bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective analysis examining the use of tissue-based and blood-based NGS in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Hines Adam , Hakim Nausheen , Wang Kevin , Shah Pratik , Lee Chung-Shien , Seetharamu Nagashree
Published: June 2021

e21195

Background: Next generation sequencing (NGS) of tumor has become an integral part of cancer diagnostics and therapeutics today. While tissue-based (TB) NGS is still considered gold-standard, cell-free DNA NGS obtained from peripheral blood (blood-based or BB) offers many advantages because of its quicker turnaround time, minimally-invasive nature and ability to address tumor heterogeneity and track development of resistance mutations over time. It however does have its disadvantages, predominant of which is its lower sensitivity. Integration of BB and TB NGS can both optimize turnaround time and increase detection of targetable mutations. Methods: We conducted a single institution, IRB approved, retrospective study evaluating NGS testing patterns in patients with advanced NSCLC treated at our institution between 1/1/16 and 3/31/20. Our primary endpoint was to evaluate the number of patients who had BB NGS performed at any point during their clinical course in addition to TB NGS testing. Our secondary endpoint was to evaluate the number of patients for who BB NGS led to change in treatment plan. Exploratory points included the concordance rate between BB and TB NGS performed within 1 month of each other and the details of discordance if any. Results: There was a total of 437 eligible advanced NSCLC patients who were treated at our institution between January 2016 and March 2020. Out of these, 104 (23.8%) had BB NGS performed at some point in their disease course. The median number of BB NGS testing done for these patients was 2 and ranged from 1 to 4. 32/104 (30.8%) of patients had change in management because of BB NGS results. TB and BB NGS were performed within one month of each other in 52 patients. 11 of these (21.2%) had detection of identical actionable mutations (AM) on both BB and TB NGS assays. 5 of the patients (9.6%) had AM detected on TB NGS alone and 6 of the patients (11.5%) had AM detected on BB NGS alone. 30/52 patients (57.7%) had no AM identified on both BB and TB NGS. Conclusions: BB NGS has added tremendous value to diagnosis and treatment of NSCLC. It is increasingly used in practice, in tandem with TB NGS. Nearly a fourth of our patients had BB NGS performed at some point in their clinical course. Nearly 20% of simultaneously performed BB and TB NGS were discordant and an AM was identified in only one of the biopsies. Although further research is needed, our study supports simultaneous BB and TB testing at diagnosis and progression thereby maximizing therapeutic potential.
Overall survival comparison in patients with and without brain metastases treated with osimertinib for metastatic EGFR mutation positive non-small cell lung cancer (NSCLC).
Authors: Giffoni de Mello Morais Mata Danilo , Romero Maria Luisa , Carmona Gonzalez Carlos Amir , Thawer Alia , Doherty Mark , Menjak Ines B.
Published: June 2021

e21216

Background: With the development of Epidermal Growth factor receptor (EGFR) tyrosine kinase inhibitors such as Osimertinib, the landscape of lung cancer treatment and outcomes has changed. We aimed to describe the outcomes of patients treated with Osimertinib who have brain metastasis compared to those without brain metastases. Methods: This study involved patients diagnosed with metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, from January 2010 to December 2018, who had treatment with Osimertinib at a dose of 80 mg daily. Retrospective data was collected through the electronic medical records from Sunnybrook Health Sciences Centre. Descriptive statistics were used to summarize the population characteristics. The log rank test was used to compare the survival distributions. Results: A total of 56 patients were included, the mean age at initial diagnosis was 63 years (range 27 – 85 years). Overall, 82.2% of this patient population received Osimertinib in 2nd line setting. A total of 50% (n = 28) had brain metastasis, and14.3% (n = 8) had leptomeningeal metastasis. Of the patients with brain metastasis, 14.3% (n = 4) had brain surgery. All patients with brain metastasis received central nervous system (CNS) radiation. With respect to radiotherapy modalities, 67.9% (n = 19) of patients with brain metastasis received gamma knife radiation, 42.85% (n = 12) were treated with stereotactic radiosurgery (SRS), and whole brain radiation was given to 57.1% (n = 16). Of those with brain metastasis, equal numbers of patients, 46.4% (n = 13), had EGFR mutations with exon 19-deletion and exon 21-L858R, 7.1% (n = 2) had unknown gene location EGFR mutation. The median OS for patients without brain metastasis was 38.6 months (95% confidence interval [CI] 37.5 – 39.8 months], compared to 35.9 months (95% [CI] 28.3 – 43.5 months] for those with brain metastasis ; log Rank (Mantel-Cox) p = 0.874. The median OS for patients diagnosed with leptomeningeal metastasis was 21 months (95% [CI] 2.9 – 39.0 months); log rank (mantel-cox). When brain metastasis was examined by EGFR mutation sub-groups, the median OS for patients with EGFR-exon 19-deletion was 26.4 months (95% CI [14.3 – 38.4 months], compared to 36.8 months, 95% CI [34.3 – 39.2 months] for those with EGFR-Exon 21-L858R; log Rank (Mantel-Cox) p = 0.49. Conclusions: Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases. However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.
Potential role of serum proteome in predicting immune-related adverse events from immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Kim Leeseul , Chae Young Kwang , Jung Chan Mi , Yu Emma , Lee Alice Daeun , Choi Yoonhee , Jung Hojung , Park Inae
Published: June 2021

