bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer.
Authors: Zeng Tao , Deng Huanhuan , Zhao Rongsong , Huang Longwu , Gong Yun , Zhu Yuetian , Wang Qingping , Li Feng , Liu Lirong , Qi Yan , Wang Xianshu , Zou Hongzhi
Published: June 2021

e16503

Background: For bladder cancer (BC), the 5-year survival rate for patients with localized tumors can reach as high as 92%, but only 45% for those with tumors spreading to nearby regions. Cystoscopy combined with tissue biopsy can miss 10-40% of the cancer cases due to multiple factors. Meanwhile, the method is invasive, causing physical discomfort and psychological trauma for the patients. Therefore, development of a noninvasive, sensitive, and specific diagnostic alternative is needed. By analyzing TCGA data and improving analytic technology currently available, we have developed an easy-to-use, convenient, and accurate detection approach for BC relying on a single methylation marker. Methods: We searched TCGA database and selected a total of 366 candidate markers including those that have been published for subsequent examination and analyzed 446 primer pairs and probe sets. Using quantitative methylight method, we narrowed the field down to top 5 performers for subsequent urine-based testing of 270 samples. Finally, two markers were selected for validation testing in a group of 530 urine samples, consisting of 161 bladder cancers, 244 normal controls, 80 renal carcinomas, and 45 carcinomas of renal pelvis and ureter. In addition, we detected the methylation level and mRNA expression of target gene in 8 bladder cancer cell lines and 1 normal bladder epithelial cell line by MSP, qMSP and qPCR. Results: Methylation marker DMRTA2 had a sensitivity of 85.7%, an AUC value of 0.924, and an accuracy of 90.6%. The specificity, from a control group consisting of patients with lithangiuria, prostatoplasia, and prostatitis as well as healthy individuals, is 93.9% (138/161). Notably, the methylation assay had the highest sensitivities for tumors at stages of T1 (94.4%) and T2 (96.6%) compared with T3 (80.0%), T4 (71.4%), and unknown stage (90.0%). While methylation was observed in 34/45 urine samples from patients with carcinomas of renal pelvis and ureter, a good sensitivity of 75.6%, it was detected at extremely low rate of 7.5% (6/80) in those with interfering cancers of kidney and prostate. Additionally, the assay specificity was significantly affected by the age of the cancer patients and selection of healthy controls, critical aspects to be carefully considered during the design and development phase of the methylation-specific testing. Compared with SV-HUC-1, the normal bladder epithelial cell line, DMRTA2 gene was hypermethylated in 8 bladder cancer cell lines, which is consistent with the results of MSP and qMSP. The mRNA levels of DMRTA2 were low in some bladder cancer cell lines, such as T24, J82, UM-UC-3 and RT4, however were fairly high levels in 5637, SCaBER, TCCSUP and SW780. Conclusions: Our data demonstrated that a single-target DNA methylation signature could be highly effective to detect bladder cancer via urine samples.
Role of adjuvant chemotherapy in the treatment of patients with node-positive bladder adenocarcinoma: An analysis of the National Cancer Database.
Authors: Reddy Akshay G , Sparks Andrew D , Whalen Michael Joseph
Published: June 2021

e16504

Background: Given the rarity of bladder adenocarcinoma, there is a paucity of data examining the role of adjuvant chemotherapy (AC) in patients with regional lymph node positivity. This study aims to elucidate the oncologic and survival outcomes of patients with node-positive disease treated with or without AC. Methods: A retrospective cohort analysis of patients with node-positive primary bladder adenocarcinoma who had either received AC or did not receive AC after either radical (RC) or partial cystectomy (PC) was performed using the National Cancer Database from 2006 to 2016. Non-metastatic node-positive was defined as pT(any)N1-3 (pN+) disease. Demographic and clinicopathological variables were compared to adjust for confounding covariates in multivariable analysis to determine appropriate oncologic and surgical outcomes. Results: A total of 106 patients met inclusion criteria, of whom 38 received AC and 68 did not. Receipt of AC was significantly associated with improved survival relative to those who did not receive AC (overall survival: 29% vs 2.7%; adjusted hazards ratio = 0.43; p = 0.003) independent of extent of surgery. There was a trend toward higher receipt of adjuvant radiation along with AC, independent of surgical margin status. Receipt of AC additionally trended towards a significant association with decreased odds of 90-day mortality and 30-day unplanned readmission (Table). Conclusions: Based on the improved survival outcomes, positive nodal status may be a useful indicator of those who may benefit from AC, and potentially adjuvant radiation therapy, in bladder adenocarcinoma. Though compelling, larger studies will be required to make more conclusive statements regarding the most appropriate treatment course in these patients.[Table: see text]
Prognostic value of galectin-1 and galectin-3 expression in local urothelial bladder cancer.
Authors: Zhu Jason , Livasy Chad , Donahue Erin E , Symanowski James Thomas , Grigg Claud , Matulay Justin T. , Kearns James T , Raghavan Derek , Burgess Earle F , Clark Peter E
Published: June 2021

