bluuebunny/crossref_metadata_2025 huggingface dataset:
B7H3 CAR-T therapy in relation to tumor growth in skin tumor.
Authors: Hu Gang , Liang Yunsheng , Li Guangchao , Ding Wen , luo min
Published: June 2022

e21502

Background: Exciting progress has been recently witnessed on the development of chimeric antigen receipt T cell (CAR-T) therapy for hematopoietic malignancies. The biological principles of CAR-T therapy are applicable to solid tumors but very little success has been achieved due to various challenges intrinsic to solid tumors. The development of new solid tumor targets is particularly important. CD276 (B7H3) is one of the most promising therapeutic targets for solid tumors and has been extensively tested in preclinical trials. However, no clinical trials have been reported on its efficacy and safety. In this study, we report a case of relapsed basal cell carcinoma (BCC) patient treated with B7H3 CAR-T cells through direct intra-tumor injection. Trial registration number: ChiCTR2100044386. Methods: We have generated a 2nd generation of B7H3 CAR-T, the extracellular scFv was derived from a humanized B7H3 monoclonal antibody, which was generated by hybridoma technology. Autologous CAR-T cells were manufactured in a cGMP facility. CAR-T cells were given by three dose-escalated intra-tumor injections without lymphodepletion conditioning. Results: A 65-year-old man was initially diagnosed with multiple BCC, the disease relapsed and spread to all over the body. Immunohistochemical staining of the tumor tissue showed positive for B7H3 (80%, ++̃+++). The patient received autologous anti-B7H3 CAR-T therapy cells through intra-tumor injection three times with dose escalation on day 1, day 14 and day 62. There were two different tumor sites that were treated in this patient (site 1 for abdominal tumor 1.8 cm × 0.6 cm; site 2 for forehead tumor 6 cm × 6 cm). For the adverse events, the patient’s AST/ALT levels slightly increased about two fold after the first infusion. However, we did not observe increases of AST/ALT levels after the second and third infusion, even with much higher dose. After three infusions, the volume of original lesion in the abdomen decreased 40% (1.8cm × 0.6cm to 1.3cm × 0.5cm), shrinking from bulging to flat. The large lesion in the forehead became dry from original ulcer and bleeding. We further performed surgery to remove the remained tumor in the abdomen after the third infusion. IHC analysis demonstrated that the percentage of B7H3 positive cells decreased from 80% to about 40%, and the intensity also decreased from ++̃+++ to +. Meanwhile, CD3 T cells increased in the tumor site, but failed to efficiently infiltrate into neighboring tumor areas, which was marked by high level of TGF-β. Conclusions: In this case, we reported for the first time that a patient with skin tumor achieved a partial response after receiving repeated intra-tumor injections of anti-B7H3 CAR-T cells. This study demonstrated that B7-H3 CAR-T cell therapy is a safe and promising treatment for relapsed skin tumor. Combination with other strategies to improve CAR-T cell infiltration in the tumor site may help to further improve the clinical response. Clinical trial information: ChiCTR2100044386.
Recombinant human adenovirus 5 injection plus toripalimab therapy in patients with advanced and refractory melanoma: A single arm, single-center, prospective study.
Authors: Zhao Huaxin , Guo Xianling , Liu Zhuqing , Xu Qing
Published: June 2022

e21503

Background: Treatment options are limited for patients with advanced melanoma and refractory melenoma, especially for acral and mucosal melanoma. Previous data showed that the objective response rate (ORR) of second-line PD1 monotherapy for acral and mucosal melanoma were 14-15.8% and 0-13.3%, respectively. We evaluate the safety and efficacy of recombinant human adenovirus 5 injection (oncolytic virus) plus toripalimab (PD-1 antibody) for patients who have progressed on checkpoint inhibitors, chemotherapy and anti-angiogenesis. Preliminary analysis of efficacy- related factors. Methods: Patients received the recombinant human adenovirus 5 injection (2ml) local lesions plus toripalimab 240mg systemic therapy every 2 weeks until progression or intolerable toxicity. The primary objective was safety and ORR. Secondary objective included progression-free survival (PFS) and disease control rate (DCR). Efficacy assessments were performed every 2 months according to RECIST v1.1 criteria. Blood samples were collected from patients prospectively. Serum interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured at baseline and after two cycles of treatment via flow cytometry. The peripheral blood neutrophils and lymphocytes were collected simultaneously. Results: Ten cases of patients were enrolled from November 2020 to January 2022. Baseline character:primary site (1 cutaneous melanoma; 5 acral melanoma; 4 mucosal melanoma), prior therapy (anti-PD1 100%; anti-angiogenesis 60%; chemotherapy 60%; second line and above 40%), 50% liver/bone lesions. All patients evaluated received at least 2 cycles of the combination regimen. The treatment-related adverse event was fever, accounting for 80%, and there were no other adverse events. The ORR was 20% (2PR) and the DCR was 70% (2PR, 5SD, 3PD). The 2-month PFS was 70%, and the median PFS has not yet been reached. Disease progression in 3 patients including liver and bone lesion. Higher baseline lymphocyte levels and lower neutrophil-to-lymphocyte ratio (NLR) values were found in the respongders compared with non-responders. The serum IL-6, IL-8, IL-10, and TNF-α levels were significantly increased in the responders after 2 cycles of treatment. Conclusions: The preliminary data showed that the combination of recombinant human adenovirus 5 injection plus toripalimab demonstrated acceptable toxicity and promising antitumor efficacy in patients with advanced and refractory melanoma, and promoted favorable changes in serum IL-6, IL-8, IL-10 and TNF-α levels in clinical responders. High baseline lymphocyte and low NLR values may be predictors of treatment response. Long-term survival data remain to continue with follow-up. It is worth to further validate the efficacy in a randomized prospective trial. Clinical trial information: 2000033959.
Comparing overall survival of patients with metastatic uveal melanoma by sequence of Tebentafusp versus combination immune checkpoint inhibitors.
Authors: Shikdar Sufana , Day Silas , Ikeguchi Alexandra , Ying Yuan
Published: June 2022