e21218

Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.
Immune status in merkel cell carcinoma: Relationships with clinical factors and independent prognostic value.
Authors: Yusuf Mehran , Gaskins Jeremy T. , Rattani Abbas , McKenzie Grant , Mandish Steven , Wall Weston , Farley Alyssa , Tennant Paul , Bumpous Jeffrey , Dunlap Neal E.
Published: June 2021

e21509

Background: Immunosuppression (IS) is not currently considered in staging for Merkel cell carcinoma (MCC). We performed an analysis of the National Cancer Database (NCDB) to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and describe the relationship between immune status and other prognostic factors. Methods: The NCDB was queried for patients diagnosed with MCC from 2010 to 2016 with known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Adjuvant radiation and chemotherapy were treated as time-dependent predictors to limit immortal time bias. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors. Multiple imputation was used to minimize missing data bias. Results: The overall cohort included 3,882 patients (3,470 patients with known immunocompetence and 412 patients with known immunosuppression). Etiologies for profound IS included chronic lymphocytic leukemia (CLL, n = 118), Other including HIV/AIDS (n = 116), solid-organ transplant (n = 106), and Non-Hodgkin Lymphoma (NHL, n = 72). 2,864 patients (73.8%) underwent surgical nodal examination. The median follow-up time was 33 months (Interquartile Range: 18 to 55 months). The 3-year OS was lower for patients with IS (44.6%, CI 39.8-49.9%) compared to immunocompetent (IC) patients (68.7%, CI 67.1-70.4%, p < .0001). IS was associated with increased adjusted mortality hazard (HR 2.36, 95% CI 2.03-2.75). Etiology of IS was associated with OS ( p = .0015) with lowest 3-year OS (32.7%, CI 24.6%-43.5%) for patients with solid-organ transplantation. IS was associated with increased odds of greater nodal burden (OR 1.70, CI 1.37-2.11) and lymphovascular invasion (OR 1.58, CI 1.23-2.03). Conclusions: Immune status was independently prognostic for OS for patients with localized MCC. Etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status and potentially etiology of IS may be useful prognostic factors to consider for future MCC staging systems.
Treatment of metastatic acral lentiginous melanoma: Systematic review.
Authors: Ospina Serrano Aylen Vanessa , Segovia Javier , Pino Luis Eduardo , Triana Ivan Camilo , Rojas Santiago
Published: June 2021

