and extensive forms of RRP.
Lerociclib diminishes stemness in pediatric sarcoma cell lines.
Authors: Hutchins Sara , Bownes Laura V. , Quinn Colin H. , Julson Janet R. , Stewart Jerry E. , Aye Jamie , Yoon Karina J , Beierle Elizabeth A.
Published: June 2022

e22010

Background: The outcomes for children with osteosarcoma and synovial sarcoma remain poor and are even worse for metastatic or relapsed disease. Those who do survive frequently suffer from long-term toxicities from current standard-of-care therapies. It is evident novel therapeutics are warranted to improve the outcomes for patients with these difficult tumors. Stem cell-like cancer cells (SCLCCs) are a subpopulation of tumor cells thought to be responsible for treatment resistance, development of metastases and tumor recurrence, making the targeting of this cell population critical. We sought to evaluate the effect of lerociclib, a CDK4/6 inhibitor, on pediatric sarcoma cell stemness. Methods: We investigated two established human osteosarcoma cells lines (U2-OS and MG-63), two metastatic synovial sarcoma patient-derived xenografts (PDXs) (COA-30 and COA-79) and a metastatic epithelioid sarcoma PDX (COA-171). Cells were treated with the CDK4/6 inhibitor, lerociclib, at concentrations below the known LD50. Synovial sarcoma stemness markers Octamer-binding transcription factor 4 (Oct4), homeobox protein Nanog, SOX 2 and nestin were evaluated by qPCR. CD117, a marker of stemness in osteosarcoma cells, was examined by flow cytometry. Finally, long-term passaged U2-OS and MG-63 cells were placed in low attachment serum-free conditions, and tumorsphere formation was evaluated using extreme limiting dilution assay (ELDA) in all cell lines. Results: Lerociclib treatment significantly decreased abundance of Oct4 (by 54%), Nanog (by 29%), SOX 2 (by 60%) and nestin (by 63%) mRNA in COA-30 synovial sarcoma cells. Cell surface expression of CD117 decreased from 17% to 11% in MG-63 cells when treated with lerociclib 2μM. Treatment of all cell types with lerociclib led to significantly decreased tumorsphere formation (Table). Conclusions: Treatment with lerociclib led to a decrease in mRNA abundance in known synovial sarcoma stem cell markers, a decrease in CD117 cell surface expression in osteosarcoma cells and decreased the ability of cells to form tumorspheres. These findings indicate lerociclib leads to decreased sarcoma cell stemness, which plays a key role in tumor progression and recurrence and should be further investigated for potential translation to the clinical setting.[Table: see text]