e21505

Background: Uveal melanoma is a rare melanoma subtype with poor outcome from immune checkpoint inhibition (ICI) compared to cutaneous melanoma. UM expresses high levels of Glycoprotein 100 (Gp-100) implicating potential sensitivity to tebentafusp (tebe), a novel immune-mobilizing monoclonal T cell receptor therapy. A recent phase 3 study compared tebe to investigator chosen standard of care (SOC) with crossover at progression. SOC regimens were single agent pembrolizumab, ipilimumab and Dacarbazine with 82% of SOC patients receiving pembrolizumab1. Other single arm studies suggest that survival with combination ICI is superior to single agent. We sought to compare overall survival (OS) of first or second line tebe in relation to combination ICI. Methods: Retrospective chart review at a single institution was conducted on patients with metastatic UM (mUM) treated with tebe on clinical trial between June 2018 and December 2021, either in first [NCT03070392] or second line [NCT02570308] setting. Patients were included if they received ipilimumab plus nivolumab either before or after tebe. Data including patient demographics and factors demonstrated in the phase 2 and 3 trials to correlate with survival including lactate dehydrogenase (LDH), size of largest liver lesion and early onset of rash with tebe were extracted. OS was the main outcome measure and was calculated as the time interval between the date of diagnosis of metastatic disease and date of death. Results: Six patients were identified in our data set as having received both ICI and Tebe, three in each sequence order. Mean characteristics were included in table. OS trended towards improvement in the cohort of patients who received tebe first in sequence both in OS in time from UM diagnosis (42.1 vs 63.5 months) (p = 0.21) and in OS in time from detection of mUM (29.8 vs 42.0 months) (p = 0.28), although neither difference was statistically significant given the small sample size. Conclusions: Our limited data demonstrate longer OS with tebe followed by combination ICI on progression compared to the reverse sequence. This comparison of patients at a single institution is underpowered to show a statistically significant OS difference but does demonstrate a trend in favor of first line tebe similar to the conclusive comparison of tebe and single agent ICI in the randomized trial. Reference: 1. Orloff, Marlana et al. Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in phase 3 randomized trial of first-line metastatic uveal melanoma. (2021): 9526-9526.[Table: see text]
Real-world comparison of outcomes in the first line treatment of metastatic melanoma according to BRAF mutation status: Nivolumab and ipilimumab therapy vs. nivolumab monotherapy.
Authors: Klein-Brill Avital , Amar-Farkash Shlomit , Fisch Michael Jordan , Aran Dvir
Published: June 2022

e21519

Background: In metastatic melanoma (MM) patients, nivolumab can be used as monotherapy or in combinations with ipilimumab. The combination therapy has been shown in a randomized clinical trial to provide survival benefit in BRAF mutant patients with an increased toxicity. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L nivo alone vs nivo+ipi. Methods: We performed a retrospective cohort study of 1L treatment of patients with MM between 1/2016 and 12/2020, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (OS) was defined as time from diagnosis to death. A Cox model with inverse probability of treatment weighting (IPTW) was used to adjust for demographic and clinical features. Adjusted hazard ratios (aHR) were estimated using weighted Cox proportional hazards models. Results: Our cohort included 708 1L MM patients, of them 466 (66%) treated with nivo+ipi. There was no difference in BRAF status between the treatment groups. Patients treated with nivo+ipi were younger and had more evidence of brain and lung metastasis. Following adjustment, nivo treated had significant longer OS compared to the nivo+ipi treated (aHR: 1.73 (1.25-2.35), p = 8e-4). This difference mostly stems from increased mortality of the combo treated in the first 6 months. At 24-months, 58% of the combination therapy treated patients were alive compared to 74% in the monotherapy group (p = 0.0006). Survival benefit was only observed in BRAF WT patients. In V600E patients no survival difference was observed (aHR: 0.8 (0.4-1.6), p = 0.5). Patients treated with the combination therapy had 5-fold more hospitalizations during the first 90 days after the treatment start (46% vs 10%, p = 3e-22). Conclusions: Our retrospective cohort study demonstrated improved survival for the monotherapy in BRAF WT patients. Combination therapy was associated with significantly more treatment-related hospitalizations and deaths, mainly in the first 6 months. The increased early morbidity of the combo should be considered in treatment decision.[Table: see text]
Discovery of AMBRA1 and SQSTM1 (p62) as putative biomarkers to identify high risk subsets of patients with cutaneous squamous cell carcinoma.
Authors: Lovat Penny , Alexander Michael , Cousins William , Ewen Tom , Stefanos Niki
Published: June 2022