e21536

Background: Acral lentiginous melanoma (AML) is infrequent malignant melanoma subtype (5%) .It does not have specific treatment. The objective of this article is to summarize the best available evidence regarding the specific treatment of metastatic acral lentiginous melanoma. Methods: A systematic review of the literature was proposed. A search was carried out in the databases of Pubmed, Embase, Scopus, Lilacs in English and Spanish, during the last 20 years. The equation used was ((“acral lentiginous melanoma”) AND (“Treatment”)). For quality assessment, the JAMA guidelines for qualifying and globally through the GRADE system, the Cochrane guideline for evaluation of clinical trial bias was used. The review process involved 3 researchers and differents filters for evaluating the scientific evidence. The primary outcome was overall survival (OSm) and progression-free survival (PFS) as a secondary outcome. Results: 208 articles were found, only 3 articles were included. No phase 3 clinical trial. The summary of the data and qualification of evidence are in Table. In total there were 63 patients. It was found high heterogeneity in the 3 studies. The outcomes were those reported directly from each study, a subgroup analysis was not required. In first study, overall survival 21.1m was found with Dasatinib and PFS 2.8m. The second clinical trial, found OS with Nivolumab of 28.7% at 3 years. The last study was observational, and included three different treatment options, the outcomes were: Chemotherapy OSm 8.3m and PFS 2.1m, Immunotherapy OSm 16.6m and PFS 11.4m and Targeted therapy OSm 21.7m and PFS 11.4m. Conclusions: Worldwide, there is no good quality scientific information to define the best specific treatment for acral lentiginous melanoma. Current available evidence suggests that treatment with targeted therapies such as c-kit, V600E or immunotherapy as some useful options. Link Prospero: CRD42020171528.[Table: see text]
Machine learning imputation of metastatic status from open claims in melanoma patients.
Authors: Vaidya Vivek Prabhakar , Prajapati Rambaksh , Manirevu Sai Vinod , George Rohini , Agrawal Smita , Narayanan Babu
Published: June 2021

e21540

Background: Metastatic status is a crucial variable in most oncology studies but is not available in claims data. The objective of this study is to develop a machine learning model for Imputation of metastatic status from claims data with ground. Truth is derived from highly curated electronic medical record data. Methods: We used a set of 11389 melanoma patients from the ConcertAI real world database of intersecting claims and EMR data that includes data from CancerLinQ Discovery. Using features from claims and our gold standard labels from EMR we built an ML model using (XGBoost) extreme gradient boosting, an algorithm that iteratively combines a set of decision trees into a single model. We used 60% of the data for training, 20% for hyper-parameter tuning, and 20% for holdout testing. The model was built using 55 features. Results: The table below summarizes results. Metrics are on the final hold out set which was unseen by the model and entirely composed of highly curated EMR data. Conclusions: We are able to build a high precision model for the imputation of metastatic melanoma status using claims data. This could enable significantly better use of claims data stemming from the ability to find a metastatic cohort with very few false positives. Providing more precise cohort identification for comparative effectiveness studies. We found features such as secondary neoplasm diagnosis, anti-neoplastic meds, and radiation ranking highly in our analysis of model feature importances. Using techniques to analyze non-linear feature interactions in our AI model we found an interaction relationship between long term anti-neoplastic therapy, reported pain and metastatic status which we plan to further study. This work is preliminary and we are working to further improve model performance.[Table: see text]
Treatment beyond progression with immune checkpoint inhibitors in advanced melanoma.
Authors: Sobczuk Pawel , Czarnecka Anna Malgorzata , Spalek Mateusz , Teterycz Pawel , Dudzisz-Śledź Monika , Switaj Tomasz , Rogala Pawel , Placzke Joanna , Kozak Katarzyna , Borkowska Aneta , Kosela-Paterczyk Hanna , Rutkowski Piotr
Published: June 2021

e21541

Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.
Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.
Authors: Robinson Mat , Vervier Kevin , Popple Amy , Harris Simon , Hudson Robyne , Adams David , Rabbie Roy , Milne Doreen , Booth Catherine , Welsh Sarah Joanne , Bruce David , Corrie Philippa Gail , Lawley Trevor
Published: June 2021

e21546

Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.
Recurrent disease in patients with stage III melanoma in the era of adjuvant immune and targeted therapy.
Authors: Lo Victor , Francescutti Valerie , McWhirter Elaine , Farrokhyar Forough , Lee Linda May
Published: June 2021

