bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of leucocyte modifications in patients with locally advanced cervical treated by chemoradiotherapy.
Authors: Gennigens Christine , de Cuypere Marjolein , Barbeaux Annelore , Forget Frederic , Hermesse Johanne , Gonne Elodie , Jerusalem Guy Heinrich Maria , Kridelka Frederic
Published: May 2020

e18014

Background: Concomitant cisplatin-based chemoradiotherapy (CCRT), followed by image guided-adaptive brachytherapy (IGABT) is the recommended treatment for patients suffering from locally advanced cervical cancer (LACC). Methods: Between January 2010 and May 2017, 103 patients with LACC (FIGO 2009-stages IB2-IVA) received CCRT followed by IGABT. The objectives of this study were to evaluate the impact of white blood cells (WBC) and polymorphonuclear neutrophils (PMN) counts variations on outcomes. This variable was calculated by substraction between WBC or PMN levels at the first cycle (CB) and the last cycle (CL) of chemotherapy (CT)(DCB-CL). The data were reviewed retrospectively, with Cox regression for univariate and multivariate analysis. Results: The median age at diagnosis was 50 years. The median tumor size at diagnosis was 47mm. The majority of the patients had FIGO stage II (60.2%) or stage I (21.4%) disease with squamous histology (88.3%). Patients received a median dose of external-beam radiotherapy (EBRT) of 45 Gy (range 40-50.4 Gy) by 1.8-2 Gy fractions, with a median cumulative dose of all the radiotherapy of 85 Gy. The median duration of EBRT+IGABT was 51 days (range 31-94). All patients received at least one cycle of cisplatin, but the majority received 5 (40.4%) or 6 (39.4%) cycles. The median follow-up time for all patients was 30.1 months. The overall survival (OS) and recurrence-free survival (RFS) at 3 years was 81,4% and 76,8% respectively. Univariate analysis associated higher DCB-CL WBC and DCB-CL PMN with better OS and RFS. Multivariate analysis confirmed that DCB-CL WBC (HR, 0.856; 95% CI, 0.737-0.986; p = 0.018) and DCB-CL PMN (HR, 0.863; 95% CI, 0.750-0.994; p = 0.041) were associated with better OS and RFS respectively. A linear regression analysis was performed to cross the DCB-CL WBC/PMN and the number of CT cycles. This analysis reveals that an increasing number of CT cycles is linked to an increased DCB-CL WBC/PMN. Conclusions: Our study reveals the impact of DCB-CL WBC and PMN on outcomes. These two tests could become biomarkers during CCRT to discuss adjuvant treatments, but also to adapt our follow-up.
Efficacy and safety of PEGylated recombinant human granulocyte stimulating factor in the prevention of neutropenia during concurrent chemoradiotherapy.
Authors: Zou Dongling , Zhou Qi , Guo Mingfang
Published: May 2020

e18018

Background: This randomized controlled prospective study aims to explore the efficacy and safety of using PEG-rhG-CSF to prevent neutropenia during concurrent chemoradiotherapy of paclitaxel and cisplatin (TP) regimen for cervical cancer. Methods: Patients who met the eligibility criteria were divided into two groups according to the randomized principle of 2:1: the experimental group (patients used 6 mg PEG-rhG-CSF prophylactically after chemotherapy) and the control group (patients did not use PEG-rhG-CSF for prevention and were given 5 ug / kg rhG-CSF when ANC < 1✕109). TP combination regimen was used for concurrent chemotherapy, specifically as follows: paclitaxel 150mg / m2 (day 1), cisplatin 35mg / m2 (day 1-2), repeated every three weeks. The PTV dose was 45 Gy in 1.8 Gy daily fractions, with five fractions per week. SPSS 25.0 software was used for statistical analysis of the data, t-test was used for measurement data, and χ2 test Fisher exact test was used for enumeration data. P < 0.05 was considered statistically significant. Results: As of September 2019, 30 patients were enrolled into this study, including 18 in the experimental group and 12 in the control group. One of the 18 patients in the test group (5.6%) had a Grade 3/4 neutropenia. Ten of the 12 patients in the control group (83.3%) developed Grade 3/4 neutropenia. The incidence of Grade 3/4 neutropenia in the two groups was statistically significant (P < 0.001, Table 1). The incidence of FN was 5.6% in the experimental group and 8.3% in the control group (P = 1.000). The incidence of delayed chemotherapy course was 11.1% in the experimental group and 58.3% in the control group (P = 0.013). The incidence of delayed chemotherapy course in the two groups was statistically significant (Table 1). As shown in Figure 4, the experimental group had a completion time of radiotherapy for 46.7 days, while the control group had 49.0 days (P = 0.278). Conclusions: Although the results of bone marrow function and overall survival are still to be obtained, it can be initially seen from the intermediate-term data that the use of PEG-rhG-CSF primary prevention reduced the granulocytopenia and the delay of the chemotherapy course during the concurrent chemoradiotherapy TP regimen for cervical cancer, which has the value of further completing this study. [Table: see text]
Treatment patterns among newly diagnosed women with cervical cancer in the United States.
Authors: Shah Anuj , Kebede Nehemiah , Shah Ruchit , Corman Shelby , Nwankwo Chizoba
Published: May 2020