e21541

Background: While surgical excision is largely curative, small subsets of patients with cSCC develop metastatic disease for which current AJCC/Brigham and Women’s Hospital staging criteria are unable to reliably identify. There is hence an unmet need for credible prognostic biomarkers to stratify patients based on personalised risk, guide the use of emerging therapeutic intervention for advanced disease and the rationalisation of current/future dermatological healthcare. AMBRA1 and SQSTM1 (p62) play a key role in autophagy and sustained keratinocyte differentiation; two vital processes disrupted in cSCC tumorigenesis, resulting in deregulated cell proliferation and autophagy-mediated tumour cell survival. While AMBRA1 expression is maintained in the normal epidermis its expression is lost in the tumour growth front of cSCCs. Conversely, p62 expression is maintained in basal keratinocytes within the normal epidermis but is lost in the peritumoural epidermis. Collectively these observations suggest tumoural AMBRA1 and peritumoural epidermal p62 expression as biomarkers of cSCC progression. The aim of the present study was to assess the immunohistochemical (IHC) expression of AMBRA1 and p62 in a retrospective cohort of localised or metastatic cSCCs and correlate expression with clinical outcome over 5 years. Methods: Automated IHC analysis of AMBRA1 and p62 expression was performed in a retrospective cohort of well, moderately or poorly differentiated non or metastatic cSCCs. Digital images were annotated prior to H-score expression analysis using optimised cytoplasmic algorithms within Aperio ImageScope software. Results: Receiving Operating Characteristic (ROC) curve analysis revealed an H score of < 20 for peritumoural epidermal p62 and < 60 for expression of AMBRA1 in the cSCC growth front defined cSCCs at high risk of progression while tumours with a p62 H score of ≥ 20 and/or ≥ 60 for AMBRA1 were defined as low risk. Subsequent Kaplan Meier analysis of 51 moderately/poorly differentiated cSCCs demonstrated loss of peritumoural p62 and tumour AMBRA1 expression in 7 tumours correlated with a significantly increased risk of metastasis of 85.7 % compared to 25% for 44 tumours defined as low risk (P < 0.0001, HR 30.07, 95% CI 5.48-165) with an assay specificity of 97%, positive predictive value of 75%, and a negative predictive value of 86%. Conclusions: Overall these data suggest the combined use of tumoural AMBRA1 and peritumoural p62 expression as a putative prognostic biomarker for cSCC metastasis, the future validation of which may provide a valuable stratification tool to guide clinical management, therapeutic intervention and the rationalisation of healthcare resources.
Correlation between homologous recombination repair gene mutation and immunotherapy efficacy in patients with advanced melanoma.
Authors: You Changxuan , Zhou Chengzhi , You Zhixuan , Lv Meng , He Xuanyu , Pan Yingqin , Ge Junfeng , Hu Xue , Zheng Yating , Huang Mengli
Published: June 2022

e21551

Background: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) was a pathway of the DNA damage response (DDR), has been shown to be associated with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy and immunotherapy in variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. Methods: An independent cohort (Samstein2018) with data from 99 patients with advanced melanoma were used to analyze the correlation with immunogenic marker the prognostic effect of HRR on immunotherapy, and another four cohorts (Miao2018, Allen 2015, Hugo2016, and Synder2014) are used for validation. Immune filtration cells scores analyzed by the TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. Results: Compared to patients with HRR pathway wild-type (HRRwt), those with HRR mutations (HRRmut) in an independent anti-CTLA-4-treated cohort had higher tumor mutation burden (TMB; median: 29.55Muts/Mb versus 4.46Muts/Mb; P = 0.0003), objective response rates (ORR; P = 0.007), and longer overall survival (OS; median: 58 versus 22 months, hazard ratio (HR) = 2.4, 95%CI 1.17-4.92, P = 0.014). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the ORR and OS. However, there was no correlation between HRRmut and OS in the anti-PD-1-treated cohort. Subgroup analysis showed that although patients with HRRmut received the same benefits from anti-CTLA-4 and anti-PD-1/L1 therapy (p = 0.59), the value of anti-CTLA-4 therapy in the HRRmut group was similar or even better than that in the anti-PD-1/L1 therapy group (24.1 months vs 22.7 months), which unlike it in the HRRwt group (10.8 months vs 32.0 months). In addition, transcriptome profiling analysis revealed that 44 (66.7%) genes mutation of HRR pathway associated with reshaping of the immunological microenvironment in melanoma tumors. Conclusions: HRRmut were associated with a higher TMB level, and immunotherapeutic effect. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.
Melanoma mortality rate trend in an era of effective treatments: A retrospective study, 1975-2019.
Authors: Kahlon Navkirat , Hamouda Danae M.
Published: June 2022