e21570

Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.
BRAF testing timelines and impact on the starting of systemic treatment.
Authors: Arteaga Diana Paola , Saeed Kamil Zaid , Pimentel Muniz Thiago , Liu Diane , King Ian , Stockley Tracy , Gray Diana , Saibil Samuel , Hogg David , Spreafico Anna , Butler Marcus O.
Published: June 2021

e21575

Background: Targeted therapy with BRAF and MEK inhibitors constitute part of the standard treatment for BRAF V600 mutated melanoma. Timely detection of BRAF mutation is necessary for clinicians and patients to make treatment decisions. We aimed to map the BRAF testing timelines from the time of request until the reported result in order to assess obstacles to timely BRAF reporting in our community, and its impact on the initiation of systemic therapy. Methods: In this single-center retrospective study, we included adult patients referred to the Medical Oncology Department at the Princess Margaret Cancer Centre (PM) from January 2019 to August 2019 with histologically confirmed cutaneous or mucosal melanoma and BRAF molecular testing performed in 2019. The Log-Rank method was applied to detect differences in BRAF turnaround time and time to treatment initiation in specified subgroups. A p value < 0.05 was considered statistically significant. Results: Sixty-six cases were identified. The median age was 64 (24-88), and 42 (64%) were male. At the time of BRAF request, 10 (15%) patients had stage II, 33 (50%) had stage III, and 23 (35%) had stage IV disease. Twenty-eight (43%) were positive for the BRAF V600E/K mutation by ARMS assay and 4 (6%) for other variants by NGS test. Thirty-three (50%) patients had the BRAF test available at their first PM Medical Oncology visit. Median time between BRAF request and result was 17 days; when a reflex BRAF test was ordered by the Pathology Department, the median turnaround time was 12 days (95% CI 8-15), compared to 20 days (95% CI 16-23) if the order was requested by another specialist ( p < 0.001). Median time to transfer samples between institutions was 6 days. If the BRAF test was processed within the institution where the biopsy was performed, the BRAF median turnaround time was 13 days (95% CI 6-19) compared to 19 days (95% CI 16-21) if a sample was transferred to another institution ( p = 0.02). In total, 49 patients had systemic therapy. Median time between the first visit with Medical Oncology and treatment initiation was 29 days and was not statistically different if the BRAF result was available or not (28 vs. 34 days; p = 0.09). In the subgroup with stage IV disease (Table), 20 patients received systemic therapy; the median time to treatment initiation was 24 days and differed with BRAF result availability (20 vs. 31 days, p = 0.03). Conclusions: The current BRAF testing timeline at the PM varies from days to weeks. A major factor impacting this timeline is transfer time, which can be streamlined by pathology reflex testing. Delays in turnaround time appears to impact subsequent timing and type of therapeutic interventions, especially in patients with stage IV disease.[Table: see text]
Somatic mutations predict immune-related adverse events (irAEs) and survival following CTLA4 blockade in melanoma patients.
Authors: Shah Savan , Yu Xiaoqing , Teer Jamie K. , Conejo-Garcia Jose , Lyons Maureen , LaFramboise William , Tarhini Ahmad A.
Published: June 2021

e21584

Background: Predicting immune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) as well as the likelihood of clinical benefit is an area of great interest. irAEs have been associated with clinical outcome measures and we were interested in examining somatic mutations that may correlate with irAEs and subsequently with relapse free survival (RFS) and overall survival (OS). Methods: Our irAEs of interest for this analysis were rash and colitis based on prior data and these were tested for association with RFS and overall OS. Nonsynonymous somatic mutations were identified utilizing tumor and matched blood samples from 22 metastatic melanoma patients treated with neoadjuvant ipilimumab. Whole exome sequencing was performed using the SOLiD 5500 Next-Generation Sequencing platform. Somatic mutations were identified by subtraction of germline variants. Total mutational burden was assessed, and individual mutations were correlated with irAEs and with clinical outcome. Results: MUC16 was the most commonly mutated gene (82%). Of notable known oncogenic mutations, BRAF was the most common (50%) followed by NRAS (23%). Among known oncogenic signaling pathways, enrichment was most common in RTK-RAS (58%), followed by NOTCH and WNT. Development of colitis showed a strong trend in association with RFS. Development of rash indicated a similar trend. 20 different statistically significant mutations (p < 0.05) were identified among patients with colitis and these were also associated with OS and RFS. Notably, PTPRO mutation status (known to antagonize PDL1 expression) appeared protective against colitis and associated with worse RFS and OS. Similarly, ADGB mutation was significantly associated with developing rash and also associated with improved RFS and OS. Correcting for TMB in a multivariate model confirmed the associations. Conclusions: Somatic mutations were found to be associated with the irAEs of rash and colitis and with clinical outcome following ipilimumab treatment of melanoma. Our findings warrant further investigation and validation in independent cohorts.
High expression of ferroptosis-sensitizer ACSL4 as an indicator of good response to immune checkpoint inhibitors and preferable survival with increased TIICs in skin cutaneous melanoma.
Authors: Wu Jinchun , He Zhengxi , Liu Xianyu , Mou Yanhua , Lu Jingchen , Duan Chaojun , Li Bin
Published: June 2021

