bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining a prognostic risk score in ovarian cancer patients by integrated analysis of serum mesothelin, HE4, CA125 and surgical outcome.
Authors: Wimberger Pauline , Klotz Daniel , Göckenjan Maren , Link Theresa , Kuhlmann Jan Dominik
Published: June 2022

e17611

Background: In ovarian cancer, serum CA125 is currently the only biomarker used in routine clinical practice and has several limitations, e.g. it is not entirely specific for ovarian malignancy. Alternative serum biomarkers have been proposed for ovarian cancer, such as mesothelin or human epididymis protein 4 (HE4). Although it is known that single marker analysis is often insufficient for diagnostic purposes or relapse prediction, no comprehensive studies on the combination of these markers have been conducted, yet. Using a multi-marker prediction model, we herein investigated the clinical usefulness of mesothelin and HE4, detected in a sequence of pre- and post-operative serum samples, in complementing the standard marker CA125. Methods: Serum mesothelin, HE4 and CA125 were quantified by Lumipulse G chemiluminescent enzyme immunoassay (Fujirebio) in a total of 432 serum samples from 90 healthy controls and 192 ovarian cancer patients (thereof 81.8% with FIGO III/IV), including 151 paired pre- and post-operative samples. Results: Pre-operative serum mesothelin and HE4 were significantly elevated compared to healthy controls with a median ratio (IQR) to controls of 2.6 and 9.6, respectively (p < 0.0001). High pre-operative levels of mesothelin or HE4 alone were significantly correlated with advanced FIGO-stage (p < 0.0001) and predicted surgical outcome (p < 0.0001). We retrospectively compiled mesothelin and HE4 levels with CA125, BRCA mutational status and surgical outcome, in order to define a multi-marker setting. Both, mesothelin and HE4 levels were independent from BRCA mutational status, however they positively correlated with CA125. Detection of pre-operative HE4 > 498pM (OR = 4.1, p < 0.0001) combined with pre-operative CA125 > 516U/mL (OR = 2.2, p = 0.001) was the best combination to predict surgical outcome (AUC = 0.815). Finally, we defined a prognostic signature, including pre-operative CA125, post-operative mesothelin, HE4 and surgical outcome, which was superior to the individual prognostic capacity of all included parameters. Our model allowed the calculation of a weighted risk score, stratifying patient at “lower risk” (score 0-4) or at “higher risk” (score 5-10). Patients with higher risk had significantly shorter PFS (19.0 months (95%CI = 16.1-21.8) vs 64.1 months (95%CI = 56.8-71.3) p < 0.0001) and OS (34.0 months (95%CI = 28.6-39.3) vs 71.2 months (95%CI = 64.6-77.7) p < 0.0001). Conclusions: This is the first study, proposing an integrated prognostic risk score for ovarian cancer patients, which could easily be implemented into routine diagnostics and may guide personalized treatment decisions. Patients at “higher risk”, as identified by this model, could potentially benefit from an intensified therapy regime, whereas patients at “lower risk” might be suitable for treatment de-escalation.
Treatment and outcome of patients with high-grade advanced ovarian cancer (AOC): Real-world data in Germany (QS Ovar of the AGO Study Group).
Authors: Mahner Sven , Harter Philipp , Du Bois Andreas , Hilpert Felix , Kerkmann Markus , Sehouli Jalid , de Gregorio Nikolaus , Hanker Lars Ch. , Heitz Florian , Marmé Frederik , Woelber Linn Lena , Holtmann Laura , Elser Gabriele , Pfisterer Jacobus ,   AGO Study Group
Published: June 2022

e17613

Background: Outcome of patients with ovarian cancer depends largely on treatment quality and expertise of treating physicians and centers. To assess treatment reality and quality in Germany, we initiated a nationwide quality assurance program. Methods: All German hospitals treating patients with ovarian cancer were asked to document their patients with primary diagnosis of epithelial ovarian cancer in the third quarters of 2012 and 2016. Details of tumor, treatment and outcome were documented in a central database. The current analysis focuses on patients with high-grade AOC stage III/IV. Results: In total, 1010 patients with high-grade AOC were documented. This represents 63% of all patients diagnosed with AOC in Germany in these periods. Median age was 65 years. The majority (774/1010 - 76.6%) were diagnosed with stage III disease and 947/1010 (93.8%) had serous, 34 (3.4%) endometrioid and 29 (2.9%) clear cell histology. 915/1010 (90.6%) had primary cytoreductive surgery. Complete resection was achieved in 434/915 (47.4%) at primary surgery and in 54/95 (56.8%) at interval debulking surgery. Median PFS and OS in patients with primary surgery and complete resection was 29.7 months and 63.1 months compared to 16.8 months and 30.7 months in patients with residual disease (HR PFS 0.46 95% CI 0.22-0.54 HR OS: 0.38 95% CI 0.31-0.45). In patients with neoadjuvant chemotherapy and interval debulking, median PFS and OS were 24.3 and 50.7 months with complete resection, compared to 15.4 and 33.9 months with residual disease (HR PFS 0.61 95% CI 0.38-0.95 HR OS: 0.48 95% CI 0.28-0.83). First-line chemotherapy was carboplatin/paclitaxel (TC) in 919/1010 (91%) of the patients, 627 (62%) also received bevacizumab (TCB) and 544 of these (87%) also received maintenance therapy. Median PFS and OS in patients with TCB was 23.3 months and 46.2 months and 18.5 months and 39.0 months in patients treated with TC (p = 0.049: HR 0.85, 95% CI 0.72-1.00 and p = 0.012: HR 0.79, 95% CI 0.65-0.95). The rate of complete tumor resection at surgery as well as the use of bevacizumab increased between the two periods. Conclusions: Based on this representative cohort of patients with advanced ovarian cancer in Germany, the majority of patients is treated with primary surgery followed by carboplatin/paclitaxel and bevacizumab. Patient outcome regarding PFS and OS was best when complete tumor resection was achieved at primary surgery and patients received combination chemotherapy with maintenance treatment. Supported by Roche, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Essex.
Real-world outcomes of niraparib treatment in patients with ovarian cancer: The first observational multicenter study in China.
Authors: Li Jin , Wu Xiaohua , Shou Huafeng , Zheng Fei , Huang Xiaohong , Liu Fang , Tang Xuedong , Yang Jianhua , Zhang Lin
Published: June 2022