e18019

Background: To address the gap in US-based real-world data, this analysis described the real-world treatment patterns among newly diagnosed cervical cancer patients. Methods: Women newly diagnosed with cervical cancer between Jan 2015 – June 2018, with a confirmatory diagnosis or treatment within 2 months, and continuous enrollment for 12 months prior and 6 months post diagnosis were identified in the Optum Clinformatics DataMart database. Surgeries (hysterectomy, conization, lymphadenectomy and trachelectomy), radiation (external beam radiotherapy [EBRT]/brachytherapy) and systemic therapies (chemotherapy/immunotherapy) received after diagnosis were described by line of therapy (LOT). The start of the first LOT was the date of the first treatment. All treatments initiated within 90 days of a surgery or the end of radiotherapy, and all systemic treatment started within 28 days of any previous treatment were a part of the same LOT. Most frequently received treatments in LOT1 and 2 and time to treatment initiation were described. Results: Out of 1,004 newly diagnosed women, 655 (65.2%) received at least LOT1 and 162 (16.14%) received LOT2. Median time to first LOT was 1.5 (1.4 – 1.7) months from diagnosis. Surgery was the most common treatment in LOT1 (58.0%). Among patients receiving radiation, the majority received a combination of EBRT and brachytherapy (LOT1: 66.9%, LOT2: 58.0%). The use of chemotherapy increased with subsequent LOTs (LOT1: 53.3%, LOT2: 61.1%). Treatments received in LOT1 and LOT2 are described in the table. Conclusions: This analysis shows that newly diagnosed cervical cancer patients are primarily receiving guideline recommended treatment with surgery or chemoradiation as primary treatment. Radiation therapy includes EBRT and brachytherapy. Counts ≤ 10 are not reported (NR). [Table: see text]
A retrospective study of carboplatin and liposomal doxorubicin in patients with locally advanced or recurrent squamous cell carcinoma of the cervix.
Authors: Chang LEI , Yuan Zhongfu , Tian Wanjia
Published: May 2020

e18021

Background: The efficacy and safety of the combination of carboplatin and liposomal doxorubicin was tested in in patients with locally advanced or recurrent cervical cancer. Methods: The combination of carboplatin (area under the concentration curve AUC = 5) and liposomal doxorubicin (starting dose, 40 mg/m2) was administered intravenously every 28 days to 75 patients with locally advanced or recurrent cervical cancer to determine the drug efficacy and safety. Results: During the observation, all patients were received surgery or radiation before combination chemotherapy. 58 patients were assessable for response, and 12 patients were assessable for toxicity. During therapy, none patients required discontinuation of chemotherapy while only 2 patients needed dose reduction, because of side effect. The overall response rate was 77.3%, the median time to response was 8 weeks, the median duration of response was 24 weeks, and the median survival was 37 weeks. The most common adverse events with these patients included myelosuppression (69.0%), neutropenia (31.0%), anemia (23.0%), thrombocytopenia (21.0%) and neutropenic fever (11.0%). Conclusions: The combination of carboplatin and liposomal doxorubicin shows clinical efficacy and acceptable safety in patients with locally advanced or recurrent cervical carcinoma. It might provide a noval treatment for late stage cervical cancer.
Quality of life of cervical cancer patients after specialized treatment in Kazakhstan.
Authors: Kaidarova Dilyara , Pak Roza , Chingissova Zhanna
Published: May 2020

e18024

Background: In Kazakhstan cervical cancer (CC) ranks 2nd in morbidity and mortality among women with malignant neoplasms. 88% of women are diagnosed in stages 1-2. Age range of patients with cervical cancer is becoming younger with women age 35-55 years old. This urges implementation of an effective system for assessing and maintaining the quality of life of people with CC who undergo special treatment. Methods: During study we used The EORTC quality of life questionnaire (QLQ C-30) Version 3.0 on 157 patients with stage 1-2 CC, 1+ year after chemoradiotherapy (CRT, n = 65) and surgical treatment (ST, n = 92). For statistical analysis, we used the Wilcoxon rank-sum test and the chi-square test using SPSS version 22.0. Results: When analyzing limitations in everyday activities (work etc) (sign 1), 13.8% -18.5% of patients with cervical cancer noted “significant” and “very strong” impact on quality of life after CRT compared with 1.1% - 3.3% of patients after ST (p < 0.001). Study showed that there is a strong correlation between treatment method and quality of life (table 1). 35.4% of patients after CRT have noted “significant” difficulties in carrying out work requiring a higher level of physical effort (sign 2). In contrast, only 16.3% of patients after ST noted “significant” difficulties, which is 2.2 times less (p < 0.006). Assessment revealed a moderate quantitative correlation (table 1). 16.9% of patients after CRT noted severe pain (sign 3) compared with 2.2% of patients who received ST (p < 0.001). Assessment revealed a moderate quantitative correlation (table 1). Absence of feeling of weakness (sign 4) was greater among patients from the ST group - 21.7% compared with CRT - 9.2% (p < 0.03). Assessment revealed a strong quantitative correlation (table). 15.4% of patients after CRT, compared with 2.2% of patients who received ST (p < 0.001) have noted that their physical condition and treatment had a “very strong” impact on their personal life (sign 5). Conclusions: Assessment revealed that CC patients who received CRT showed lower physical and social indicators of quality of life. [Table: see text]
Relative gene copy numbers in various patterns of cervical cancer growth.
Authors: Timoshkina Natalya N. , Petrusenko Natalia A. , Nikitina Vera P. , Spiridonova Diana A. , Verenikina Ekaterina V. , Nikitin Ivan S. , Zhenilo Oksana E. , Vladimirova Liubov Yu , Kit Oleg I.
Published: May 2020