e21594

Background: Skin cutaneous melanoma (SKCM) has a high incidence and mortality. Immune checkpoint inhibitors (ICIs) are promising but show heterogeneous efficacy in the SKCM treatment. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of ICIs. Acyl-CoA synthetase long chain family member 4 (ACSL4) can sensitize ferroptosis by facilitating lipid peroxidation. So we proposed that ACSL4 is a positive predictor for ICIs efficacy and correlated with tumor-infiltrating immune cells (TIICs) in SKCM. Methods: The responses of SKCM patients to ICIs were evaluated from Tumor Immune Dysfunction and Exclusion (TIDE) using the gene expression data of The Cancer Genome Atlas (TCGA)-SKCM downloaded from UCSC Xena browser and datasets within TIDE. The correlation between ACLS4 expression and survival was obtained from the Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) and TIDE databases. The relationships between ACSL4 and TIICs were evaluated using the database of Tumor Immune Estimation Resource 2.0 (TIMER2.0). Results: ACSL4 expression was positively correlated with the predicted responder of ICIs in TCGA dataset (R = 0.12, p = 0.0093) and therapy outcomes of ICIs in Gide2019_PD1+CTLA4 (Progression-free survival(PFS), contimuous z = -2.39, p = 0.0169) and Lauss2017_ACT (PFS, contimuous z = -2.08, p = 0.0371; overall survival(OS), contimuous z = -2.96, p = 0.00309). Favorable OS was observed in the patients with high ACSL4 expression in the TCGA (HR = 0.6567, 95% CI = 0.5015̃0.8599, p = 0.0022) and GSE19234 (HR = 0.4135, 95% CI = 0.1748̃0.9784, p = 0.0445) from OSskcm and the GSE8401 (contimuous z = -2,24, p = 0.025) and GSE54467 (contimuous z = -2.26, p = 0.0239) from TIDE database. TIICs including CD8+ T cells, CD4+ T cells (memory, Th2), B cells, neutrophils, monocytes, M1 macrophages, and cancer-associated fibroblasts (CAFs) were positively associated with the expression level of ACSL4. Conclusions: High ACSL4 expression maybe indicates a good response to ICIs and long survival in SKCM. The increased T cells within the tumor microenvironment correlated with high ACSL4 expression possibly implied the synergism effects of ferroptosis and ICIs, deserving further investigation. Keywords: ACSL4, ICIs, TIICs, SKCM.
CD8+ T-cell lymphocyte infiltration predict clinical outcomes Wilms’ tumor.
Authors: Rahbar Mahtab , Mardanpour Keykhosro , Mardanpour Sourena
Published: June 2021