e21555

Background: Skin cancer is the most common cancer in the US. Among all skin cancer cases, melanoma represents only about 1%, but it causes most of the deaths due to skin cancer. Unfortunately, the incidence of melanoma has increased over the last three decades. In the past decade, new and effective therapies for melanoma have emerged, with FDA-approval of multiple checkpoint inhibitors (such as PD-1 inhibitors and CTLA4 inhibitors), and multiple tyrosine kinase inhibitors (TKIs) targeting v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutated melanoma. The aim of this study is to review mortality trends in melanoma since the FDA-approval of these agents. Methods: Long term age adjusted cutaneous Melanoma Mortality Rate (MMR) trends in the United States were reviewed and evaluated using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program from 1975 to 2019. The Annual Percent Change (APC) with 95% confidence interval (CI) and p-value has been used to report long term trends. APC has been calculated using Joinpoint regression. Results: The MMR was found to be increased during 1975-1988 (APC 1.65%; p < 0.01). No statistically significant change in MMR was seen during 1988-2013 (APC 0.01%; p = 0.85). MMR was significantly decreased during 2013-2017 (APC -6.24%, p < 0.01). No statistically significant decrease has been seen during 2017-2019 (APC -1.56%, p = 0.53); however, there is a downward trend. Conclusions: This SEER database retrospective review of MMR provides the insight into change in long term mortality trends for melanoma in the United States. During 1975-2019, the MMR first increased, then stabilized and then decreased. After introduction of checkpoint inhibitors in 2011 and TKIs in 2013, significant reduction in melanoma mortality rate (MMR) was seen during 2013-2017 in the United States, even in the setting of increasing melanoma incidence. This likely reflects a benefit from the availability of effective therapies in the last decade. These treatment options are now also approved for use in the adjuvant setting, primarily after 2017. It will be interesting to see if a further significant reduction in MMR will be seen. It may also be worthwhile to study real-world population trends in other cancers where similar treatments have been found to be effective in recent years.[Table: see text]
Antimetastatic effect of benzimidazole derivative on the model of melanoma B16 in the experiment.
Authors: Kurbanova L. Z. , Shevchenko Nataliya , Verenikina Ekaterina V. , Komarova Ekaterina Fedorovna , Filatova Elena V. , Khomutenko Irina A. , Goncharova Anna S. , Lukbanova Ekaterina A. , Khodakova D. V. , Galina A. V. , Mindar Maria V. , Zaikina Ekaterina V. , Komarova Elizaveta
Published: June 2022

e21562

Background: Study of the influence of a pharmacological substance dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole on the tumor growth on a model of experimental transplantable B16 melanoma in mice. Methods: B16 melanoma strain were transplanted subcutaneously to 80 female C57/Bl6 mice weighing 18-20 g. Intragastric dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole injections (0.5 ml a day) began 48 h after tumor transplantation once a day for 10 days at single doses of 50, 220 and 500 mg/kg (groups 1, 2 and 3, respectively). Mexidol was used for comparison, and saline as control (injected at similar regimens and doses). Results: Intragastric enoxifol injections did not significantly inhibit the melanoma growth. Only group 2 showed inhibition of the tumor growth by 48.7 % on day 22. Median survival of mice in all experiment groups was similar to that in the control group. The number of metastatic nodes in the lung tissues in groups 1, 2 and 3 decreased by 2.1, 4.8 and 2.5 times, respectively, compared to controls. The average index of metastasis inhibition was 71.3 % in all groups being 1.3 times higher than in the mexidol group (54.2 %). Conclusions: The revealed significant changes in parameters of the metastatic activity of the tumor suppose that dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole at all studied doses has a greater effect on the development of spontaneous lung metastases and metastasis rates than on the growth of primary B16 melanoma in mice.
Clinical and pathological predictors of micrometastasis in marginal thickness melanoma.
Authors: Yaghi Marita , Bilani Nadeem , Dominguez Barbara , Jabbal Iktej Singh , Rivera Carlos , Liang Hong , Benedetto Paul X , Mrad Chebli , Nahleh Zeina A. , Arteta-Bulos Rafael
Published: June 2022

e21585

Background: Sentinel lymph node biopsy (SLNB) remains controversial in patients with localized marginal thickness melanoma (MTM). Nonetheless, micrometastasis (miLN) i.e. the presence of clinically occult lymph node (LN) metastasis, upstages localized tumors to Stage III, indicating the need for more extensive surgical resection and escalated systemic therapy. We aim to identify disease predictors associated with miLN in MTM. Methods: This National Cancer Database (2004-2018) analysis includes patients with T1a/T1b, N0, and M0 (AJCC 8th edition) melanoma (Breslow’s depth: 0.76-1.00 mm). We selected 2 cohorts based on the pathological status of LN metastasis, as per SLNB or elective lymphadenectomy: negative LN versus miLN. Bivariate association of various clinical characteristics and LN status was assessed using Chi-square and Fisher’s exact tests. Significant covariates were integrated into a multivariable logistic regression (MLR) with a backward elimination model to identify the risk factors associated with the presence of miLN. A multivariable Cox regression model with backward elimination compared overall survivor (OS) between both cohorts, adjusting for significantly unbalanced factors. Results: N = 72,945 patients with clinical N0 MTM were identified. N = 68,912 (94.5%) had negative LN and N = 4,033 (5.5%) had miLN on pathology. Ethnicity (p = 0.260), Charlson/Deyo comorbidity score (p = 0.0894) and LDH levels (p = 0.2278) did not significantly vary across cohorts. On MLR analysis, patients with miLN were more likely to be younger and have tumors located outside the head & neck. Tumors with miLN were more likely to show lymphovascular invasion, vertical growth, and a mitotic rate of ≥ 1 but less likely to show positive tumor regression. Ulceration was not an independent risk factor of miLN (p = 0.9305). Multivariable analysis showed that patients with miLN had lower OS rates than those with negative LN (HR = 1.66; 95% CI: 1.45-1.90; p < 0.0001). Conclusions: miLN is associated with a worse prognosis, warranting early recognition and prompt treatment initiation. Despite NCCN guidelines incorporating tumor ulceration into decision-making regarding the need for SLNB in clinical N0 MTM, we show that tumor ulceration was not significantly associated with miLN in MTM. However, patient age, tumor location, tumor mitotic rate, lymphovascular invasion, and vertical growth phase were associated with miLN and thus need to be assessed when considering SLNB.[Table: see text]
Nodal surveillance and adjuvant therapy in sentinel lymph node-positive melanoma patients.
Authors: Brunsgaard Elise Kornreich , Asare Elliot Amponsah , Bowles Tawnya Lynn , Hyngstrom John Robert
Published: June 2022