e16520

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins which regulate cellular adhesion, proliferation, and apoptosis in solid tumors . Prior studies have reported that Gal-3 expression is associated with non-muscle invasive UC progression to muscle invasive disease. Therefore, we assessed whether UC Gal-1 and Gal-3 protein expression in cystectomy specimens was prognostic for overall survival (OS) or recurrence free survival (RFS). Methods: Tissue microarrays (TMA) were generated from chemotherapy naïve cystectomy specimens. Biopsies included benign urothelium, noninvasive papillary UC (Ta), UC in situ (Tis), and invasive UC (p1-pT4: INV). Gal-1 and Gal-3 IHC expression was scored by intensity (0-3) and % of cells staining positive (0-100). An H-score (product of % and intensity) was utilized for analysis. Clinical data including pathologic T stage, N stage, surgical margins, tumor size, and Charlson Comorbidity Index (CCI) were included in multivariable analysis. Results: 656 biopsies were evaluated from 301 patients. 198 (30%) were from benign urothelium, 28 (4%) Ta, 178 (27%) Tis, and 252 (38%) were INV. With a median follow up of 64 months, median OS was 47.5 mo and median RFS was 38.4 mo. Gal-1 H-score was significantly higher in INV specimens than non-INV specimens, and the inverse relationship was found with Gal-3 (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, p < 0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, p < 0.01). In multivariable analysis, T stage, N stage, margins, tumor size, PCV pre-op and CCI score were prognostic of OS and RFS. Gal-1 and Gal-3 H-scores were not predictive of RFS (Gal-1: HR 1.0, p = 0.67, Gal-3: HR 1.0, p = 0.25) or OS (Gal-1: HR 1.0, p = 0.71, Gal-3: HR 1.0, p = 0.37). Intra-tumoral Gal-1 and Gal-3 expression heterogeneity was observed. 203 (67%) patients had 2 or more tissue specimens and of these, 99 (49%) had discordant H-scores at the same level of invasion. Conclusions: In this cohort, both Gal-1 and Gal-3 expression correlated with biopsy T stage; however, the highest intra-tumor H-score per specimen did not independently predict for RFS or OS. This result differs from prior observations from smaller cohorts that showed an association between Gal-3 expression and RFS, suggesting that intra-tumoral Gal-1/Gal-3 heterogeneity may confound the study of Gal-1 and Gal-3 as a potential biomarker in UC. The biological significance of intra-tumoral Gal heterogeneity in UC merits further investigation.
Bladder cancer in young adults: Disease and treatment characteristics of patients treated at tertiary cancer center.
Authors: Abu-Hijlih Ramiz Ahmad , Salah Samer , Al-Ibraheem Akram , Abuhijla Fawzi , Abu Serhan Hashem , Shahait Mohammed
Published: June 2021

e16521

Background: The incidence of bladder cancer in the Middle East is increasing. The data on young population with urothelial carcinoma (UC) of urinary bladder in the region is scarce. We evaluated clinical and tumor characteristics, in addition to management details in patients younger than 45 years old. Methods: We reviewed of all patients presenting with UC of the urinary bladder from July 2006 to December 2019. Clinical characteristics including demographics, stage at presentation, and treatment outcomes were described. Results: Out of 1,272 new cases of bladder cancer, a total of 112 patients (8.8%) were ≤45 years old. Seven patients (6%) had non-urothelial histology and were excluded. The remaining 105 eligible patients with UC had a median age at presentation was 41 years (35-43). Ninety three patients (88.6%) were males. Tumor stage at presentation: non-muscle invasive disease (Ta-T1), locally advanced muscle invasive bladder cancer (MIBC) (T2-3), and metastatic disease were 14 cases (84.7%), 2.8%, and 12.5%, respectively. All patients with MIBC received neoadjuvant cisplatin-based chemotherapy. Radical cystectomy was performed in 8 cases (7.6%); 3 patients with MIBC and 5 with high volume non-MIBC. Neobladder reconstruction was done in 6 patients. A total of 13 patients with metastatic disease (93%) received palliative chemotherapy (Gemcitabine/Cisplatin), and one (7%) was candidate of best supportive care only. Conclusions: Bladder cancer is relatively rare in young population, though the incidence at our region is higher than other reports in the literature. Most of patients present with early disease. Early diagnosis and multidisciplinary approach are paramount for management of these patients.
Prognosis impact of serous metastases (SMs) in clear cell renal cell carcinoma patients in the GETUG-AFU-26 NIVOREN phase II trial.
Authors: Bardet Florian , Dalban Cécile , Chevreau Christine , Negrier Sylvie , Laguerre Brigitte , Gravis Gwenaelle , Gross-Goupil Marine , Oudard Stephane , Barthélémy Philippe , Ferrero Jean Marc , Thiery-Vuillemin Antoine , Mahammedi Hakim , Narciso Berangere , Geoffrois Lionnel , Tantot Florence , Escudier Bernard , Ladoire Sylvain , Albiges Laurence
Published: June 2021

e16566

Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p<0.0001) were significantly lower in patients with SMs. The dismal prognostic impact was observed both with pleura and peritoneum SMs. These 2 sites were not significantly associated. Using multivariate Cox models, SMs remained significantly associated with poor survival, independently of IMDC category, gender, age, and number of previous lines of therapy. Objective response rate in patients with SMs was not significantly different from others patients (16.4 vs 22.1%; p=0.147). SMs were not statistically associated with known poor prognosis metastatic sites (cerebral, bone, and liver.) Conclusions: SMs are a strong independent prognostic impact in patients receiving N for metastatic ccRCC Poor prognostic metastatic sites should be considered when assessing the prognosis of patients with metastatic ccRCC
Hot clear cell renal cell carcinoma immune status: Illusion or reality?
Authors: Bi Xingang , Lu Yi , Bi Xinyu , Luo Zhiwen
Published: June 2021