e18029

Background: Numerous studies on cervical cancer confirm an important role of specific genomic changes in the onset and development of cervical intraepithelial neoplasia and their effect on the progression of cervical cancer. Solid tumors are characterized by genomic changes leading to a change in the DNA sequence copy number. The purpose of the study was to reveal changes in the relative copy number of the ESR1, ESR2, GPER1, STS, SULT1A1, SULT1E1, CYP1A1, CYP1A2 genes responsible for the reception and metabolism of estrogens in cervical tissues in endophytic and exophytic patterns of tumor growth in order to find predictive markers of malignancy. Methods: The study included 40 patients aged 28-65 years with cervical cancer of endophytic (n = 20) and exophytic (n = 20) growth patterns. Eligibility criteria included a morphologically confirmed cervical squamous cell cancer T1b-2aN0M0, stage I-II. The Thermo Scientific GeneJET FFPE DNA Purification Kit was used for the DNA extraction from FFPE blocks of tumor and healthy tissues. DNA concentrations were measured on the Qubit 2.0 fluorimeter (Invitrogen, USA) using the Quant-iT dsDNA High-Sensitivity (HS) Assay Kit (Invitrogen, USA). Results: The relative copy number of the GPER1, SULT1A1, CYP1A1 genes in tumor samples increased (p < 0.05) compared with normal tissues in the total sample of patients diagnosed with cervical cancer. In contrast to the total sample, an increase in the SULT1A1 gene dosage did not reach a statistically significant level in any group (p = 0.242 and p = 0.157); the copy number of the GPER1 locus significantly increased only in the group with the endophytic growth pattern (p = 0.040), as well as the CYP1A2 gene dosage (p = 0.025). Patients of 36-55 years with endophytic tumors showed a statistically significant (p < 0.05) increase in the GPER1 and CYP1A1 gene copy numbers with the rates of 41.7% and 66.7%, respectively, as well as an increased amplification of the CYP1A2 gene in 41.67% of patients. In women of 56-75 years with endophytic tumors, an increase in the copy numbers of the ESR2, GPER1, SULT1A1 genes was observed with a frequency of 50%, 100% and 75%, respectively. Patients aged 20-35 and 36-55 years with exophytic tumors showed a statistically significant (p < 0.05) increase in the CYP1A1 gene copy numbers in 33.33% and 45.45%, respectively. Conclusions: The results suggest the use of the GPER1, SULT1A1 and CYP1A1 gene copy numbers as biomarkers of cervical tumors.
Treatment patterns of advanced or recurrent endometrial cancer following platinum-based therapy in the US real-world setting.
Authors: Klink Andrew J. , DeMars Leslie , Huang Joice , Maiese Eric M. , Feinberg Bruce A. , Hurteau Jean
Published: May 2020

e18036

Background: Following disease progression on or after primary (1L) platinum-based therapy (PBT) for advanced/recurrent (A/R) endometrial cancer (EC), patient (pt) prognosis is poor and no consensus on standard second-line therapy exists. This retrospective analysis aimed to understand real-world (RW) treatment patterns of pts with A/R mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC who progressed after 1L PBT. Methods: Physicians in Cardinal Health’s Oncology Provider Extended Network submitted retrospective data by abstracting outpatient electronic medical records of pts who received systemic treatment for A/R EC following PBT from 2016 to 2018. Demographics, clinical characteristics, treatments received, and outcomes were summarized descriptively. Results: This study included 84 pts with A/R dMMR/MSI-H EC (table). The majority of participating physicians were hematologists/medical oncologists (80%) and practiced in the community setting (70%). Median duration of therapy (mDOT) in 1L was 4.9 months (95% CI, 4.47–5.57); 64% of pts discontinued treatment due to therapy completion and 35% due to disease progression. In contrast, mDOT in 2L was 6.2 months (95% CI, 5.40–6.37); 37% of pts discontinued treatment due to therapy completion and 44% due to disease progression. The most common MMR/MSI testing modalities were next-generation sequencing (NGS) only, immunohistochemistry (IHC) only, and polymerase chain reaction (PCR) only (table). Conclusions: RW treatment patterns in pts with A/R dMMR/MSI-H EC show that most will undergo PBT retreatment. However, progression is the main reason for discontinuation during retreatment. An urgent need exists for durable therapies that improve prognosis. Opportunities to improve timely testing of MMR/MSI exist. [Table: see text]
Is there a high risk of renal dysfunction and the need for its prevention in patients with gynecological cancers after surgery?
Authors: Tumanyan Sergey V. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Frantsiyants Elena M. , Menshenina Anna P. , Oros Oksana V. , Sugak Elizaveta Yu.
Published: May 2020