e21586

Background: Since the publication of the Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) in 2017, completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive patients has mainly been deferred for ultrasound surveillance of the nodal basin. Additionally, there is now widespread use of adjuvant therapy in these patients. However, CLND was required for the major adjuvant therapy trials, therefore information on recurrence patterns in SLN-positive patients receiving adjuvant therapy without CLND is limited. Methods: In this retrospective cohort study of patients with SLN-positive melanoma identified from 2017 to 2021 at a single institution, the primary aim was to evaluate the incidence of local, nodal, in-transit, and distant recurrence in patients receiving adjuvant therapy with nodal surveillance compared to nodal surveillance alone. Method of detection of recurrence, compliance with ultrasound surveillance, and clinicopathologic risk factors were also assessed. Chi-square tests were used to evaluate for any associations between clinicopathologic characteristics, initial location of recurrence, and receipt of adjuvant therapy. Results: Of 157 SLN-positive melanoma patients identified, 21 (13%) received CLND and 13 (8%) had insufficient follow-up information for inclusion. Among 123 eligible patients (mean 55 years, 54% male), the median follow-up time was 24.5 months during which 33 (27%) patients recurred. Of 13 patients with isolated nodal recurrence, three were detected by ultrasound alone, five were detect by CT alone, and five were detected by both CT and ultrasound (Table). 90 (73%) patients in the cohort received adjuvant therapy (92% anti-PD1, 6% BRAF/MEK, 2% anti-CTLA4). The main reasons for exclusion of adjuvant systemic therapy were minimal nodal disease or patient refusal. The average time to recurrence was 13.4 months. There were no significant differences in recurrence rates (p = 0.49) or location of initial recurrence (p = 0.64) by receipt of adjuvant therapy. 29 (24%) patients missed more than one ultrasound. Ultrasound surveillance was most frequently missed due to clinician omittance or patient distance to clinic. Conclusions: In our cohort of SLN-positive melanoma patients, the majority received adjuvant anti-PD1 immunotherapy and were followed in surveillance without CLND. There was no significant difference in recurrence patterns based on receipt of adjuvant therapy and a quarter of nodal recurrences were detected by ultrasound alone. Our results support the use of ultrasound surveillance in addition to cross-sectional imaging to monitor for recurrence in these high-risk patients.[Table: see text]
VEGFR-C mutation serves as a potential negative predictor for immunotherapy in metastatic melanoma.
Authors: Du Zhenguang , He Qianru , Xing Xiaodan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang
Published: June 2022

e21593

Background: Immune checkpoint blockade has shown significant promise as an anticancer treatment and anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. Vascular endothelial growth factor-C (VEGF-C), a member of the VEGF gene family, has been characterised as a prime mediator of lymphangiogenesis and angiogenic growth factors that promote the growth and metastasis of neoplasms. Previous studies provided evidence that VEGF-C correlated with poorer survival in melanoma. We aimed to determine the association of VEGF-C mutations with melanoma survival to immune checkpoint inhibitors (ICI). Methods: Data from Allen study (n = 110, anti- CTLA-4 therapy) was obtained and analyzed. Meanwhile, we extracted skin cutaneous melanoma (SKCM) RNA data from The Cancer Genome Atlas (TCGA). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm, the relative proportions of 22 types of infiltrating immune cells were determined in TCGA cohort. Results: In Allen cohort, the frequency of VEGFR-C mutation was 5.45% (6 in 110). Meanwhile, the frequency of VEGFR-C mutation in TCGA cohort was 7.37% (33 in 448). VEGFR-C-mutant (VEGFR-C-mut) group showed a poorer progression-free survival (PFS) (HR, 2.34; 95%CI, 1.01 to 5.4, p = 0.041) and overall survival (OS) (HR, 2.84, 95%CI, 1.22 to 6.62, p = 0.012) than the VEGFR-C-wild (VEGFR-C-wt) group, based on results of the log-rank test and Kaplan-Meier analysis. Moreover, COX proportional hazards model analysis showed VEGFR-C mutation was associated with poorer PFS (HR, 2.54; 95%CI, 1.04-6.25, p = 0.0042;) and OS (HR, 3.25; 95%CI, 1.30-8.12, p = 0.0117) compared with VEGFR-C-wt. In addition, we identified that the levels of naive B cells and resting CD4+ memory T cells were more abundant in VEGFR-C-mut group according to CIBERSORT algorithm. Conclusions: In our study, the frequency of VEGFR-C mutation in melanoma was investigated in Allen and TCGA cohorts, which might provide useful information to guide precision medicine. VEGFR-C mutation may serve as a potential negative predictor of response to anti-CTL4 treatment in melanoma via higher levels of naive B cells and resting CD4+ memory T cells.
AYA rhabdomyosarcoma: Evolving changes in regional service delivery impacting on outcomes and meningeal disease.
Authors: Hatcher Helen , Wong Han , Harrington Jenny , Prewett Sarah , Horan Gail
Published: June 2022