e16575

Background: High tumor mutation burden (TMB) and increased CD8+ T cells infiltration are associated with positive ICIs response in many solid cancers. But non-responsive clear cell renal cell carcinoma (ccRCC) features modest TMB, high CD8+ T-cell infiltration but poor survival. Costimulatory molecules confer immune cell activation within the immune response. Therefore, we aimed to investigate ccRCC’s unique immune environment related prognosis and ICIs’ sensitivity from the aspect of co-stimulation alteration. Methods: We analyzed the combined ccRCC cohort of 844 patients’ RNA sequencing data, from two sources: One ccRCC group (533 patients) was from The Cancer Genome Atlas KIRC (TCGA-KIRC), and the validation group (311 patients) was from an ICIs treated clinical trial. Univariate, LASSO, and multivariate Cox regression analyses were used to identify overall survival-related costimulatory genes, which were used to build an immune prognostic model (IPM) stratifying survival risk level in ccRCC. Comprehensive bioinformatics discovered the relationship between immune status, ICIs’ sensitivity with IPM’ prognosis risk. Results: The survival related co-stimulatory genes were identified in 533 ccRCC patients to construct an immune prognostic model (IPM) to differentiate patients with a low or high risk of poor survival (AUC = 0.75). Functional enrichment analysis showed T cell homeostasis represented the major function alteration related to IPM risk score ( P< 0.05). ICIs clinical trial cohort validated the IPM’s moderate prediction performance for the ICIs response ( P= 0.028), for IPM-high risk patients are more likely to be resistant to ICIs. The high-risk group had higher CD8 + T cell infiltration, higher TMB, and higher cytolytic activity, while such a hot immune status was an illusion concealing the T cells homeostasis alteration with the increased proportion of dysfunctional CD8+ and CD4+ T cells, immunosuppressive cells (i.e., iT-regs, nT-regs, and CAFs) in IPM-high risk, this kind of refractory ccRCC subtype. Conclusions: Baseline CD8 + T cell infiltration, TMB, and cytolytic activity could not predict response to ICI in the ccRCCs, and hot tumor immune status represented by CD8+T cells in resistant ccRCC is an illusion concealing T cells homeostasis alteration. T cells homeostasis could provide critical insights into immunogenomic mechanisms contributing to the immunotherapy sensitivity in ccRCC. Our five-gene based IPM tested easily by PCR, was clinically accessible, cheap and useful for indicating refractory ccRCCs to undergo ICIs.
Predicting benefit of radium 223 based on biochemical response and site of metastasis: A real life multicenter UK study.
Authors: Das Prantik , Davies Jessica , Sharma Anand , Nair Ajith , Vengalil Salil , Perna Carla , Branagan Jenny , Masters Benjamin , Goh Chee , Otter Sophie , Prakash Vineet , Singh Sadmeet
Published: June 2021

e17034

Background: Studies have shown an improvement in overall survival (OS) and symptom control in metastatic castration-resistant prostate cancer (mCRPC) with Radium-223 treatment. However, there is little information about predicting outcomes using either PSA or Alkaline Phosphatase (ALP) response or comparing bone only disease to bone and lymph node (LN) involvement. Methods: 335 patients receiving Radium 223 at 6 UK centres between March 2014 and June 2020 were included. The primary endpoint was overall survival, secondary endpoints were toxicity, symptomatic benefit and skeletal-related events(SRE) Results: The median age was 75, with 71% having bone only metastases and 29% also having lymph node involvement. Those with PSA response (30%) had a statistically significant improvement in OS, compared to non-responders (18.2 vs 13.8 months, p = 0.026). They also showed highest rate of imaging response/stable disease (54% vs 34%). ALP response was seen in 82%. This did not translate to significantly improved OS, but did correlate with better symptomatic benefit (40% vs 29%). Those with bone only disease showed a survival benefit compared to those with LN involvement (19.4 vs 11.4 months, p = 0.046). Other than anaemia (23.5%), Grade 2 or above toxicities were uncommon including thrombocytopenia and neutropenia(5.5 and 6.2% respectively ) . 14% patients required at-least one blood transfusion. SRE were seen in 24% overall, but lower of in PSA responders(18%). Conclusions: Real life multicentre data suggests that PSA response and bone only disease could be predictors for better survival following Radium-223, whereas ALP response correlates better with symptomatic benefit.
Propensity score matching analysis of ovarian cancer patients with multiple primary malignant neoplasms using multicenter real-world data.
Authors: Gao Qing-lei , Jiao Xiaofei , Li Ruyuan , Zeng Shaoqing , Zhao Yingjun , Ma Guanchen , Huo Yabing , Li Ming , Liu Xingyu , Yu Yang , Liu Jiahao , Chi Jianhua , Dai Yun , Wang Ya , Chen Youguo , Yao Shuzhong , Wang Jing , Li Qingshui , Wang Li
Published: June 2021

e17501

Background: Multiple primary malignant neoplasms (MPMNs) in patients with ovarian cancer is rare and has not attracted enough attention. It is unclear how the MPMNs affect the prognosis of ovarian cancer (OC) patients. Methods: This is a multicenter retrospective analysis of 5, 268 ovarian cancer patients from six centers who was diagnosed with ovarian cancer from January 1, 1989 to August 21, 2020. Propensity score matching was used to balance the baseline characteristics between patients with and without MPMNs. Cox regression analysis was utilized to analyze the influence of MPMNs on overall survival (OS). Results: After excluding unqualified medical record, totally 4, 848 patients were analyzed and 240 were concurrent at least one MPMNs other than OC. Ten patients had two MPMNs and one patient had three. The most common concurrent cancer was breast cancer (111/240, 46.25%), followed by endometrial cancer (37/240, 15.42%), and cervical cancer (30/240, 12.50%). Patients with MPMNs were elder than those without MPMNs (52 vs. 51, P = 0.03) when ovarian cancer was diagnosed. And the proportion of early-stage cases was lower in patients with MPMNs (25.8% vs. 27.2%, P < 0.001). Patients with breast cancer had a higher proportion of high-grade serous ovarian cancer (HGSOC) than those without MPMNs. After using the propensity score matching method adjusting age, pathological type, grade, and stage, concurrent MPMNs, including breast cancer, had no effect on OS of ovarian cancer patients. Among 240 patients with MPMNs, patients with breast cancer shared similar age and stage compared with the rest patients, while their proportion of HGSOC was higher than patients with other cancer (68.4% vs. 51.1%, P = 0.028). However, the median OS of those two groups were similar (27.3 m vs.27.1 m, P = 0.744). In addition, 94 patients were diagnosed with breast cancer prior to ovarian cancer, seven diagnosed posteriorly to ovarian cancer, four diagnosed simultaneously, and six had no precise diagnosed dates. There was no remarkable difference in clinical characteristics between the prior and posterior groups, however, the median OS of those seven patients was significantly longer than the prior group (76.0 m vs. 25.4 m, P = 0.002). Conclusions: The MPMNs showed no influence on the overall survival of ovarian cancer patients. The order of diagnosis of ovarian cancer and breast cancer might affect the prognosis.
Preliminary results of niraparib and brivanib dual therapy evaluation in recurrent, metastatic and persistent cervical cancer (CQGOG0101): An open-label, phase II clinical trial.
Authors: Wang Haixia , Shu Jin , Zou Dongling , Zhou Qi
Published: June 2021