e18037

Background: Renal dysfunction in cancer patients is an urgent problem of clinical practice in oncology which can often challenge the efficacy of anticancer treatment and the disease prognosis. The purpose of the study was to reveal risk factors for renal dysfunction in oncogynecological patients. Methods: A prospective randomized study of the renal function included 174 patients aged 54-82 years with reproductive tumors. The control group included 34 patients with benign uterine tumors. Glomerular filtration rate (GFR) was estimated using the CKD-EPI equation. Results: GFR in the main group was 71.6±2.3 mL/min/1.73m2. Renal dysfunction was found in 42.5%. The majority of patients (115 patients, 66.1%) had concomitant diseases classified as modifiable risk factors for the development and progression of chronic kidney disease (KDIGO, 2017), including hypertonic disease in 46.6% (χ2= 4.4, p < 0.05), diabetes in 39.1% (χ2= 7.9, p < 0.05), cardiovascular diseases in 27.6% (χ2= 3.9, p < 0.05), and morbid obesity in 68.9%. This confirmed the decisive importance of hypercholesterolemia, hyperglycemia and hypertension as risk factors for reduced GFR. 52.9% of patients had a combination of these factors, which together with the initial renal dysfunction suggested a high probability of acute renal failure in the perioperative period. Conclusions: The assessment of kidney function in patients with gynecological cancers is required to determine the intensity of treatment in the perioperative period, the general disease prognosis and risks of possible complications.
Utilizing porcupine (PORCN) and DKK1 inhibition to improve anti-tumor immunity in a murine model of ovarian cancer.
Authors: Wall Jaclyn , Katre Ashwini A. , Meza-Perez Selene , Londono Angelina , Norian Lyse , Arend Rebecca Christian
Published: May 2020

e18041

Background: Epithelial ovarian cancers (EOC) are immunologically “cold” tumors and consequently have seen limited success with immunotherapy. Wnt-beta/catenin signaling is dysregulated in multiple cancers, including EOC, and is characterized by immune exclusion. Porcupine (PORCN) is the enzyme necessary for secretion of Wnt ligands, which is required for activation of Wnt/beta-catenin signaling. Up-regulation of the Wnt/beta-catenin pathway leads to increased levels of the target gene DKK1, which plays a role in immune exclusion. Our goal is to improve the tumor immune response via targeting Wnt-signaling in EOC. Methods: We utilized a syngeneic murine model (ID8 cell line) deficient in p53 (ID8p53−/−) with and without the addition of a Luciferase tag (Luc+/-) to assess the effect of treatment with a PORCN inhibitor, CGX-1321, with and without DKN-01, a monoclonal antibody targeting DKK1. Mice were treated with vehicle/control, CGX-1321, DKN-01, or CGX-1321/DKN-01. Treatment was given for either 14 or 31 days. In Luc+ mice, bioluminescence imaging was performed weekly. Following mouse sacrifice, omental weights and ascites volume were measured. Omental tumor was used for flow cytometry and representative samples were sent for NanoString analysis. Results: Treatment with CGX-1321 for 14 days reduced omental weight and ascites volume in Luc- mice only (p = 0.02); however, earlier and extended treatment with CGX-1321 and CGX-1321/DKN-01 in Luc+ mice decreased omental weight (p = 0.008 and 0.0025); mice treated with CGX did not develop any ascites with the same treatment schedule. While treatment with DKN-01 alone did not decrease omental weight, treatment with DKN-01 and combination CGX-1321/DKN-01 increased total percentage of NK cells (p = 0.0192 and 0.0070). CGX-1321 and DKN-01 alone and in combination increased the total percentage of CD8+ T cells in omental tumors (p = 0.0238, 0.037, and 0.0127). Conclusions: CGX-1321 decreased omental weight and ascites volume, while DKN-01 increased the cellular percentage of NK cells. Both DKN-01 and CGX-1321 increased CD8+ T cells. Wnt-inhibition is therapeutically promising in EOC, and the combination of a PORCN inhibitor with DKN-01 could improve the response to immune checkpoint blockage and further investigation is warranted.
Endocrine biomarkers in low-grade serous ovarian cancers (LGSC) and serous ovarian tumors of low malignant potential (LMP).
Authors: Taylor Sarah E. , Wield Alyssa , Fang Yusi , Bhargava Rohit , Lang Susan , Tseng George , Coffman Lan Gardner , Oesterreich Steffi
Published: May 2020