e17614

Background: Compared with western countries, the application time of PARP inhibitor in China is shorter and the real world outcomes are affected by many factors. The objective of this study was to present the real-world patients’ portrait, and the results of Niraparib treatment in China. Methods: This study included 142 patients treated with Niraparib from 8 hospitals in China between Dec. 2018 and Sep. 2021. Patients’ characteristics were summarized. The efficacy and safety in first-line maintenance (1L-M), platinum-sensitive recurrence maintenance (PSR-M), and treatment for ovarian cancer were evaluated. Survival outcomes and the factors influencing PFS were estimated. Results: 93 patients received Niraparib as 1L-M, 31 as PSR-M and 18 as salvage. BRCA status was wild-type or unknown in 87.3% of patients. With a median follow-up time of 8.7m, the mPFS for 1L-M has not yet been reached, and the mPFS for PSR-M and salvage therapy was 10.5 months (95%CI: 3.9-NE) and 5.7 months (95%CI: 3.0-13.0), respectively. Responses to last chemotherapy (CR vs. PR, P= 0.0077) and CA125 value before taking Niraparib (≤35UI/ml vs. > 35UI/ml, P= 0.0344) were two important factors affecting PFS among 1L and PSR patients. 12.7%(18/142) of patients experienced grade ≥3 hematologic adverse events and 23.2% experienced dose adjustment. It was noteworthy that when the interval of chemotherapy and Niraparib < 21 days, the incidence of Grade ≥ 3 adverse events increased significantly ( P= 0.0355). Conclusions: This was the first and largest observational multicenter study reporting the outcomes of Niraparib treatment for ovarian cancer in real-world setting in China. Generally, Niraparib was effective and well tolerated, which was consistent with the results of prospective trials. However, in real world, it was more inclined to use Niraparib in late-line treatment without genetic testing.
Evaluation of homologous recombination deficiency biomarkers in patients with ovarian cancer treated with PARP inhibitors.
Authors: Campoverde Leticia , Lopes Da Silva Laercio , Silveira Hyan , Coelho Nogueira Wilson , Mina Lida A. , Lopes Gilberto , Batalini Felipe
Published: June 2022

e17615

Background: Germline BRCA1/2 mutations are associated with response to Poly(ADP-ribose) polymerase inhibitors (PARPi). In addition to BRCA1/2 mutations, there are other Homologous Recombinations Deficiency (HRD) biomarker candidates already available in clinical practice including genome-wide loss-of-heterozygosity (gLOH) and myChoice score. Inconsistencies in biomarkers used in clinical trials with PARPi are a challenge to clinical interpretation. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi. Methods: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a random-effects model. Patients were classified into three categories according to their HRD status: 1) BRCAmut (patients with BRCA1/2 mutation of germline or somatic origin), 2) non-BRCA HRD (patients BRCA wild-type (wt) with a different HRD biomarker - gLOH or myChoice); and 3) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice+ with gLOH-high. Results: Eight studies (n = 4372 patients) with PARPi as first-line and recurrence settings were included. BRCAmut had PFS HR 0.29 (95%CI, 0.24-0.35), BRCAwt & HRD 0.43 (95%CI, 0.34-0.53) and HRP 0.74 (95%CI, 0.62-0.89). In a secondary analysis by HRD stratification method, patients with BRCAwt & myChoice > = 42 had PFS HR 0.43 (95%CI, 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95%CI, 0.28-0.62). Conclusions: Patients with BRCA mutations benefited the most from PARPi. From patients with BRCA1/2 wild-type, a similar benefit was found in patients with gLOH-high and those myChoice+, which was superior to HRP patients. The clinical development of further HRD biomarkers (i.e. Sig3, HRDetect) may help identify more patients who benefit from PARPi.
Comparison of AYA versus non-AYA ovarian cancer genomic landscape in NCI-MATCH trial.
Authors: Sankaran Hari , Kotliarov Yuri , Zhao Yingdong , Temkin Sarah M , Williams Paul M. , Karlovich Chris Alan , Coffey Brent , Das Biswajit , Chang Ting-Chia , Seibel Nita , Tricoli James V. , Best Ana F. , Gray Robert James , Wang Victoria , Wei Zihan , Hamilton Stanley R. , Patton David R. , Chen Alice P. , McShane Lisa
Published: June 2022