e17506

Background: Early-stage cervical cancer (CC) has a good long-term prognosis, with 5-year survival rate more than 90% for localized disease. However, once the CC relapsed, patients lack effective solutions and usually die in less than one year. In this study (CQGOG0101), we aimed to assess the efficacy and safety of niraparib combined with brivanib or toripalimab in patients with recurrent CC. Herein, we report the cohort 1 portion of the study (patients recieving Niraparib 200mg and Brivanib 400mg orally).Findings for the cohort 2 of patients receiving niraparib and toripalimab will be reported separately. Methods: The cohort 1 of CQGOG0101 trial was to evaluate the safety and activity of Niraparib combined with Brivanib in patients with recurrent, metastatic, or persistent cervical cancer. 10 patients were planned to be enrolled (Actually nine patients). Eligible patients were aged 18–70 years with measurable lesions and had an ECOG performance status of 0-2. Patients received oral niraparib 200 mg and brivanib 400 mg once daily until disease progression, intolerable toxicity, or withdrawal of consent. Primary endpoint was the objective response rate (ORR) assessed by RECIST version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and safety. Results: Between May 8th, 2020 and Jan 22nd, 2021, 9 patients (median age, 50 years old [28-73]) were enrolled. Patients had received a median of two (1-3) previous lines of platinum-based therapy. All of nine patients had distant metastatic lesions and had underwent at least one post-baseline tumor assessment (To deadline for submission), including 1 confirmed partial response, 4 with stable disease, 4 with progressive disease. Median duration of treatment was 3.8 months (3-8.2), three patients were still on treatment. No drug-related grade 3 or worse treatment-emergent adverse events were detected, the most common grade 1-2 adverse events (AEs) included: neutropenia (4 of 9 patients), anemia (2 of 9 patients), thrombocytopenia (1 of 9 patients), hypertension (2 of 9 patients), proteinuria(1 of 9 patients), fatigue (1 of 9 patients), and increased ALT/AST (1 of 9 patients). Conclusions: This combo seems to show a similar efficacy compared to other recurrent cervical cancer late-line therapies. We are planning to initiate the cohort 2 to explore niraparib combined with anti-PD-1 antibody (Toripalimab) in recurrent CC in our trial later. Clinical trial information: NCT04395612.
Efficacy and safety of systemic treatments for patients with recurrent/metastatic head and neck squamous cell carcinoma: A systematic review and network meta-analysis.
Authors: Meng Lingbin , Ji Rui , Wang Huanhuan , Jiang Xin
Published: June 2021

e18001

Background: A variety of systemic chemotherapy regimens have been used for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, most guidelines were derived from a single clinical trial, and no studies have comprehensively compared their efficacy and safety. This study is aimed to compare the efficacy and safety of systemic chemotherapies for patients with R/M HNSCC. Methods: We conducted a systematic review of published studies in PubMed, Embase, Web of Science, and Cochrane Library databases up to July 31, 2020. Studies were included if they were randomized controlled clinical trials including treatment regimens recommended by the latest NCCN guidelines. Eligible studies should report at least one of the following outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and ≥3 adverse events rate (AEs). Literature screening, data extraction and quality assessment were independently conducted by two researchers. Disputes were settled by a panel of other researchers. Network meta-analysis was used to compare the efficacy and safety of various treatment regimens. Heterogeneity and consistency using the Bayesian model were evaluated in the network meta-analysis. Results: Eighteen eligible trials involving 4930 patients and 15 treatment regimens were included. Cetuximab/platinum/5-FU regimen showed higher ORR values than the following agents, including cisplatin/5-FU (odds ratio 2.96, 95% credible interval 1.42 to 6.15), cisplatin (5.43, 1.90-15.54), 5-FU (8.12, 2.22-29.61), methotrexate (8.25, 2.86-23.79), cetuximab (10.16, 1.44-71.48), and afatinib (3.64, 1.00-13.32). Immunotherapy regimens pembrolizumab/platinum/5-FU and pembrolizumab alone also showed significantly higher ORR values than these agents, while nivolumab alone showed higher ORR than the single agents. However, no significant difference was observed between Cetuximab/platinum/5-FU and pembrolizumab/platinum/5-FU. Regarding ≥3 AEs, cisplatin/paclitaxel caused the highest toxicity. No significant difference was observed on OS and PFS among all these treatment regimens. Conclusions: Cetuximab/platinum/5-FU, pembrolizumab/platinum/5-FU or pembrolizumab alone displayed high ORR with low AE rate. Nivolumab also showed better efficacy than other single agents. Although it was reported that pembrolizumab/platinum/5-FU showed better efficacy than cetuximab/platinum/5-FU, we did not find a statistically significant improvement in ORR, OS or PFS when comparing the two regimens. Therefore, further prospective trials comparing these treatment regimens remain warranted.
Identification of factors related to immunotherapy prognosis in patients with advanced head and neck squamous cell carcinoma.
Authors: Zhang Lin , Xu Xuanli , Ren Dandan , Wu Lijia , Gong Xiaoli , Li Rongrong , Zhu Guopei
Published: June 2021