e18045

Background: LGSC and serous ovarian LMP tumors are rare entities along a disease continuum. Because they are relatively chemotherapy resistant, there is interest in targeted treatment, including endocrine therapy. In studies of endocrine agents for treatment of recurrent ovarian cancer, tumor estrogen receptor (ER) status alone does not effectively predict outcomes. The objective of this study is to utilize protein and gene expression from ER and downstream targets to identify signaling components that will act as prognostic and predictive biomarkers. Methods: A single institution tumor registry was queried for patients with LGSC or serous LMP tumors between 1993-2016. Formalin-fixed, paraffin embedded (FFPE) tissue was obtained. Clinicopathologic data was collected. Immunohistochemistry (IHC) was performed and scored as dichotomous (+/-) and continuous (H-score). NanoString nCounter platform was used for gene expression of a predesigned endocrine biomarker panel. Wilcoxon Rank Sum was used to compare mRNA and protein expression. Survival analyses were performed using Cox proportional hazard (PH) method with elastic net to fit the prediction model for the gene panel. Results: Tissue was analyzed from 23 LGSC, 71 serous LMP tumors, and 2 recurrences. At diagnosis, 86% of patients with LMP tumors had stage I disease vs 78% of patients with LGSC had stage III/IV disease. There were 7 (10%) LMP and 13 (56.5%) LGSC recurrences. Median initial PFS was 76 and 37 months and median OS was 88 and 82 months for LMP and LGSC, respectively. Fourteen received endocrine therapy; nine for treatment of recurrent LGSC. Median therapy was 21 months, with 3 complete responses, 2 partial responses and 1 stable disease. All tumors were ER+ (median H-score 210) and 89% were PR+ (median H-score 130). ER H-scores and ESR1 expression levels were not significantly different between LGSC and LMP tumors (p = 0.1942, p = 0.0893). PR H-scores were higher in LMP tumors (p < 0.00001) but PGR expression was not significantly different (p = 0.6581). In the Cox PH analysis, ER H-score was a significant predictor of both PFS and OS (p < 0.001, p = 0.004). The Cox model identified independent sets of gene expression associated with PFS and OS in both the LGSC and LMP cohorts (c-indices 0.679, 0.570, 0.626, 0.689). Conclusions: Endocrine therapy is an active area of interest in the treatment of ovarian neoplasms. ER H-score and gene expression of downstream ER targets could improve upon the use of hormone receptors to determine risk of recurrence and guide use of adjuvant endocrine therapy.
Characterization of mutations in HRR genes, TMB, and PD-L1 expression in Chinese patients with ovarian cancer.
Authors: Zheng Hong , Gao Min , Gao Weijiao , Zhang Nan , Wang Hongguo , Song Nan , Zhang Naiyi , Wang Wei , Li Qian , Yuan Mingming , Chen Rongrong , Gao Yunong
Published: May 2020

e18048

Background: A great number of clinical studies have confirmed the promising efficacy of ICIs and PARPi in multiple solid tumors. Here we aim to investigate the biomarkers related to these emerging therapies, including mutations in DNA homologous recombination repair (HRR) genes, tumor mutation burden (TMB) and PD-L1 expression in Chinese patients (pts) with ovarian cancer. Methods: A total of 209 pts with ovarian cancer were enrolled. Matched tumor-normal NGS of 1021 cancer-related genes was performed in 98 pts (T: 71 pts, T+B: 25 pts, B: 2 pts). Germline variants in ovarian cancer susceptibility genes were analyzed in 209 pts. PD-L1 expression was assessed by immunohistochemistry (Dako 22C3). Pts with TPS≥50 were considered as high expression and pts with 1≤TPS<50 was considered as expression. Tissue TMB was calculated as the number of somatic non-synonymous SNVs and Indels per Mb in the coding region (with VAF ≥0.03). The threshold of TMB-high was 5.76 muts/MB. Results: Germline pathogenetic or likely pathogenetic variants were identified in 28.7% of pts ( BRCA1 15.3%, BRCA2 7.7%, RAD51D 2.0%, PALB2 1.0%, and 0.7% for CHEK2, MSH2, RAD51C and MSH6). Germline variants in HRR genes was identified in 27.3% of pts. The mutation detection rates in 96 tissue samples from surgery or biopsy and 25 ctDNA samples collected at disease recurrence were 100% and 96%, respectively. An average of 34.6% of tissue-derived mutations can be identified in ctDNA, and 55.2% of tissue-derived actionable mutations were observed in ctDNA. Besides, there were 83 private mutations, including PPMID (5), ARID2 (3), CHEK2 (3), PIK3CA (3) and ARID1B (2). Mutations in HRR genes were found in 36.5% (35/96) of tissue samples, and 12 pts harbored more than one HRR mutations. The detection rate of HRR mutations in ctDNA was 40% (10/25), and cases harbored more than one HRR mutations. The status of TMB and PD-L1 was analyzed in 30 pts. Two pts were evaluated as PD-L1 highly expressed and 9 pts were considered as expressed. Eight pts were assessed as TMB-high. Five pts with PD-L1 negative expression were TMB-high, and 8 pts with TMB-low were PD-L1 positive expression. TMB and PD-L1 expression are independent indicators with the spearman r of 0.01 (p = 0.96). Conclusions: The detection rate of germline and somatic mutations in HRR genes were 27.3% and 36.5-40%, respectively, which defined a large number of ovarian cancer pts who can benefit from PARPi. PD-L1 expression and TMB are independent biomarkers, which may be combined to predict the efficacy of immunotherapy in future exploratory trials.
Identification of new lesion with disease progression in Ovarian cancer per RECIST 1.1.
Authors: Sharma Manish , Bohnsack Oliver , Jarecha Rudresh , Narang Jayant , Singareddy Anitha , Bajpai Surabhi
Published: May 2020