e22001

Background: The abundance and location of CD8+ tumor-infiltrating lymphocytes demonstrate important facets of the anticancer immune response. CD8-expressing lymphocytes have been used in immunotherapy for multiple cancers. This study aims to determine the association between the abundance and localization of CD8+ tumor-infiltrating lymphocytes and clinical outcomes Wilms’ tumor. Methods: This retrospective study employed 42 pediatric patients diagnosed with Wilms’ tumor. CD8+ tumor-infiltrating lymphocyte counts were calculated based on the mean percentage of stroma occupied by CD8+ lymphocytes at the center and the invasive border of the tumor using immunohistochemistry. Results: CD8+ tumor-infiltrating lymphocyte counts were significantly higher in the center and the invasive border of the early-stage tumor samples. CD8+ tumor-infiltrating lymphocytes in the invasive border and tumor center positively correlated with tumor invasion, regional lymph node invasion, histological type, metastasis, and stage of the tumor. A high CD8+ tumor-infiltrating lymphocyte scores at the invasive margin of the tumor correlated with low tumor recurrence. Low CD8+ tumor-infiltrating lymphocyte scores in the two tumor regions correlated with poor prognosis and shorter disease-free survival. Conclusions: Overall, these findings show that patients with high CD8+ tumor-infiltrating lymphocytes are associated with better clinical outcomes. Therefore, measuring the abundance of CD8+ tumor-infiltrating lymphocytes may be useful in predicting response to cancer immunotherapies.
Single agent high-dose ifosfamide in refractory or relapsed osteosarcoma.
Authors: Jiwani Zahra Merchant , Ramiz Sarah Watheq Shakir
Published: June 2021

e22006

Background: Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone in children and adolescents, typically occurring in the metaphysis of long bones. Historically, patients were treated with surgical resection, but the addition of neoadjuvant chemotherapy over the last 50 years has greatly improved prognosis, with survival rates increasing from 20% to almost 70% for non-metastatic tumors. However, prognosis remains poor for patients with refractory or recurrent disease, and Ifosfamide containing regimens are the standard 2nd line chemotherapy. Ifosfamide has been utilized in various combinations with other chemotherapeutic agents including methotrexate, cisplatin and epirubicin with variable reported results. Alternatively, it has been used as a single agent at an escalated dose of 12-14 gm/m2 with improved response. However, high dose Ifosfamide (HDI) is associated with nephrotoxicity. We aim to evaluate our institution’s experience with single agent HDI in terms of both outcome and safety. Methods: This is a single institutional retrospective study conducted at the Children’s Hospital of Michigan. All pediatric patients up to age 21 years with refractory or relapsed osteosarcoma who received at least 2 cycles of HDI therapy after MAP over the course of 20 years were included. Progression free and event free survival were calculated. Nephrotoxicity was documented as per common terminology criteria for adverse events (CTCAE) v.50 grading. Results: A total of 46 charts were screened, 19 patients were found to have recurrent or refractory OS. 3 patients were only treated surgically. 16 patients received 2nd line chemotherapy with/without surgical resection. 13 patients received single agent HDI and were included in our analysis. The mean age at diagnosis was 13.78, with 6 recurrent and 7 refractory patients. Patients received an average of 5 cycles of HDI. At end of therapy, objective response rate was 46% and disease control rate was 61%. 5 patients in our analysis had reported nephrotoxicity, with 3 patients having transient grade 1 elevations in creatinine that improved while remaining on chemotherapy. 2 patients developed persistent grade I elevation of creatinine, both developed this nephrotoxicity after being off therapy for more than 1 year. Nephrotoxicity was associated with higher number of cycles of HDI, with these patients receiving at least 4 cycles. At this point of follow up, 3 patients are alive without evidence of disease at least 2 years after completion of chemotherapy. Conclusions: Our experience is consistent with prior reports that HDI is efficacious as single agent therapy for patients with osteosarcoma that is refractory or recurrent with acceptable nephrotoxicity. In our experience, nephrotoxicity occasionally developed months after the cessation of therapy. As such, long term follow up of survivors is necessary.
Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory neuroblastoma.
Authors: Zhu Jia , Zhen Zijun , Wang Juan , Chen Tingting , Lu Suying , Sun Feifei , Huang Junting , Que Yi , Zhang Lian , Zhang Yizhuo , Sun Xiaofei
Published: June 2021