e18003

Background: Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Anti-PD1/PD-L1 checkpoint inhibitors have shown survival benefit for the treatment on HNSCC, and are better tolerated than chemotherapy. Unfortunately, the response rate of immunotherapy is low for advanced HNSCC. Therefore, the identification of predictive biomarkers of response to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit from immunotherapy. Methods: The present study included 44 patients with advanced HNSCC who received anti-PD-1 immunotherapy. Follow-up was available for them. Primary tumor tissues and matched blood samples were collected. Genome profiles were analyzed using a designed 543-gene panel based on NGS, and were available on 39 of 44 patients. Profiles of infiltrating immune cells were available for 44 patients. The infiltrating intensity of PD-1, PD-L1, CD8, CD68 and CD57 positive cells were assessed by multiplex immunohistochemistry. Results: The most frequently mutated genes were TP53 (79%), CDKN2A (33%), NOTCH1 (21%), CASP8 (13%) and PIK3CA (10%). Patients with mutations in the PI3K pathway showed a trend of longer OS (P = 0.06). Moreover, the TMB-high group showed significant superior OS than the TMB-low group (p = 0.0018). PD-L1 expression was positively correlated with CD8 expression within stroma, and PD-1 expression correlated significantly with PD-L1 and CD8 expression within both tumor and stroma areas. In addition, tumor/stromal PD-L1 and PD-1 expression were both associated with better OS (P < 0.05). Prolonged OS was also observed in patients with more tumor and stromal infiltration of CD8+ cells, CD8+PD-L1+ cells, CD68+ macrophages, or nature killer (NK, CD57+) cells. Conclusions: Higher TMB, PD-L1 expression, as well as the infiltration of immune cells within both tumor and stromal area might serve as favorable prognostic markers in advanced HNSCC patients treated with anti-PD-1 immunotherapy.
Survival results of phase I dose escalation of stereotactic body radiation therapy and concurrent cisplatin for re-irradiation of unresectable, recurrent head and neck squamous cell carcinoma.
Authors: Echevarria Michelle , Chung Christine H. , Kirtane Kedar , Muzaffar Jameel , Kish Julie Ann , Arrington John , Farinhas Joaquim , Caudell Jimmy J.
Published: June 2021

e18020

Background: Stereotactic body radiation therapy (SBRT) is a standard option for re-irradiation of recurrent or second primary cancers of the head and neck. We conducted performed a phase I clinical trial to establish a maximum tolerated dose of SBRT with concurrent cisplatin. We previously reported our safety data, and now present our secondary disease control endpoints. Methods: Major inclusion criteria were recurrence of previous squamous cell carcinoma of the head and neck in patients who had previously undergone radiotherapy to doses ≥ 45 Gy to the area of recurrence, ≥ 6 months prior to enrollment, and who were medically unfit for surgery, deemed unresectable, or refused surgery. Patients were treated with radiation therapy every other day for five fractions at three dose levels: 30 Gy, 35 Gy, and 40 Gy. Cisplatin was given prior to every SBRT fraction at a dose of 15 mg/m2. Secondary end points reported herein are locoregional control (LRC), freedom from distant metastasis (FFDM), and overall survival (OS). Results: Twenty patients were enrolled and of those 18 patients were evaluable for secondary endpoints. Nine patients had a primary tumor in the oropharynx, four patients in the oral cavity, three in the neck, one in the larynx, and one simultaneously in the larynx and neck. All patients received the planned dose of Cisplatin. Five patients received a radiation dose of 30 Gy, three patients received a dose of 35 Gy, and 9 patients received a dose of 40 Gy. Median gross tumor volume (GTV) was 11.725 cm3. With a median follow up of 9 months the 1-year OS was 38.9%. LRC at 1 year was 45.7% and FFDM at 1 year was 87.8%. There was a trend to improved OS with increasing SBRT dose, 40 Gy vs < 40 Gy (p = 0.08). There was an improved 1-year OS with a GTV ≤11.725 cm3 of 77.8% vs 0% for tumors > 11.725 cm3 (p < 0.001). For patients with a GTV < 11.725 cm3 who received 40 Gy the 1 year OS was 100% compared with 0% for tumors larger than 11.725 cm3. Conclusions: For patients with previously radiated locally or regionally recurrent head and neck cancer, SBRT up to 40 Gy given concurrently with cisplatin provides reasonable locoregional control and overall survival for patients with smaller tumors. Further evaluation in prospective trials is warranted. Clinical trial information: NCT02158234.
Molecular profiling and survival outcomes of p16+ compared to p16- oropharynx squamous cell cancer patients.
Authors: Hughes Brittany Nicole , Shaikh Hira Ghazal , McGrath Julie Elaine , Xiu Joanne , Sukari Ammar , Korn Wolfgang Michael , Nabhan Chadi , Grover Punita , Darabi Sourat , Chernock Rebecca , Ikpeazu Chukwuemeka , Wise-Draper Trisha Michel
Published: June 2021