e18058

Background: Metastasis is the leading cause of ovarian cancer (OC) related death with more than 70% of OC patients diagnosed with metastasis with five-year survival rates below 45%. OC cells mainly metastasize within the peritoneal cavity at presentation and throughout the course of the disease in 85% of the patients which involves exfoliation from the primary tumor, followed by survival and transport in the peritoneal fluid and finally metastatic colonization of the organs within the peritoneal cavity. There is a tendency of conventional imaging to underestimate the frequency of peritoneal spread. The purpose of the study was to obtain the frequency of organ involvement in OC metastasis and identify the most common route of OC metastasis. Methods: Retrospective study and analysis of two randomized double-blind trials was performed in patients with OC. Data was analyzed from these studies using blinded independent central review using RECIST 1.1 involving a total of 895 subjects, 528 and 367 respectively. A double read with adjudication by independent radiologists was performed for each scan based on the RECIST 1.1 criteria. Baseline tumor burden was assessed for all subjects using RECIST 1.1 criteria. At follow-up visits, data was specifically analyzed for New lesions. The readers had to select New lesion location from a pre-defined location list from a drop-down menu. Data was tabulated with frequency of subjects with New lesion per each location. Results: With both studies combined involving 895 subjects, total subjects with new metastasis observed in decreasing order for various organs were peritoneum/omentum (406), lymph nodes (315), ascites (207), liver (94), pleural effusion (65), pelvis (52) & lung (56). Other less common locations for new metastasis was abdominal wall, pleural deposits, spleen, brain, retroperitoneum and adrenal. We also looked at the possibility of disagreement between 2 readers in identifying such lesions leading to progression as below. Conclusions: It can be concluded that subjects with ovarian cancer tend to develop metastasis leading to progression per RECIST 1.1 in peritoneum / omentum, lymph nodes, liver and lung. Due to significant variability in identification of such discrete, ill-defined and/or small nature of lesions, targeted awareness and training should be incorporated to improve clinical outcome. [Table: see text]
Capturing the pathway logic of cell signaling for epithelial-mesenchymal transition in ovarian cancer cell lines.
Authors: Morris Matthew , Clark Jeselle , Lyman Cole , Brown Broderick Jennifer , Kramer Zachary B. , Skuse Gary , Broderick Gordon
Published: May 2020

e18063

Background: Epithelial-to- mesenchymal transition (EMT) plays a key role not only in cancer invasiveness and progression but also in treatment resistance. Experimental models suggest that epithelial and mesenchymal phenotypes may represent steady states supported by the regulatory logic of intracellular signaling networks. Using known regulatory interactions between intracellular signaling molecules as a framework, we explored EMT in silico with the aim of identifying potentially novel means of inhibiting metastasis in ovarian cancer. Methods: A mathematical model connecting 27 genes involved in EMT through 153 regulatory interactions was assembled from the Mogrify, Reactome, String and Pathway Studio (PS) databases, the last of which used the MedScan natural language processing (NLP) engine to process over 8,000 full-text publications. Logic model parameters dictating the regulatory response dynamics of the EMT circuit were constrained to values that accurately predicted the proteomic profiles characterized as either epithelial or mesenchymal in 30 cell lines in the publicly available MaxQB database. Results: A total of 94,672 candidate models predicted the protein expression in stable epithelial and mesenchymal cells equally well, clustering into 24 classes of slightly different EMT transition kinetics. Discrete event simulations based on these models identified 7 unique combinations, involving the concurrent modulation of at least 3 gene products capable of effecting this transition successfully even in the presence of noise. Every combination required inactivation of ZEB2, along with 2 other manipulations. Inactivation of TP53, HOXA5, or IRF7 was required in 3 combinations, while inactivation of ICAM1 was required in 2 cases. Only BCL2 was required to be activated in any of these scenarios. Interestingly, BCL2 inhibition is now applied clinically in some hematologic cancers and proving effective in patient-derived cell lines for high-grade serous ovarian cancer when combined with MEK inhibition. Conclusions: This work suggests that EMT might at least in part be driven by normal regulatory interactions between specific proteins in a network of pathways, without the requirement for additional mutations or alterations in the underlying circuitry. Maintenance of ZEB2 or TP53 activation as well as BCL2 inhibition may thus represent promising avenues for future research in arresting EMT and associated chemo-resistance.
Effect of MUC5B mutation on prognosis by enhancing the infiltration and antitumor immunity of cytotoxic T lymphocytes in the endometrial cancer.
Authors: Zheng Hong , Duan Wei , Zhao Qun , Li Chengcheng , Wang Guoqiang , Zhang Yuzi , Bai Yuezong , Zhou Yingchun
Published: May 2020