e22006

Background: Rhabdomyosarcoma (RMS) is a rare and aggressive sarcoma with a variable prognosis dependent upon age, histology, PAX-FOXO1 translocation status, site, stage of disease and treatment. RMS has a peak age of incidence in adolescents and young adults (AYA). Centralisation of care in the UK has impacted on treatments given and outcome. With extended outcomes in an age associated with poor prognosis we have seen increased rates of meningeal disease as a late event. We examined factors predisposing to meningeal involvement and associated outcomes in changing treatments. Methods: Retrospective review of AYA with RMS, treated between 2004 and 2022 at a regional AYA center serving a population of 2.5 million. Results: 17 patients (9 males, 8 females) were identified (median age 18). At diagnosis, 5 patients had locally advanced disease and 11 had metastases. Meningeal disease developed in 11/17 after a median of 11 months (range 6-87) from diagnosis. Overall survival was 14 months (range 14-87) for those who developed meningeal disease versus 54 months (range 6-167, not reached in 3) in those who did not. Following meningeal involvement, survival ranged from 0-7+ months. Histology of those with meningeal disease: embryonal (5) alveolar (6). 5/6 patients with alveolar RMS (ARMS) had FOXO1 gene rearrangement. Presentation of meningeal disease included: headaches (7), visual phenomena (3), nausea/vomiting (2), unusual chest or back pain (5). Risk factors included bone marrow infiltration (2/2), para-meningeal/orbital primary (4/4), and widespread metastatic or locally advanced primary disease 10/11. 10/11 received treatment with radiotherapy and/or chemotherapy with symptomatic benefit. Conclusions: Meningeal disease in RMS occurs more frequently in those with a primary close to the brain and with bone marrow involvement. Site and extent of primary disease was more predictive than histology for meningeal disease, but not of survival. Adaptation to longer initial treatments with maintenance therapy has increased survival in AYA RMS. Early recognition of key warning symptoms is important to guide prognostication and symptom control.
Clinical implications of next-generation sequencing on pediatric solid tumors.
Authors: Guo Wei , Xie Lu , Xu Jie , Chen Lijuan , Wang Liwei , Wang Aodi , Wang Mingmin , Dong Xiaowei , Mei Lei , Chen Hui , Yuan Shaohua , Wang Kai
Published: June 2022

e22012

Background: To assess the impact of next-generation sequencing (NGS) on Chinese pediatric cancer, we reported the first study of largest cohort in Chinese children with genomic landscape and highlighted the potential application with respect to molecular diagnosis and predictive biomarkers etc. Methods: A retrospective analysis was conducted on patients aged < 19 years diagnosed with solid tumors sequenced by targeted NGS panel. Somatic variants were analyzed following CAP/CLIA-certificated workflows, including Single Nucleotide Variant (SNV), Copy Number Variation (CNV), large insertion and deletions (Lindel) and gene rearrangements. Results: A total of 356 patients enrolled with three major cancer types including osteosarcoma (OS) (n = 78), rhabdomyosarcoma (RMS) (n = 51), Ewing sarcoma (EWS) (n = 13). Hepatocellular carcinoma (n = 9), medulloblastomas (n = 7) and colorectal adenocarcinoma (n = 5) were also included. 3487 somatic alterations were identified, TP53 (16%), EWSR1 (8.7%), CDKN2A (7.8%), BCOR (7%) and RB1 (5.6%) rank the top five reported. TP53 (21% % vs 7.9%), RB1 (10% vs 5.3%) mutations showed higher frequency in OS and BCOR (14% vs 17.6%) showed lower frequency in RMS compared to published paper (Gröbner et al 2018). We found PIK3CA mutations presented in RMS with 11.7% frequency, twice than reported (5.8%), mostly occurring at the known oncogenic codon E545. The obscure boundary of soft tissue tumor and bone tumor perplexed the pathologic diagnosis, NGS provide an important auxiliary examination. In 140 soft tissue tumor and bone tumor patients, 14.2% patients were further diagnosed with different subtype, 4.2% patients with unknown subtype were diagnosed with a specified subtype by supportive genetic alterations. Moreover, 41.5% (138/356) patients received treatment recommended . Twelve NTRK-fusions were detected and the patients were recommended therapy method upon Larotrectinib, recruitment in matched clinical trial is still on-going. Conclusions: We investigated the different genetic profiling of Chinese pediatric solid cancer and found the clinical value of NGS in pathological diagnosis and biomarker discovery.
Use and correlates of carotid ultrasound in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Bryce Yolanda C , Armstrong Gregory T. , Leisenring Wendy M. , Whitton Jillian , Chow Eric Jessen , Weil Brent R. , Dieffenbach Bryan , Howell Rebecca M. , Oeffinger Kevin C. , Nathan Paul C. , Tonorezos Emily S.
Published: June 2022