e18026

Background: Previous studies have consistently shown that p16+ oropharynx squamous cell cancer (OPSCC) patients have better outcomes. The significance of molecular and transcriptional signatures and its correlation with p16 expression remains unclear. Methods: We queried the Caris Life Sciences database to assess the molecular and transcriptional signatures related to p16+ and p16- head and neck squamous cell cancer (HNSCC) patients. Comprehensive molecular profiling including whole exome sequencing (WES), targeted Next-Generation Sequencing (NGS), and immunohistochemistry (IHC) 22c3 for PD-L1 was performed (CPS ≥1 considered positive) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. A standard cut-off of 2+, > 70% p16 staining was used. HPV16/18 was tested using WES. Patients were considered smokers if they had > 15 pack-years. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of start of treatment to the date of last contact. Results: 948 cases of OPSCC were identified in the Caris database. 41% (82/199) were smokers. Where p16 and HPV data was available, 41% were p16+ (171/420) while HPV positivity rate was 52% (71/148). We noted a small number of patients with discordant p16 and HPV status (7 p16+/HPV-, 8 p16-/HPV+) in 327 patients who had HPV status available. Most common mutations were TP53 (33%), PIK3CA (17%) and KMT2D (10.6%). 87% were PD-L1 positive (342/394), with high expression in both p16+ and p16- subgroups, 90% and 85% respectively. 10% had TMB≥10/Mb (48/463). TP53 mutations were more common in p16- (49%) tumors in contrast to p16+ (10%) (p < 0.0005), while no statistical difference was detected in TMB≥10/Mb between the groups. CDKN2A, TERT and NOTCH1 mutations were more prevalent in tumors that were p16- or HPV- in contrast to tumors that were p16+ or HPV+ (p < 0.05). FGF3, CCND1, FGF4, FGF19 copy number alterations (CNA) were less common in p16+ OPSCC compared to p16- or HPV16- OPSCC (p < 0.0005). P16+ patients had longer rwOS when compared to p16-, 47 months versus 20 months (HR = 0.55, p = 0.014) respectively. Conclusions: Higher frequency of CDKN2A, TERT and NOTCH1 mutations among p16- (versus p16+) raise the possibility of potential targets for treatment in this group with poor prognosis. However, it remains unclear if these can serve as independent predictors of survival.[Table: see text]
Adjuvant radiotherapy plus systemic chemotherapy in resected head and neck mucosal melanoma.
Authors: Duan Rong , Tang Bixia , Chi Zhihong , Cui Chuanliang , Lian Bin , Li Siming , Mao Lili , Yan Xieqiao , Wang Xuan , Bai Xue , Zhou Li , Wei Xiaoting , Guo Jun , Sheng Xinan
Published: June 2021

e18042

Background: The median over survival (OS) of resected head and neck mucosal melanoma (HNMM) is 49.0 months. About 65% of patients experience local recurrence or distant metastasis after surgery. Therefore, adjuvant therapy is critical to improve the poor prognosis. Methods: Data regarding HNMMs with radical surgery (stage III-IVa, AJCC HNMM 8th version) between September 1, 2006 and February 28, 2020 at Peking University Cancer Hospital was collected retrospectively. Postoperative radiotherapy was usually prescribed as GTV 60-70Gy/CTV 60Gy/30f. Patients were divided into four groups by the adjuvant regimens: radiotherapy+chemotherapy (RC), chemotherapy (C), radiotherapy (R) and observation (O). Results: In total, 368 patients were enrolled, including 104 RC,114 C, 53 R, 97 O, respectively. After median follow-up of 63.9 mo (range: 0.9-146.7), the median local relapse-free survival (LRFS) was 10.1 mo (95%CI: 6.7-13.6) in the O group, as compared with 65.9 mo (95%CI: 31.7-100.1, P＜0.001) in the R group, 75.6 mo (95%CI: 50.1-101.0, P＜0.001) in the C group, and 84.6 mo (95%CI: 48.5-120.8, P＜0.001) in the RC group. The median distant metastasis-free survival (DMFS) was 13.7 mo (95%CI: 8.0-19.5) in the O group, 15.3 mo (95%CI: 8.7-21.9, P = 0.898) in the R group, as compared with 25.7 mo (95%CI: 14.6-36.8, P = 0.001) in the C group, 49.3 mo (95%CI: 32.6-66.0, P＜0.001) in the RC group. Estimated OS was 36.4 mo (95%CI: 24.0-48.8) in the O group, as compared with 30.8 mo (95%CI: 23.0-38.6, P = 0.733) in the R group, 40.8 mo (95%CI: 34.8-46.8, P = 0.289) in the C group, 58.2 mp (95%CI: 36.4-79.9, P = 0.002) in the RC group. Primary location, age, gender, UICC staging and adjuvant regimens were included for multivariate Cox analysis. With regard to OS, UICC stage and RC were the prognostic factors. With regard to DMFS, UICC stage, RC and C were the prognostic factors. With regard to LRFS, UICC stage, RC, R, C were the prognostic factors. Conclusions: It is the largest study on the role of adjuvant radiotherapy and chemotherapy on HNMM till now. The results demonstrate that postoperative radiotherapy improves LRFS but has no impact on DMFS, while adjuvant radiotherapy plus chemotherapy prolongs OS. It further validates the clinical practice of UICC stage of HNMM, which might shed lights on the study of the whole mucosal melanoma.
Access to radiation oncology centers with brain tumor treatment expertise for patients with resectable brain tumors.
Authors: Choi Mehee , Martin Brian P. , Misell Lisa , Zabramski Joseph M. , Brachman David G.
Published: June 2021