e22009

Background: The combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed or refractory neuroblastoma (NB). Methods: Forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2 /day i.v. days 1–5) and temozolomide (100 mg/m2 /day p.o. days 1–5) (VIT) during the period 2011–2019. All toxicities were documented. Results: A total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade III or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. Overall objective response rates to VIT combination for patients with mediastinum, bone marrow/bone, lymph node, abdomen and brain involvement were 100.0%, 80.0%, 77.8%, 50.0%, 42.9%, respectively. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them. Conclusions: The shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.[Table: see text]
Predictors of inpatient admission for pediatric cancer patients visiting the emergency department.
Authors: Lee Terrence C. , Qiao Edmund M. , Qian Alexander S. , Nalawade Vinit , Voora Rohith S. , Kotha Nikhil V. , Dameff Christian , Coyne Christopher John , Murphy James Don
Published: June 2021

e22019

Background: Pediatric cancer patients represent a vulnerable cohort at risk of adverse outcomes after presenting to the emergency department (ED). Given the severity of cancer-related complications and uniqueness of this population, approaches to better risk stratify this cohort could potentially help define future interventions geared towards improving outcomes. We used a high-dimensional machine learning approach to help define the risk of hospitalization after an ED visit among pediatric patients with cancer. Methods: A cohort of cancer patients under 18 was identified from the Nationwide Emergency Department Sample (NEDS) between 2016-2018. We used a lasso regression model to predict inpatient admission after an ED visit. Model covariates included patient demographics, hospital characteristics, and International Classification of Diseases, version 10 (ICD-10) diagnosis codes. The data were split 75%/25% into training/testing data. The model was constructed with training data, and performance assessed on the test data using the area under the curve (AUC), with an AUC of 1.0 indicating perfect prediction. Results: We identified 129,631 pediatric cancer patients who visited the ED, of which 54.5% were subsequently admitted. The final predictive model included 150 variables, including 9 demographic, 6 hospital, and 135 unique ICD-10 codes. The model demonstrated excellent ability to predict hospitalization with an AUC of 0.96. The top 5 most important variables associated with inpatient admission were diagnoses of paralytic ileus/intestinal obstruction, neutropenia, sepsis, aplastic anemia/bone marrow failure, and bacterial infection. Conclusions: Pediatric cancer patients frequently present to the ED with complications of their cancer or their treatment, and over half of these patients are admitted. This study demonstrates the capacity of high-dimensional prediction models to help identify pediatric patients at risk of hospitalization. Additional research is needed to determine how to implement these predictive models in clinical practice.
Improved universal tumor screening program with paired testing: Experience at a large community-based teaching hospital.
Authors: Majmudar Gnyapti , Ivan Kristina , Rangarajan Tara , Zakalik Dana
Published: June 2021

e22505

Background: Lynch syndrome (LS) is the most common cause of hereditary predisposition to colon, endometrial, and other cancers. The universal tumor screening program for LS at Beaumont Health (BH) utilizes immunohistochemistry (IHC) of the mismatch repair (MMR) proteins to identify patients for genetics evaluation. We present the 8-year experience of the program at a large community-based teaching hospital. Methods: The MMR IHC results for all colorectal cancer (CRC) resection specimens screened from August 2012 to September 2020 were reviewed. Specimens with absent MLH1 and PMS2 were evaluated for MLH1 promoter hypermethylation with reflex to BRAF V600E mutation analysis. All abnormal results were referred for cancer genetics evaluation. The distribution of abnormal MMR and germline genetic testing results was analyzed. Results: Specimens from 2361 CRC resections were screened, and 511 specimens had abnormal MMR IHC (22%). Most cases of absent MLH1 and PMS2 were explained by hypermethylation or BRAF analysis (n = 338, 66% of all abnormal, 89% of MLH1 and PMS2). Of the remaining cases showing MMR deficiency (n = 173), the most common result was absence of MSH2 and MSH6 (n = 67), followed by absence of MLH1 and PMS2 (n=41, see table). Germline genetic testing of 83 individuals with abnormal MMR IHC revealed 49 cases of Lynch syndrome [MLH1 (n=9), MSH2 (n= 25), MSH6 (n=7), PMS2 (n=7), EPCAM (n=1)]. A significant proportion of cases (n=34, 40%) had negative germline testing, and had unexplained MMR deficiency. Paired germline/tumor testing was implemented in 2017, and 14 patients had this analysis. Using this approach, 5 individuals were identified to have somatic mutations explaining their result, and the proportion of unexplained cases was reduced to 29% (n = 4). Conclusions: Recent advances in cancer screening and therapeutics have underscored the importance of analyzing tumors for mismatch repair deficiency (dMMR), with known challenges to implementation and interpretation of results. The BH cancer genetics program has demonstrated successful growth of a universal tumor screening program over 8 years. This has led to the identification of a large number of dMMR tumors (22% of all CRC resections) and LS cases (2% of all CRC resections), which impacts management for patients and their families. Recent implementation of paired germline/tumor testing has improved the testing algorithm, and resulted in more accurate interpretation of a greater proportion of abnormal IHC results. This combined approach allows for focused high-risk screening for LS patients, access to novel therapeutic interventions including immune therapies for patients with dMMR tumors, and future precision oncology approaches.[Table: see text]
Prevalence of pathogenic mutations and variants of uncertain significance in patients undergoing hereditary cancer genetic testing in Cambridge, MA.
Authors: Jani Chinmay , Rupal Arashdeep , Al Omari Omar , Agarwal Lipisha , Stafford Katherine A. , Singh Harpreet , Dar Abdul Qadir , Lotz Margaret , Dangelo Abby , Lam Prudence B.
Published: June 2021