e18105

Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Associations between MUC5B mutation and survival and RNA expression were analyzed. Results: MUC5B mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.47; 95% CI, 0.28-0.79; P < 0.05), progression-free survival (PFS) (HR, 0.31; 95% CI, 0.17-0.56; P < 0.001) and overall survival (OS) (HR, 0.29; 95% CI, 0.14-0.60; P = 0.001) in endometrial cancers. MUC5B mutation was significantly associated with patients' age at diagnosis (P = 0.027) and histological type (P < 0.001) and grade (P < 0.001). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade, tp53, pole and TCGA molecular subtypes, the association between MUC5B mutation and PFS was still significant (HR, 0.40; 95% CI, 0.20-0.81; P = 0.011), indicating the MUC5B mutation is an independent prognostic factor for PFS. Moreover, MUC5B mutation have a tendency for a favorable OS (HR, 0.52; 95% CI, 0.23-1.22; P = 0.13). Patients harboring MUC5B have a higher tumor mutation burden (TMB). An analysis of immune signature revealed that MUC5B mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. These results have further been confirmed by GSEA. Moreover, an increased level of cytotoxic T lymphocytes infiltration was observed in the patients with MUC5B mutations. Conclusions: MUC5B mutation was related with a favorable prognosis through increasing T cells signature. Identification of MUC5B mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis.
Effect of inducing HR deficiency using AVB500, a receptor tyrosine kinase AXL inhibitor, on response to olaparib in uterine serous cancer.
Authors: Toboni Michael Driscoll , Blachut Barbara , Mullen Mary M , Tankou Jo'an , Noia Hollie M , Oplt Alyssa , Wilke Danny , Kuroki Lindsay M , Hagemann Andrea R. , McCourt Carolyn K , Thaker Premal H. , Mutch David Gardner , Powell Matthew A. , Fuh Katherine Cynthia
Published: May 2020

e18108

Background: Evidence suggests DNA repair is a therapeutic target in endometrial cancer (EC). Given this, we determined whether combination therapy with AVB500, an AXL inhibitor, could improve response in a uterine serous cancer (USC) model. Methods: Two USC cell lines (ARK1 & ARK4) were treated with AVB500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB500 alone, olaparib alone or combination treatment (olaparib + AVB500); colonies were stained and absorbance was obtained to calculate relative cell viability using Graph Pad Prism. Baseline homologous recombination (HR) status was determined after radiating cells with 10Gy and identifying RAD51 foci by immunofluorescence (IF). Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 ( > 5 foci per cell). IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. In vivo studies were performed using NOD-SCID mice injected with 1 x 107 ARK1 cells intraperitoneally followed by treatment q3 days for a 14 and 21 day treatment period. Treatment groups were vehicle control, AVB500 alone, olaparib alone and olaparib with AVB500. Results: The absorbance for olaparib + AVB500 was significantly less than the olaparib only group in two assays involving ARK1s (0.417nm vs 0.756nm, p = 0.001; 0.320nm vs 0.620nm, p = 0.008) as well as in ARK4s (0.186nm vs 0.641nm, p = 0.003). The HR assay indicated both cell lines were HR proficient. After baseline HR proficiency was established, the cell lines were pretreated with AVB500 prior to radiation. When compared to cells without treatment with AVB500, IF showed a decrease in RAD51 foci per cell in ARK1 (2.7 vs 7.3, p = 0.0003) and ARK4 (6.3 vs 13.0, p = 0.0054). The proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Lastly, NOD-SCID mice receiving olaparib + AVB500 had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p = 0.002) and AVB500 alone (0.008g vs 0.145g, p = 0.0006) in a 14 day and a 21 day treatment period (0.212g vs 0.586g, p = 0.027 and 0.212 vs 0.494g, p = 0.005, respectively). Conclusions: HR proficient USC cell lines treated in vitro and in vivo with the combination of AVB500 and olaparib demonstrate an improved response to olaparib or AVB500 alone with a greater decrease in tumor burden. AVB500 appears to induce HR deficiency. Additional therapeutic and mechanistic experiments are ongoing.
Impact of inpatient hospitalization on opiate usage for minimally invasive hysterectomy amongst gynecologic oncology patients.
Authors: Gee Amy Dawn , Grabosch Shannon Michelle , Gavard Jeffrey
Published: May 2020