e18509

Background: Many patients with brain tumors face challenges with access to care. For rural patients, prolonged travel times may limit access to appropriate radiotherapy. Radiation centers (RCs) offering specialized brain radiotherapy, e.g., stereotactic radiosurgery (SRS), are geographically limited. Utilization of brain brachytherapy at the time of resection offers an option for such patients, but technical challenges have limited the adoption. To address the limitations of traditional brachytherapy, a device with Cs-131 seeds embedded in a bioresorbable collagen tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. GammaTile (GT) is FDA-cleared for permanent implantation at the time of resection for all recurrent intracranial tumors and for newly diagnosed malignant intracranial neoplasms. To investigate if wider availability of this treatment could possibly lower the geographic barrier to access to care, we mapped the US population against existing RCs with brain tumor expertise and neurosurgery centers (NSCs) performing craniotomies. Methods: We analyzed 2018 CMS claims data using CPT codes for single- and multi-fraction SRS to identify RCs with brain tumor treatment expertise and mapped these against the population. Using similar methodology, using CPT codes for craniotomies, we identified NSCs, as any facility performing craniotomies is potentially eligible to implant GT. Results: 135 RCs used CPT codes for SRS. 193-, 119-, 82-, and 52-million Americans lived >30-, >60-, >90-, and >120-minutes from one of these centers, respectively. 530 NSCs preform craniotomies, including ≥1 in every state, a 4-fold increase over the number of RCs offering SRS. Conclusions: For many patients, substantial travel distances limit their access to RCs with brain tumor treatment expertise. In contrast, the 530 craniotomy-performing NSCs have far greater geographic dispersion. The option of undergoing brain radiation with GT implantation at the time of brain tumor craniotomy brings treatment closer to millions, ensures compliance, and reduces additional travel for follow-up radiation treatment.[Table: see text]
Comparison of care process for newly diagnosed breast cancer in insured versus uninsured populations: Opportunities for improving health equity.
Authors: Botrus Gehan , Ertz-Archambault Natalie , Nafissi Nellie , Gonzalez Velez Miguel , Kosiorek Heidi E. , Ernst Brenda , Northfelt Donald W.
Published: June 2021

e18518

Background: Initiatives enhancing equitable oncologic care are an increasingly emphasized priority. Our study aims to identify aspects of breast cancer (BC) care in which differences exist based on insurance coverage status. Methods: We performed a retrospective, case control study consisting of 39 Hispanic ethnicity uninsured patients (UP) with newly diagnosed BC at federally qualified health centers and 119 insured patients (IP) diagnosed at Mayo Clinic Arizona (MCA). Patients were matched 3:1 for age, stage, year of diagnosis, ER and HER2 status. Demographic information, clinical variables, and zip code level specific socioeconomic information were compared. Continuous variables were compared by Wilcoxon rank-sum test and categorical variables by chi-square test. All patients ultimately received their cancer treatment at MCA. Results: Similar treatment patterns with chemotherapy, surgery, and radiation treatment were observed between groups. Primary language was Spanish for 94% of UP and English for 97.5% of IP. The majority of UP were of Hispanic ethnicity (97.4%); IP were 83.2% non-Hispanic White, 9.2% Hispanic, 3.4% African American. Zip code level information reflected more unemployment with a median of 10.6% versus 6.9% p ˂ 0.001, percent of high school or lower (53.0 % v 23.2 %, p ˂ 0.001), and lower income for UP (33733.5 v 64728.0 p values ˂ 0.001). UP BMI was significantly higher (30.6 V 24.7, p=0.005), with presence of more co-morbidities; diabetes (28.2% v 5.0%, p ˂ 0.001), hypertension (35.9 % v 20.2%, p= 0.046), dyslipidemia (28.2% v 12.6%, p = 0.023), metabolic syndrome (p 23.7% v 8.5, p= 0.013), and tobacco use (17.9% v 2.5%, p ˂ 0.001). IP had higher alcohol use (52.9% v 5.3%, p ˂ 0.001). Genetics consultation was performed for 62.2% IP versus 35.9% UP (p=0.004), lower acceptance of oncology nutrition consultation for UP (29.4% vs 7.4%, p= 0.024) Median time from abnormal mammogram to biopsy (25.5 days vs. 14 days, p=0.056), and interval from diagnosis to treatment (62 days vs. 39 days) (p=0.001) were less favorable for UP compared to IP. Conclusions: In comparing the status of UP (primarily Hispanic, Spanish-speaking) and IP (primarily non-Hispanic White, English-speaking) with newly diagnosed BC we identified greater prevalence of co-morbidities and adverse social determinants of health in the former group. We identified access to genetic counseling services, access to oncology nutrition consultation, and timeliness of diagnostic biopsy and initiation of treatment as disparate features in the care pathway. These observations can allow development of tailored interventions to achieve greater equity in delivery of BC care.
Disparities in breast cancer by race and ethnicity.
Authors: Warrior Surbhi , Rao Ruta D.
Published: June 2021