e17617

Background: NCI-MATCH, a signal-finding precision medicine trial, centrally screened tumors from ̃6000 patients age > 18 with refractory/relapsed cancer using Oncomine Comprehensive Assay (OCA) targeted gene panel. Screened cohort included a subset of patients with ovarian cancer age 18-39 yrs, overlapping adolescent and young adult (AYA) range (NCI consensus definition: 15-39 yrs). Objective of this study was to compare tumor genomic features of AYA to non-AYA ovarian cancers. Methods: Patient clinicopathologic, demographic, and tumor mutation (SNVs, Indels, CNVs by central OCA) data from NCI-MATCH were available. Analyses were restricted to mutation profiles generated by OCA version 2 (OCA v2), which assessed 143 genes and was used for most samples. Proportions of cases with mutations in each gene were compared for AYA and non-AYA groups by 2-sided Fisher’s exact tests. For each gene, association between age (continuous independent variable) and presence of mutation (binary dependent variable) was assessed using logistic regression. Benjamini-Hochberg adjusted p-values were computed; false discovery rate (FDR) was controlled at 10%. Results: Data from 455 ovarian cancers (437 epithelial, 18 stromal), including 21 AYA and 434 non-AYA cases, were included in this analysis. Among the 28 genes most frequently (in > 6 patient tumors) mutated and altered, CTNNB1 was mutated in 9.5% of AYA patients compared to 0.9% in non-AYA (unadj. p=0.027) but failed to meet 10% FDR criterion (FDR-adj. p=0.7). KRAS mutation was more frequent in AYA than non-AYA but not significantly after adjustment (FDR-adj. p=0.7). Logistic regression results showed TP53 mutation was significantly associated with older age (FDR-adj. p<0.0001), and ATM mutation was borderline associated with younger age (FDR-adj. p=0.052). No other differences, including in clinically actionable mutations ( BRCA1/2, MSH2), were observed. Table displays selected results. Conclusions: This preliminary study shows that no genes were mutated in significantly different proportion between AYA and non-AYA groups, but modeling age as a continuous variable highlighted known association of TP53 mutation with older age and a trend towards association of ATM mutation with younger age. More comprehensive tumor mutation profiling and analyses of additional tumor types may reveal further insights into rare AYA cancers. [Table: see text]
Efficacy and safety of pembrolizumab in Chinese patients with recurrent/unresectable/metastatic head and neck squamous cell carcinoma.
Authors: Li Jieying , Song Kai , Feng Yuanyong , Shang Wei ,   Affiliated Hospital of Qingdao University
Published: June 2022

e18001

Background: The efficacy and safety of Pembrolizumab in recurrent /unresectable/metastatic head and neck squamous cell carcinoma have been well documented in KEYNOTE-048 and other studies, and the effectiveness of different areas’ population have been shown in related studies. However, there is no native data based on the Chinese population. The purpose of this study was to investigate the efficacy and safety of Pembrolizumab in the treatment of R/U/M head and neck squamous cell carcinoma in Chinese population. Methods: We reviewed patients data from the department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University. The patients with R/U/M head and neck squamous cell carcinoma were treated with or without combined chemotherapy / targeted therapy according to their PD-L1 expression status (CPS). Pembrolizumab was infused intravenously with 200mg every 3 weeks for a maximum of 35 cycles. The primary endpoint was Objective Response Rate(ORR). The secondary endpoints were Quality of Life, Safety and Progression Free Survival(PFS). Results: A total of 23 eligible patients with R/U/M head and neck squamous cell carcinoma were included from February 2021 to February 2022, including 18 males (78.26%) and 5 females (21.74%) with a median age of 68 years. The primary sites were oral cavity in 16 cases (69.56%), oropharynx in 4 cases (17.39%), hypopharynx in 1 case (4.35%), and larynx in 2 cases (8.70%). P16 status was positive in 4 cases (17.39%), negative in 12 cases (52.17%), and unknown in 7 cases (30.43%). The expression status of PD-L1 in all patients was known. Patients with CPS ≥ 20 were treated with Pembrolizumab monotherapy and patients with CPS < 20 were treated with Pembrolizumab combined with chemotherapy / targeting therapy, of which 22 (95.65%) were treated with first-line therapy and 1 (4.35%) were treated with second-line therapy. The median follow-up period was 6 months. 15 patients were assessed as remission (as of February 2022), of which 4 (17.39%) showed CR, 11 (47.83%) showed PR, 7 (30.43%) showed SD, and 1 (4.35%) showed PD. ORR was 65.22%, DCR was 95.65%. After 4 cycles of treatment, 14 patients (60.87%) achieved tumor remission and control, and the functional status score (KPS) increased from 65 to 85. The incidences of thyroid dysfunction, skin rash, fatigue, neutropenia and immune pneumonia were 2 (8.70%), 3 (13.04%), 2 (8.70%), 1 (4.35%) and 1(4.35%), respectively. Conclusions: This retrospective data have shown excellent efficacy and safety of pembrolizumab in the Chinese population of R/U/M head and neck squamous cell carcinoma, and provide data support for follow-up related research.Due to the short follow-up time, most of the patients have not yet reached PFS, and follow-up will continue.
Nivolumab in squamous cell carcinomas of the head and neck (SCCHN): A real-world outcome study in Ontario, Canada.
Authors: Zereshkian Arman , Shafi Ruaa , Pond Gregory Russell , Hotte Sebastien J.
Published: June 2022