e22506

Background: Genetic testing allows for enhanced prognostication and early intervention in patients with high risk of developing cancer. Genetic testing often reveals variants of uncertain significance (VUS), for which association with disease risk is unclear. The ambiguity of this finding creates a dilemma for patients and providers and has been associated with significant communication error and distress. In this retrospective observational study, we seek to characterize the indications, outcomes, and trends in patients undergoing genetic testing in a community hospital in Cambridge, MA. As our study spanned the beginning of the COVID-19 pandemic, we also assessed its impact on care accessibility. Methods: We included patients undergoing genetic testing at our hospital between December 2019 and October 2020 (n=371). Medical charts were abstracted to identify patient characteristics, family history, indication for genetic testing, genetic findings, and subsequent management. Results: Our population had a mean age of 48 years (SD=15), was predominantly female (88.1%), and had a high proportion of Ashkenazi Jewish descent (15.3%). The vast majority (351, 94.6%) had a family history of cancer, while 123 (33.2%) had a personal history of cancer, most commonly breast (n=89). The most common indications for genetic testing were Hereditary Breast and Ovarian Cancer (HBOC in 280, 75%), Lynch Syndrome (LS in 22, 5.9%), and Familial Adenomatous Polyposis (FAP in 7, 2%). Of patients who met HBOC, LS, or FAP criteria for genetic testing, pathogenic mutations were identified in 9.5% and VUS in 28.6%. Out of total 35 (9.4%) pathogenic mutations found in our entire study population, the most common were in BRCA (9, 25.7%), MUTYH (5, 14.2%), and Lynch genes (3, 8.6%). Out of 103 patients with VUS (27.8%), the most common sites were APC (14) and MSH3 (9). We found no significant trend in genetic counseling consultations over our 11 months study period despite the COVID-19 pandemic (R2 = 0.006). Conclusions: Among patients who met criteria for genetic cancer screening at a community hospital, 9.5% were found to have a pathogenic mutation while 28.6% were found to have VUS. These numbers are comparable to previously published estimates. Despite advances in our understanding of genetic colon and gynecological cancers, the majority of patients presenting for genetic cancer counseling continue to do so due to breast cancer concerns. Lastly, we noted high efficacy in our conversion of in-person genetics consultations to telemedicine during the COVID-19 pandemic, suggesting telemedicine is a robust format for genetic counselling. Mutations (N): BRCA1 (3), BRCA2 (6); MUTHY (5); MSH2 (2), MSH6 (1); ATM (2), and one each in PALB2, RAD50, RAD51C, RAD51D, Tp53, CDKN2A, APC, F2, SDHA, SDHB, VHL. FANCL, NTHL1.