e22023

Background: Survivors of childhood cancer with history of radiation therapy (RT) to the head/neck/chest are at increased risk for stroke. Children’s Oncology Group Guidelines recommend carotid ultrasound (CU) when clinically indicated or 10 years after RT ≥ 40Gy to the neck. Yet, the use of CU has not been previously described. Methods: 8,693 survivors of childhood cancer (median age at diagnosis 8.0 years, range 0-20; median age at evaluation 37.4, range 18-65) diagnosed between 1970-1999 were asked if they had ever had a CU. Cardiovascular disease (CVD) was defined as any of the following: stroke, congestive heart failure, hypertension, myocardial infarction, coronary heart disease, or arrythmia. Prevalence ratios (PR) were calculated; age and sex-adjusted multivariable Poisson regression models evaluated factors associated with CU. Results: 4.9% (427) of survivors had a history of stroke and 28% (2,442) had a history of any CVD. Of these, 40.0% (171) with a history of stroke and 28.6% (748) with any CVD had CU. Comparatively, 14.6% (1,404) without a stroke and 11.1% (798) without any CVD had a CU (both p<0.0001 vs those with condition). Among survivors without CVD, having seen only a primary care physician was not associated with CU (PR 0.84 95% CI 0.58-1.25, p = 0.36), while seeing a cancer specialist (+/- a primary care physician) (PR 1.83 95% CI 1.23-2.79, p = 0.036) was associated with increased likelihood of CU compared to seeing neither. Survivors who had had other surveillance studies, including a colonoscopy (PR 1.76 95% CI 1.44-2.17, p<0.0001), skin cancer exam (PR 1.62 95% CI 1.30-2.03, p=0.0002), or mammogram (PR 2.06 95%CI 1.42-3.07, p<0.0001) were more likely to have a carotid ultrasound, compared to those without that test. Having a history of anthracyclines or RT to the neck were associated with higher prevalence of CU, with RT to the neck exhibiting a dose-response relationship (Table). Conclusions: CU was more common among survivors with a history of stroke or other CVD event. In those without CVD, CU use was associated with anthracyclines and RT dose exposures and with care provided by a cancer specialist. A high proportion (70%) of survivors who received >40Gy RT to the neck have never had a CU, suggesting that greater awareness of guidelines is needed.[Table: see text]
Development and validation of the Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) Japanese version.
Authors: Kato Miho , Yoneoka Daisuke , Urayama Kevin , Kiyotani Chikako , Matsumoto Kimikazu , Sato Satomi
Published: June 2022

e22025

Background: The lives of childhood cancer survivors (CCS) may be impacted by symptoms of neurocognitive dysfunction. Decline in executive function, one component of the construct concept of neurocognitive function, may affect the ability to be independent in later life; thus,ssessment and intervention are important. In the United States, the Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) developed by St. Jude Children’s Research Hospital has been widely utilized in clinical practice. It is a self-administered scale for screening daily difficulties regarding organization, emotional regulation, memory, and task efficiency which all fall under the concept of the executive function. To expand the tools for executive function assessment in Japan, we developed the CCSS-NCQ Japanese version and performed a validation study among the adolescent and young adult (AYA)-CCS population. Methods: The Japanese version of the CCSS-NCQ was developed by conducting linguistic validation. Japanese AYA-CCS of all cancer types were recruited and asked to complete this 32-question self-administered questionnaire. Exploratory and confirmatory factor analysis (FA) with the Promax rotation were conducted. Results: In total, 106 participants responded. The mean age of participants was 20.6 ± 5.3 years, and 49.1% were male. The mean age at diagnosis was 8.7 ± 4.8 years; 46.2% of participants were diagnosed with brain tumors, 37.7% with hematological malignancy, and 12.3% with solid tumors. The FA identified the similar four-factor structure of organization, emotional regulation, memory, and task efficiency as the original CCSS-NCQ with factor loading set at 0.4. The Cronbach’s alpha was 0.84 - 0.92. Conclusions: Neurocognitive dysfunction could be a crucial late complication of childhood cancer, and maintaining executive function, in particular, is essential for sustaining the quality of life among CCS. The CCSS-NCQ Japanese version is the first internationally translated CCSS-NCQ. The successful validation in the Japanese population will expand opportunities for future international collaboration to identify race/ethnicity-based disparities, as well as scale enhancement for application to CCS worldwide.
The implementation of fertility guidelines and impact on the rate of pre-therapy fertility risk discussions in pediatric oncology: A retrospective cohort study.
Authors: Crowell Cameron , Digout Carol , Romao Rodrigo L. P. , Flanders Annette , Howitt MaryJean , Erker Craig
Published: June 2022