e18017

Background: The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic squamous cell carcinomas of the head and neck (SCCHN). We evaluated outcomes of SCCHN patients in Ontario, Canada treated with nivolumab since its funding through the New Drug Funding Program (NDFP) of Cancer Care Ontario (CCO). Methods: Retrospective review using the provincial treatment registry (CCO NDFP) was undertaken. Patient characteristics, reason for treatment, treatment length, and date of death were collected. Kaplan-Meier method was used to estimate overall survival and Cox regression to evaluate prognostic effect of selected factors. Results: 134 patients with SCCHN received nivolumab between March 2017 and March 2019. Median patient age was 63 years with 80.6% male. Nivolumab was used as second-line therapy after disease relapse within 6 months of curative-intent platinum chemotherapy (PC) in 39.6% of patients (Indication 1 – I1), used as second-line therapy post PC in non-curative intent in 42.6% of patients (Indication 2 – I2), and used as first-line therapy in non-curative intent due to contraindication for PC in 17.2% of patients (Indication 3 – I3). Median overall survival (mOS) was 5.8 months (95% confidence intervals (CI) 4.5-7.3), and one-year OS was 28.4% (CI 2.10-36.1). HPV status had no statistically significant impact on OS (p = 0.12). Patients with a lower BSA (< 1.81) had median OS of 3.9 months (CI 3.1-6.7) versus 9.0 months (CI 6.5-14.8) in those with higher BSA, HR = 0.12 (CI 0.04-0.39, p < 0.001). Differences between indications was statistically significant (p < 0.001). Patients who received nivolumab for I1 had mOS 7.2 months (CI 3.8-9.8) versus 11.9 months (CI 6.2-not reached) for I3, HR = 1.73(CI 0.94-3.16). Patients who received nivolumab for I2 had mOS 3.9 months (CI 2.9-5.4) as compared to I3, HR = 3.27(CI 1.80-5.94). Patients who received nivolumab for I2 had poorer mOS as compared to I1 HR = 1.90(CI 1.23-2.92). Conclusions: Real world data in Ontario demonstrates poorer mOS, but similar 1-year survival compared to CheckMate-141 trial. HPV status had no significant impact on mOS. Patients who received nivolumab as first-line therapy in the non-curative setting appeared to have longer mOS than those who received initial PC for non-curative intent followed by nivolumab. Patients who received nivolumab as second-line therapy post PC in non-curative intent setting as compared to within 6 months of curative-intent therapy had poorer mOS.
Penpulimab plus gemcitabine in combination with cisplatin or anlotinib as first-line treatment for metastatic nasopharyngeal carcinoma (M NPC): A phase II study.
Authors: Huang Shuang , Chen Xiaozhong , Qu Song , Qu Shenhong , Han Yaqian , Yang Kunyu , Huang Shiting , Li Min , Zhang Lin , Ding Qian
Published: June 2022

e18032

Background: Cisplatin (P)-based combination regimen is the backbone in the first-line treatment of M NPC while the toxicity limited its usage. This study investigated the efficacy and safety of penpulimab (an anti-programmed death-1 antibody) plus gemcitabine (G) in combination with cisplatin (P) or anlotinib (a multikinase inhibitor) as first-line treatment of these pts. Methods: This is a multicenter, three cohorts, randomized, phase II study (NCT04736810). Pts with histologically confirmed regional or distant M NPC who had measurable lesions per RECIST 1.1 and received no systemic treatment for metastatic lesions were enrolled. Other inclusion criteria included 18-75 years old and ECOG PS 0-1. Pts in cohort A, B and C were given G + P + penpulimab + anlotinib; G + P + penpulimab or G + penpulimab + anlotinib, respectively. G (1000mg/m2, d1, d8) and P (80mg/m2, d1) were given intravenously for 4 to 6 cycles, 3 weeks per cycle. Penpulimab (200mg, d1) and anlotinib (12mg, qd, d1-14) were given intravenously and orally respectively until confirmed disease progression, or unacceptable toxicities, or up to 2 years, whichever occurred firstly. Pts who developed disease progression but still had clinical benefit could receive penpulimab and anlotinib continuously based on the decision of physicians. The primary endpoint was objective response rate (ORR). Here we report the preliminary results of this study. Results: Between March 2021 and September 2021, 17 pts were randomly assigned to cohort A (n = 5), B (n = 5) or C (n = 7), and the median age was 52, 49 and 52 years old, respectively. Nearly half (7/17, 41.2%) had liver metastasis and the majority (5/7, 71.4%) was in the cohort C. At the data cutoff date on January 17, 2022, the median treatment cycles were 6, 8, 8 across three cohorts. All pts received tumor response and the confirmed ORR was 80.0%, 80.0% and 100%. The details of tumor response were summered in followed table. Notably, in cohort C, 1 pts achieved confirmed complete response (CR) and all others had confirmed partial response (PR). Replacement of cisplatin with anlotinib seemed to show better safety profile that ≥ grade 3 adverse events (AEs) occurred in 6 pts (85.7%) in cohort A, 5 (100%) in cohort B while only 4 (57.1%) in group C. Moreover, the overall incidence of serious AEs was 28.6%, 20%, 14.3% across three cohorts. The most common ≥ grade 3 AEs were white blood cell decreased and neutrophil count decreased. Conclusions: This preliminary analysis indicated that penpulimab plus gemcitabine and anlotinib had promising efficacy and favorable tolerance profile as first-line treatment for M NPC. Further investigate is ongoing. Clinical trial information: NCT04736810. [Table: see text]
Establishment of a visualized mouse orthotopic model of nasopharyngeal carcinoma.
Authors: Kang Min , Chen Wei , Chen Sixia , Jiang Li , Shu Gege , Yin Yuanxiu , Quan Zhipeng , Zhou Ziyan , Shen Mingjun , Qin Yating , Yang Chaolin , Su Xuejin , Chen Weimin
Published: June 2022