e18526

Background: Breast cancer is the most common female malignancy. While there have been significant advances in diagnosis and treatment of breast cancer, there are gaps in care leading to high mortality rates in low socio-economic populations and ethnic minorities. This inequality is attributed to poor access to care and later stages at diagnosis. Methods: All female breast cancer patients between 2000-2020 (N=8,444) were included. Statistical analysis was done with X2 testing for categorical variables and T-tests for continuous variables. A univariate logistic regression was used to understand impact of each characteristic. Results: Black women were more likely to have poor prognostic factors for breast cancer compared to white women: distant metastatic disease at diagnosis (4.6% vs 3.2%, p=0.02), triple negative disease (25% vs 13.6%, p<0.01), high oncotype dx score >25 (37.2% vs 26.1%, p=0.04), recurrence (14.9% vs 12.1%, p=0.04), and mortality rate (24.2% vs 15.6%, p<0.01). Despite these high-risk factors, white women were more likely to have a mastectomy than black women (43.8% vs 35.4%, p<0.01), and the average age at diagnosis was higher in black women at 59.2±13.5 years compared to white women at 57.5±12.8 years (p<0.01). The most prominent poor prognostic factor in black women was having triple negative breast cancer with OR 2.13 (95% CI 1.7- 2.6) compared to others in Table. Hispanic women were more likely to have higher stage at diagnosis (OR 1.21), lymph node involvement (OR 1.03), metastatic disease (OR 1.43), and tumor size >1cm (OR 1.06) than nonHispanic women, but only lymph node involvement at diagnosis was statistically significant (29.1% vs 24.5%, p=0.02). Conclusions: There is a high prevalence of racial and ethnic disparities in women with breast cancer. Black women are more likely to have poor prognostic factors including metastatic disease at diagnosis and triple negative breast cancer, leading to higher recurrence and mortality rates. Hispanic women are also more likely to have poor prognostic factors, but this data was not statistically significant due to small sample size. Efforts to improve access to health care leading to earlier diagnosis may decrease the gap in mortality rate for minority women with predisposition to high-risk malignancies.[Table: see text]
Outcome disparities in rural versus urban patients with head and neck cancer: Leveling the playing field.
Authors: Kaur Varinder , Rooney Anthony , Desai Raj Piyush
Published: June 2021

e18529

Background: Multiple studies indicate that rural patients experience disproportionately adverse cancer related outcomes, compared to their urban counterparts. This has been attributed to inequities in access to healthcare, monetary and technological resources, disease characteristics, adverse health status and lower life expectancy of rural populace. Whether treating patients with uniform protocols can help mitigate outcome disparities remains to be determined. Methods: We conducted a retrospective cohort study to evaluate survival outcomes of Head-Neck Squamous Cell Cancer (HNSCC) patients from rural versus urban locales. Only patients with locally advanced HNSCC who completed radiotherapy (RT) at the Emily Couric Clinical Cancer Center were included. Rural patients had access to affordable lodging for the duration of radiotherapy (RT), were treated regardless of health insurance status and by the same multidisciplinary team. Patients with distant metastases were excluded. Patients were classified as urban or rural using the Rural-Urban Commuting Areas (RUCA) zip-code database. Overall survival (OS) was analyzed using Kaplan-Meier curves and log-rank test. OS was modeled with a COX proportional hazards model, adjusting for several covariates including race, age, gender, HPV status, smoking, treatment received (RT, chemotherapy, surgery) and stage. Results: 230 patients with Stage I-IVB HNSCC who met the inclusion criteria were analyzed, of which 136 were categorized as residentially urban and 94 were categorized as rural. Approximately 83% were male, 87% were Caucasian and 71% were smokers (52% current smokers and 19% former smokers). In addition to RT, 42% patients had undergone surgery and 57% received chemotherapy. There was no statistically significant difference in OS for patients residing in rural vs urban zip-codes (HR 1.36, p = 0.24). Rural patients were less likely to undergo surgery (34% vs 44%, p = 0.04), and more likely to receive chemotherapy (67% vs 54%, p = 0.0325), likely indicating more advanced tumor stage at diagnosis. Conclusions: Rural and urban patients had similar OS when treated with similar treatment protocols. Improving access to uniform treatment regimens may help mitigate the widening gap in cancer-related outcomes between rural and urban populations.
Impact of social determinants of health on a late diagnosis and survival of patients with pancreatic cancer.
Authors: Fabregas Jesus C. , Lam Miranda
Published: June 2021

e18530

Background: While disparities in pancreatic cancer (PC) are documented, it is unclear whether these inequities occur at the time of diagnosis or throughout treatment. We hypothesize social determinants of health (SDH) such as income, education, race and insurance status are a) associated with a late diagnosis of PC (Stage IV vs Stages 0-III) and b) associated with overall survival (OS) in Stage IV patients. Methods: The National Cancer Database 2017 version was accessed. Primary outcome: diagnosis of Stage IV PC. Secondary outcome: OS. Primary predictors: race, income, education, insurance. Confounders: Charlson comorbidity score, age, sex. Univariate and multivariate regression models evaluated the association between SDH and a late diagnosis of PC. Univariate and multivariate Cox proportional hazards model examined OS. 95% Confidence Intervals were used. Results: 230,877 patients were included. Median 68 yrs, mean 67.3 SD(12.1). In univariate analysis, education (>93% high school completion (HSC) vs <82.4%, OR 0.93 [0.91 – 0.95]), income (>$63,333 vs<$40,277, OR 0.94 [0.92– 0.96]), and insurance (Private vs No, OR 0.70 [0.66 – 0.73]), decreased the odds of Stage IV PC. Black race was associated with higher odds of Stage IV PC (vs White, OR 1.11 [1.08 – 1.14]). In multivariate analysis, education and having insurance decreased the risk of a late diagnosis, whereas black race increased it (table). In univariate Cox analysis, higher income (>$63,333 (vs<$40,277), HR 0.82 [0.81– 0.83]), insurance (Private vs No, HR 0.77 [0.73 – 0.76]) and education (>93% HSC vs <82.4%, HR 0.87 [0.86 – 0.88]) improved OS. Black race was associated with poorer OS (vs White, HR 1.03 [1.02 – 1.05]). In multivariate Cox analysis, only higher income (>$63,333 (vs<$40,277), HR 0.87 [0.85 – 0.89]) and having insurance (Private vs No, HR 0.77 [0.74 – 0.79]) were associated with improved OS. Conclusions: SDH impacted the continuum of pancreatic neoplasia care, from diagnosis to treatment. Expanding insurance coverage could be an effective public health intervention to improve early diagnosis and survival rates.[Table: see text]