e22027

Background: Pediatric cancer patients undergoing treatment are often at risk for infertility or subfertility. Healthcare providers do not consistently deliver fertility information prior to therapy. Our objective was to assess if development and implementation of a fertility guideline improves the frequency of pre-treatment fertility discussions with pediatric cancer families. Methods: This retrospective cohort study analyzed all consecutively eligible patients over two time periods. The pre-guideline time period was 18 months prior to implementation and the post-guideline time period was 12 months after implementation. Guideline implementation included an education session with oncology staff. Eligible patients were < 19 years old at cancer diagnosis and received chemotherapy and/or radiation therapy. Patients treated with palliative intent were excluded. Pre-guideline rate of pre-treatment fertility discussions was estimated at 40%. An estimated 40 participants in the post-guideline cohort can detect a 30% increase in fertility discussions with β 0.8 and α 0.05. Exploratory analysis assessed factors associated with the frequency of fertility risk discussions. Results: Ninety-five patients were included. Fifty-seven percent were < 10, 26% were 10-15, and 17% were ≥ 16 years old. Pre- and post-guideline cohorts are compared in table. In the pre-guideline cohort, 41% of patients had a discussion about risks of fertility impairment documented, while post-guideline cohort had 49% documented ( p = 0.531). Exploratory assessment of combined cohorts found males (OR 0.2.7, 95% CI 0.1.2-6.3-0.87) and patients ≥ 10 years old (OR 5.0, CI 2.1-12.1) were more likely to receive fertility discussions prior to therapy. Radiation and cancer type did not influence whether fertility discussions occurred. Conclusions: Implementation of a fertility guideline did not increase discussions of fertility risk, and less than half of patients had a documented fertility risk discussion. Male patients and age ≥ 10 years old were more likely to have documented discussions about risks to future fertility. Effective strategies are needed to improve the rate of discussions regarding fertility risk to ensure families receive this information prior to therapy. [Table: see text]
How to regulate vaping products to advance cancer prevention: Evidence from online stores.
Authors: Shang Ce
Published: June 2022

e22502

Background: The use of electronic cigarettes has significantly increased in the past decade, and online stores are one of the most common outlets for e-cigarette users to purchase vaping products. The goal of this study is to examine the appeal of different e-liquid flavors to vapers, using a revealed preference method to estimate consumer demand. Methods: We collected data on e-liquid sales prices, volume (in ml), and a variety of product flavors, from online vaping stores using web data extraction. We standardized prices for e-liquid products and used the hedonic pricing model to assess the associations between standardized e-liquid prices and flavors, controlling for nicotine concentration (in mg) and product VG/PG ratio. In total, we collected data of 10,870 e-liquid products from four popular online vaping stores that sell nationwide across the U.S. Results: Higher e-liquid prices (standardized to $/ml) are associated with higher nicotine concentrations. E-liquid products with fruit tobacco flavors are associated with higher sales prices. E-liquid prices are higher when VG/PG ratio deviates from 70/30 except for 90/10: the prices of e-liquid products with a 90/10 VG/PG ratio are lower than the prices of products with a 70/30 ratio. All of the findings above are statistically significant at a 5% level. Conclusions: Higher nicotine concentration and fruit flavors are associated with higher e-liquid prices in national online vaping stores, suggesting that they are preferred attributes and are in greater demand among vapers in the market of heterogeneous e-liquid products.
A binational cancer registry analysis of Hispanic patients in Mexico and the United States.
Authors: Lopez Pineda Arturo , Garrido-Sanchez Josue Abinadi , Gonzalez-Arroyo Gilberto , Alvarez-Aguilar Cleto
Published: June 2022

e22513

Background: A marked disparity in cancer burden exists between regions of the world. This global picture can only be obtained because of data obtained from population-based cancer registries, which allow estimates for different geographic areas. We investigate the data differences, clinical characteristics, tumor information, and patient outcomes of Hispanic patients in North America. Methods: We used data from Mexico’s National Cancer Registry and the United States Surveillance, Epidemiology, and End Results Program (SEER) program with four years of follow-up on each registry. of Mexican registry, we excluded outliers and records with more than 80% missing variable; of the United States registry, only patients identified as hispanic or latino were included. On the Mexican registry we re-coded all variables and the United States registry data on secondary neoplasm was excluded to match boths registry. Baseline characteristics and a geographical information system was constructed to map cancer registries and their relative frequencies. A survival analysis was done to understand the correlation between covariates. Lastly, we build machine learning models to predict 3-year overall survival. Results: The Hispanic cancer database (HCB) consists of 291,178 patients (19,904 from Mexico, and 271,274 from the United States). The top three most frequent cancer types were breast, prostate and hematological. The age of diagnosis was 55±17 years. Mexico has a slight skewness towards the earlier age of diagnosis of females. The registries with the highest burden of cancer were New Mexico (USA) and Baja California Sur (Mexico). Average survival months seem very stable across registries in the United States, but not in Mexico. Our linear regression model achieved a coefficient of determination (R-squared) of 0.49, while the logistic regression achieved an AUC of 0.82, with an F1-score of 0.88. Conclusions: Cancer registries are important tools for prevention and development of control programs. Hispanics are a traditionally neglected population in oncological clinical trials, with low enrollment of patients outside of the United States. Mexico enacted its National Cancer Registry Law in 2017, which alongside the Hispanic data on the SEER program in the United States offers enormous opportunities for continued collaboration and understanding of cancer. Both Mexico and the United States can strengthen their cancer prevention strategies and generate trans-border collaboration, research, and patient-support networks.