e18048

Background: Nasopharyngeal carcinoma, one of the most common head and neck tumors, is particularly prevalent in Southeast Asia and is characterized by high rates of metastasis and recurrence. Although mouse orthotopic tumor models are commonly employed in studies investigating the mechanisms underlying tumor development and progression, as well as preclinical treatment, currently no such model exists for nasopharyngeal carcinoma. The aim of the current study is to, therefore, establish an orthotopic murine model for nasopharyngeal carcinoma. Methods: To this end, human nasopharyngeal carcinoma C666-1-luc cells, stably expressing the firefly luciferase gene, were injected subcutaneously into the right axilla of BALB/C nude mice. Four weeks later, the resulting subcutaneous tumors were cut into small blocks and grafted into the nasopharynx of immunodeficient BALB/C nude mice to induce tumor formation. Tumor growth was monitored by bioluminescence imaging and small animal magnetic resonance imaging. The histological and immunological antigen expression associated with orthotopic nasopharyngeal carcinoma were analyzed by tissue section analysis and immunohistochemistry (IHC). Results: The tumor formation rate was over 90%. Fluorescence signal detection, micro-magnetic resonance imaging and hematoxylin and eosin staining revealed the successful growth of tumors in the nasopharynx of nude mice. Moreover, IHC analysis detected positive CK, CK5/6, P40 and P63 expression in the mouse orthotopic tumors, which is consistent with the reported antigen expression in the nasopharyngeal tumors of patients. Conclusions: Hence, we successfully established a mouse orthotopic model of nasopharyngeal carcinoma that is highly reproducible, and simple in operation, with low mortality and high tumor formation rates. Moreover, this model facilitates real-time monitoring of tumor growth via in vivo imaging technology, thus, providing a platform for researching nasopharyngeal carcinoma that is more conducive to preclinical research.
A novel drug combination strategy that redesigns the pharmacological management of oral cancer.
Authors: Chakraborty Rajdeep , Darido Charbel , Hu Honghua , Vickery Karen , Ranganathan Shoba
Published: June 2022

e18053

Background: Biofilm formation is a continuous process in oral cancer patients, despite proper extirpation/elimination of a bacterial plaque via a surgical procedure or antibiotic treatment. Also, elimination of a bacterial plaque does not necessarily remove extant bacterial antigen-stimulated oral cancer cells. Therefore, combination drug treatment may be an appropriate approach to elucidate the confounding effects of bacterial antigens on anti-cancer drugs. Methods: Our drug combination strategy addressed both Gram-positive (Lipoteichoic acid [LTA]) and Gram-negative (Lipopolysaccharide [LPS]) bacterial antigens, to determine the effect of anti-cancer drugs on LPS/LTA/LPS+LTA-stimulated preclinical oral cancer models (SCC4, SCC9, SCC25, and Cal 27). The drug combination strategy was designed in six phases of treatment. In phase 1, plated cells were treated with different combinations of bacterial antigens in combination with anti-cancer drugs. In the phases 2 and 3, inhibitory drugs were introduced in the presence of bacterial antigens after 24 hours and 72 hours of bacterial antigen stimulation. In phases 4 and 5, inhibitory drugs were added after 24 hours and 72 hours of bacterial antigen stimulation. In phase 6, inhibitory drugs were applied in the absence of, and without stimulation with, bacterial antigens. Metabolic assays, reverse transcription quantitative PCR, Western blot, Proteome Profiler, apoptotic and ELISA assays were performed to validate the novel drug combination strategy. Results: Anti-cancer drug treatment on preclinical oral cancer models resulted in 43.6% ± 3.3% of precancerous models being apoptotic. To mimic pre-existing unhygenic conditions in oral cancer patients, prior stimulation of preclinical model with LPS+LTA 72 hours before drug treatment, reduced apoptosis to 32.2% ± 1.1% of cells. Apoptosis was almost annulled (2.98% ± 0.3%; p < 0.01) when drug treatment was carried out along with bacterial antigens. Treatment with drugs in the absence of bacterial antigens resulted in significantly more apoptotic cells than in presence of bacterial antigens (p < 0.0001). Metabolic and viability assay showed similar results like apoptotic assay. Conclusions: Bacterial antigens mimic the presence of Gram-negative and Gram-positive bacteria and thus severely affect the efficacy of anti-cancer drugs. The novel drug combination strategy redesigns the pharmacological management of oral squamous cell carcinoma.
Generative adversarial neural networks augment marker and pathway analysis of treatment resistant HPV+ head and neck squamous cell carcinoma.
Authors: Waters Michael , Inkman Matthew , Andruska Neal , Brenneman Randall , Markovina Stephanie Subasic , Schwarz Julie Kristina , Zhang Jin
Published: June 2022

e18059

Background: Biological behaviors of cancers are extremely complex and governed via nonlinear interplay of thousands of genes. This complexity has become a major hurdle to generating mechanistic conclusions in rare clinical scenarios, such as treatment resistant HPV+ head and neck squamous cell carcinoma, when observations are limited. Recently, data augmentation algorithms have served to increase the number and diversity of training observations while preserving the underlying structure and nonlinear relationships of data features. Deep learning techniques such as generative adversarial neural networks (GANs) have shown promise as robust tools for data augmentation of nonimage data. This study aims to evaluate the utility of employing separate GANs to highlight gene expression differences between treatment sensitive (TS) vs treatment resistant (TR) HPV+ head and neck squamous cell carcinoma. Methods: We performed RNAseq on 17 patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). We defined TR patients as those with locally advanced OPSCC at presentation, who rapidly recurred following receipt of standard of care therapy (n = 11). In most cases, patients failed to respond to salvage therapies and rapidly died. In contrast, we defined TS patients as those with locally advanced OPSCC at presentation, who received standard of care therapy, and were followed for 5 years without any evidence of recurrence (n = 6). These two cohorts were used to train two separate GANs, which synthesized 500 robust synthetic samples of each phenotype for downstream analysis. Results: Analysis of 17 samples yielded less than 100 differentially expressed (DE) genes passing FDR cutoffs, inhibiting pathway enrichment analysis (PAE). DE testing between synthetic samples yielded 1196 DE genes. Validating our deep learning approach, these genes belong to coherent pathways as determined by PAE. Namely, the VEGFA-VEGFR2 pathway was strongly enriched in the TR population (p = 1.5 x 10-4). Further, the NKT cell signature (p = 3.0x10-62), and the gene library of T-cell receptor induction of apoptosis (p = 5.4 x 10-9), was enriched in the TS population. Lastly, to validate the experimental method, DE testing on GAN augmented cohorts of renal papillary vs renal clear cell samples from The Cancer Genome Atlas, trained on 10 samples per condition, reliably predicted DE genes when comparing the full cohort of renal papillary n = 534 vs renal clear cell n = 295 samples, with an accuracy of 93% and F1 score of 88%. Conclusions: To our knowledge this is the first study to utilize separate GANs to augment structural gene expression changes occurring in rare clinical scenarios such as treatment resistant HPV+ OPSCC. Utilizing this method uncovers changes in angiogenesis and T-cell function between treatment sensitive and resistant HPV+ OPSCC.
Etiology of oral candidiasis in patients with oropharyngeal cancer.
Authors: Ulianova Yulia V. , Kutsevalova Olga Yu. , Pustovaya Irina V. , Volkova Viktoriya L. , Bauzhadze Mamuka V. , Chertova Natalia A. , Goncharova Elena G. , Maldonado Mary L.
Published: June 2022

e18068

Background: The purpose of this study was to assess the etiology of oral candidiasis in patients with oropharyngeal cancer as potential causative agents of invasive candidiasis and to analyze in vitro activity of isolates of Candida fungi to caspofungin, fluconazole and voriconazole. Methods: Isolates were obtained in a prospective study from the oral mucosa of patients with oropharyngeal cancer in 2020-2021. Identification of Candida fungi was performed using MALDI-TOF MS. Result of activity of isolates to caspofungin, fluconazole and voriconazole after 24 hours of incubation were registered according to CLSI M60-ED2:2020 (Performance Standards for Antifungal Susceptibility Testing of Yeasts). Results: 45 patients aged 30-85 years were examined. 92 isolates of Candida fungi were obtained: C. albicans 31.5% (29) and Candida non albicans 68.5% (63). Candida non albicans included: C.parapsilosis 30.2% (19), C.glabrata 28.6% (18), C.krusei 19.0% (12), C.tropicalis 15.9% (10), C.guilliermondii 6.3% (4). Candida carriage on the oral mucosa was noted in 62.2% of patients in the first days of hospitalization, with a predominance of C. albicans 42.8% compared with 32.1% after chemotherapy (p = 0.003) and 25.0% after antibiotic therapy. The distribution of species varied depending on the age of patients. The table presents comparative activity of caspofungin, fluconazole and voriconazole (susceptible (S), moderately resistant (I), resistant (R)) in % to Candida spp. High sensitivity to caspofungin was noted for both C.аlbicans and Candida non albicans. Voriconazole was characterized by lower sensitivity and natural resistance in C.glabrata which makes it less suitable for empirical therapy, as well as fluconazole. Conclusions: Candida non albicans (68.5%) were predominant in the oral candidiasis etiology in patients with oropharyngeal cancer, which was probably due to the use of azole antimycotics for prevention and empirical therapy. Reduced activity to voriconazole and fluconazole was observed in the dominant isolates, given the natural resistance of C. krusei to fluconazole and C. glabrata to voriconazole. Acquired azole resistance was noted for C. parapsilosis and C. albicans. The pathogen type should be determined in all cases of invasive candidiasis to exclude natural resistance and sensitivity to azoles before starting therapy.[Table: see text]
Selective treatment de-intensification with reduced-dose radiation and omitted concurrent chemotherapy guided by response to induction chemotherapy in HPV-associated oropharyngeal squamous cell carcinoma: A single-arm, phase II trial (IChoice-01).
Authors: Lu Xueguan , Xu Tingting , Zhou Xin , Shen Chunying , Zhang Qixian , He Xiayun , Ou Xiaoming , Ying Hongmei , Wang Yu , Ji Qinghai , Hu Chaosu
Published: June 2022

e18069

Background: De-intensification in chemoradiation provides a strategy to optimize the trade-off between treatment efficacy and toxicities in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, the failure of RTOG 1016 and De-ESCALaTE indicated the pitfall of de-escalation in an unselective population and the importance of patient selection for future study design. Induction chemotherapy (IC), as a potential biomarker, has been adopted in several trials to screen candidates for de-intensified treatment based on its tumor response. In present trial, we investigated the feasibility of selectively de-intensified chemoradiotherapy by reducing radiation dose and omitting concurrent chemotherapy guided by response to IC. Methods: From Jan 2019 to July 2021, 48 patients with p16 positive OPSCC, T1-2/N1-3M0 (excluding T1N1M0 patients with single and≤3cm lymph node) or T3-4N0-3M0 according to the UICC/AJCC 8th staging system were enrolled. All of them received two cycles of IC with cisplatin and docetaxel. Those with major response to IC (defined as cCR or ≥50% cPR of both primary site and lymph nodes) received de-intensified treatment with intensity modulated radiation therapy (IMRT) alone with 60Gy to high-risk and 54Gy to low-risk regions (Di cohort). Those with less than major response were given standard chemoradiotherapy with 70Gy to both primary tumor and positive lymph nodes, 63Gy to high-risk and 56Gy to low-risk regions, concurrently with two cycles of cisplatin (St cohort). The primary endpoint was 2-year progression-free survival (PFS). Results: 26/48 (54.2%) patients entered Di cohort while other 22/48 (45.8%) patients entered St cohort. With a median follow-up time of 20.5 months (2.8-36.7months), 3 deaths (1 in Di cohort and 2 in St cohort), 5 loco-regional recurrence (1 in Di cohort and 4 in St cohort) and 6 distant metastases (1 in Di cohort and 5 in St cohort) were documented. The 2-year PFS rates for Di and St cohort were 100% and 60.0% (P = 0.002) with overall survival (OS) rates of 100% and 83.1% (P = 0.062), loco-regional recurrence-free survival (LRFS) rates of 100% and 77.0% (P = 0.035), metastasis-free survival (MFS) rates of 100% and 66.8% (P = 0.011), respectively. Conclusions: For major responders to IC, reduced-dose radiation with omitted concurrent chemotherapy yielded good survival results. In comparison, patients resistant to IC showed poor prognosis even under standard-dose chemoradiotherapy, calling for treatment intensification or development of novel therapeutic agents. Selective de-intensification of chemoradiation guided by response to IC is promising in HPV-associated OPSCC and warrants further evaluation in future studies. Clinical trial information: NCT04012502.
FAST-FNA molecular diagnostic assay facilitates rapid diagnosis and ntrk biomarker testing of salivary gland tumors.
Authors: Pai Sara I. , Oh Juhyun , Yoo Tae Yeon , Faquin William C , Carlson Jonathan C.T. , Saal Talia M. , Deschler Daniel G. , Weissleder Ralph
Published: June 2022

e18089

Background: Primary epithelial salivary gland tumors (SGTs)are classified into 31 tumor types. Diagnosing SGTs through fine needle aspiration (FNA) biopsies is challenging due to the overlapping cytomorphologic features between benign and malignant tumors. In this study, we developed an innovative, multiplexed cycling technology which allows for the rapid cellular analyses of single cells obtained from FNA which can facilitate the rapid molecular analyses and diagnosis of SGTs. Methods: Antibodies against 29 cell surface markers associated with 7 SGT subtypes were validated and chemically modified via custom linker–bio-orthogonal quencher probes (FAST). Single cell homogenates and a FNA sample set representing 7 SGT subtypes were profiled by FAST cyclic staining, imaging, and automated computational analysis. A prediction model was generated utilizing a training set of 151,926 single cells obtained from primary SGTs (N = 26) and validated on a separate cohort of SGTs (N = 30). Companion biomarker testing, such as NTRK, was also assessed with the FAST technology. Results: The customized FAST-FNA SGT molecular diagnostic and biomarker panel was validated on human cell lines and specificity confirmed by both flow cytometry and clinical immunohistochemical staining on primary SGTs. The FAST molecular diagnostic assay was able to distinguish between benign and malignant SGTs with an accuracy of 0.86 for single-cell suspension samples and 0.88 for FNA samples. Profiling of multiple markers as compared to a single tumor marker increased the diagnostic accuracy of the SGTs, 0.82 as compared to 0.65-0.74, respectively. The results of the assay were highly reproducible and independent of the cell number sampled. NTRK expression in SGTs was also assessed by the FAST assay within hours, highlighting the potential therapeutic application of this technology. Conclusions: High dimensional single-cell profiling and molecular diagnostic testing on FNA samples are feasible at relatively low cost and as a rapid test. Application of the novel multiplexed single cell technology improves the diagnostic accuracy of SGT biopsy and facilitates multiplex biomarker testing from FNA samples. The customizable and modular FAST-FNA approach has relevance to multiple pathologies and organ systems where cytologic samples are often scarce and/or indeterminate resulting in improved diagnostic workflows and timely therapeutic clinical decision making.
Disparities in timely treatment among lung cancer patients.
Authors: Chhabra Jatin , Ray Herman , Derkach Sergii , Thompson David , Whyte Warren
Published: June 2022

e18515

Background: NSCLC is the leading cause of cancer-related deaths in the US. There are no federal standardized guidelines regarding timely treatment (TT) of NSCLC care and little is known regarding the sociodemographic differences in TT of anticancer therapies among NSCLC patients. This is particularly notable among Black Americans, who are less likely to receive lung cancer screening, more likely to be diagnosed with advanced or metastatic NSCLCL, and less likely to receive NCCN-concordant targeted therapy relative to their white counterparts. The objective of this retrospective study is to assess racial differences in TT and related outcomes among patients with advanced or metastatic NSCLC (aNSCLC). Methods: We identified 3,603 patients from ConcertAI’s Real-world data (RWD) sources, including CancerLinQ Electronic Medical Records. Patient demographics included: a) aged 18 to 64 years; b) confirmed diagnosis of aNSCLC between January 1, 2010, and December 31, 2019; and c) self-identify as White or African American. For this study the primary endpoint was receipt of TT, defined as start of systemic therapy within 30 days after diagnosis of aNSCLC. Logistic regression was leveraged to obtain adjusted odds ratios of comparisons between White and Black American populations on receipt of TT, controlling for demographic and baseline characteristics such as type of setting, ECOG score and smoking status. Results: Descriptive analyses revealed 79.1% of Black aNSCLC patients did not receive TT, as compared to 71.4% of White aNSCLC patients. When controlling for associated confounding factors, Black aNSCLC patients had a 21.4% less chance of receiving TT as compared to White patients, and the same was evident from the predicted probabilities of TT for Black vs. White aNSCLC patients. When evaluating institutional setting type, 76.1% of community hospitals provided TT vs. 61.3% of academic centers. Conclusions: This real-world study shows Black aNSCLC patients were associated with treatment delay. While present findings suggest improving access to effective screening and timely access to NCCN-concordant targeted therapies may be used as a means through which to lessen NSCLC disparities, further investigation is required to assess how it may improve overall outcomes for minorities. [Table: see text]
Patient-reported reasons for no-shows to screening mammogram appointments among African American women.
Authors: Hensing Whitney L , Tao Yu , Park Chaelee , Redding Dori , Arb Teresa , Clark Pechaz , White Stephanie , Thompson Tess , Ademuyiwa Foluso Olabisi
Published: June 2022

e18534

Background: Mammography screening significantly reduces breast-cancer related mortality; however, many women fail to undergo screening as recommended by national guidelines. No-shows are responsible for a significant proportion of delayed or missed cancer screening exams. Further, no-shows disproportionately affect underserved and minority populations. We previously identified a high no-show rate for screening mammograms among patients seeking care our institution. African American (AA) women were almost three times more likely to no-show than non-Hispanic white women. The racial disparity in no-shows persisted after adjustment for socioeconomic factors. The objective of this survey study was to identify reasons for missed mammogram screening appointments among AA women. Methods: We conducted a survey (via mail or telephone) of AA women who missed their screening mammogram appointment in summer 2021. Using a structured survey instrument, we collected information on patient-specific and health service barriers. Patient-specific barriers included procedure-related concerns (e.g., concern about discomfort), cognitive-emotional factors (e.g., fear of finding cancer), and changes in health status. Health service barriers included logistical factors (e.g., transportation), cost (e.g., lack of insurance) and scheduling problems (e.g., forgot about appointment or scheduled at an inconvenient time). Here we describe the most common reasons for missed appointments and compared women who reported patient-specific versus health service barriers. Results: 255 women who no-showed for their appointment were contacted and 91 participated in the study survey (35.6% response rate). Most respondents (90%) attributed their no-show to at least one of the listed barriers. Nineteen (7.5%) attributed their no-show to COVID-19, but only 1 person reported this as their only barrier. Scheduling issues were the most commonly reported barriers (57.8%), followed by transportation (38.9%). Three-quarters of respondents reported health service barriers, while only 40.7% reported patient-related barriers. The most common patient-related barriers were cognitive-emotional (25%), changes in health status (20.9%) and procedure-related concerns (15.6%). The majority of respondents (82.6%) were interested in rescheduling their mammogram. Conclusions: Most appointment no-shows among surveyed AA women resulted from potentially preventable scheduling and transportation issues. Relatively few respondents reported cognitive-emotional or procedure-related concerns. Further, the majority of respondents were interested in rescheduling their mammogram; which suggests that these women remain motivated to undergo breast cancer screening. Programs which address preventable health-service related issues may help these women keep their appointments.
Estimating patient demand for oncologists in the United States using Google trends.
Authors: Waris Shanawar , Raiker Rahul , Siva Nanda , Koirala Monika , Pakhchanian Haig , Boustany Osama , Khalid Ahmed A.
Published: June 2022

e18535

Background: Cancer accounts for a massive burden of global disease, healthcare expenditure, and is one of the leading causes of death worldwide, accounting for approximately 1 in 6 deaths. As both the incidence and prevalence of cancer continue to increase, along with the percentage of the population over the age of 65, it is important to understand patient demand for oncologists. Previous studies have predicted a shortage of over two thousand oncologists by 2025. The inconsistencies between supply and demand for oncologists require analysis and supervision to identify potential gaps in oncological care and fulfill patient demand for quality care. Methods: The average relative search volume (RSV) for the term “oncologist” was determined by analyzing Google Trends from 2004-2019 for each state. The oncologist per capita values were computed by taking the number of oncologists per state and then dividing by the corresponding 2019 Census estimates. The RSV values were then divided by per capita values to quantify demand index and standardized to generate a relative demand index (RDI). A spearman’s rho correlation test was also conducted to assess the relationship between RDI and overall 2019 state health rankings as conducted by the America’s Health Rankings group. Results: The states with highest RSV was New Jersey (100), Florida/Tennessee (98), and Connecticut (97), while the lowest RSV were Oregon (53), Alaska (44), and Vermont (41). The RDI for oncologists was greatest in Idaho (100), Mississippi (86), and Arkansas (77) while the lowest were for Vermont (15), Massachusetts (14), and District of Columbia (8). Spearman’s rho test revealed a strong negative relationship between RDI and overall state health ranking that was statistically significant (rs= -0.6363, p < 0.001). Conclusions: These trends may give us a preliminary idea of states that have unmet healthcare needs in oncology. Further studies are warranted.