e18109

Background: The overdose death rate related to opiates has quadrupled in the last two decades. Up to 27% of chronic opiate users report initiation in the post-op period. Among cancer patients, 10% of opioid-naive patients continue chronic use one year after surgery. Restrictive opiate prescribing has demonstrated promise in other studies. However, lacking from current literature is an analysis of the effect that same day discharge (SDD) has on post-op opiate usage at home. The objective of this study is to evaluate the impact of SDD versus physician-elected observation for 1 to 2 days on acute post-op opiate usage and safety following minimally-invasive hysterectomy (MIH). Methods: This is a prospective observational study of women undergoing MIH. Sixty patients were assigned to either the SDD or hospitalization group at provider discretion based on practice pattern, distance from hospital, or comorbidities. One patient was lost to follow up. Patients were followed through 30 days after surgery. Total opiate usage included the inpatient usage (if hospitalized) and home usage assessed at the post-op visit. Anonymous surveys were used to collect home opiate usage practices, satisfaction, and self-reported risk factors for continued use. Continuous variables were analyzed by independent Student’s t-test and the Mann-Whitney U test. Categorical variables were analyzed using Chi-square test and Fisher's Exact test. Results: 29 SDD and 30 hospitalized patients were available for review. Demographics including age, BMI, tobacco use, and procedure indication were well matched. SDD patients used a median 5.0 (1.5-13.5) versus 8.5 (2.25-14.25) 5mg oxycodone tabs (p 0.33). SDD patients used opiates less for non-pain indications including to sleep (4 vs 9, p 0.24) or relax (3 vs 5, p 0.71). One SDD patient had a complication of a cuff hematoma, which spontaneously drained. There were no readmissions. Only one SDD patient felt she would have benefited from longer stay due to nausea. All hospitalized patients took their own opiates at home while 7 SDD had a family member dispense. Psychiatric disorders were the highest comorbidities in both groups (depression n = 12 and 10, anxiety n = 10 and 12). Conclusions: SDD demonstrated a trend towards less opiate usage, although not statistically significant. Patients did not feel that they needed to stay longer in the hospital. The safety of SDD is supported by lack of readmissions and one minor post-op complication. The high rates of psychiatric disease are a concerning risk factor for chronic use.
Survey of the experience of head and neck cancer patients with a percutaneous endoscopic gastrostomy tube.
Authors: Sahu Kamal Kant , Gibbs Lisa , Siddiqui Ahmad Daniyal
Published: May 2020

e18501

Background: Many patients with advanced head and neck cancer become unable to obtain enough nutrition and hydration orally, leading to considerable weight loss and compromised clinical outcomes. PEG tube is ideal for this population who require longer term nutrition support because of cancer treatment. The study objective was to learn about the experience of patients with a PEG tube. Methods: A questionnaire was developed, tested, and used to collect data. This survey consisted of 20 questions pertinent to various domains of quality of life and aiming at various aspects of patient life: physical, emotional and social sectors and noting their experiences in the form of multiple-choice options using Likert scale and free text option for suggestions. Results: A total of 22 participants were involved in this study, 64 years,7 males and 5 females. Cancer site: Tongue (10), tonsils (5), pharynx (5) and larynx (2). All patients belonged to stage III or more. Majority were treated with chemoradiotherapy (17 ). Out of 22 patients, 18 had PEG tube placement before starting treatment and the other 4 agreed during the cancer treatment. Most patients had the PEG tube for 3-6 months (8/22 cases). 21 patients strongly agree that PEG tube insertion was useful to them for their treatment and nutrition. 21 patients agreed relying on PEG tube FOR > 75% of their daily nutrition. While 4 patients agreed that PEG hampered their ADLs, 13 patients suggested that only rarely (7 cases) or sometimes (6 cases) they encountered difficulty in managing their ADLs. Only 2 patients had often trouble with sleep.15 cases did not feel any social embarrassment with PEG and did not miss any social events.19 patients answered that they followed oncologists to have PEG tube placement. Majority (15) managed the tube feed on their own. 16 cases never had any clinic/ER visit solely due to PET tube issues. 20 patients considered dietician as the first person to connect for concerns. 8 patients experienced issues like tube site infection (5), leakage (5), bleeding from site (4), tube blockade (5) or tube replacement (2). All patients except one agreed to have PEG placement again in future if required for any medical reason and would recommend others as well. Similarly, all patients except one thought that they would not have completed the cancer treatment without PEG tube support. Conclusions: Results indicate that the patient experience with the PEG tube is generally positive. This study will help improve understanding regarding the experience of living with a PEG tube from the patient perspective.
Effectiveness of PD-L1 inhibitors in metastatic or recurrent squamous cell carcinoma of head and neck: An observational, indirect comparison.
Authors: Bila Michel , Clement Paul M. , Van Dessel Jeroen
Published: May 2020

e18503

Background: The prognosis for recurrent or metastatic Squamous Cell Carcinoma of Head and Neck (HNSCC) remains dismal and its treatment poses a challenge for oncologists. Agents against programmed cell death ligand 1 (PD-L1) have shown beneficial effects on overall survival (OS) for HNSCC. The aim of the present study was to compare differential effects of PD-L1 inhibitors on recurrent and metastatic HNSCC. Methods: In an indirect comparison of patients with recurrent HNSCC were matched to patients with metastatic HNSCC. All patients were treated with PD-L1 inhibitors at the general medical oncology department of UZ Leuven. Kaplan-Meier methods and Cox regression models were used to calculate the overall survival. Results: From December 2013 to July 2019, 68 patients with metastatic and 59 with recurrent HNSCC were enrolled and evaluable. A significant difference in OS was found between recurrent and metastatic groups (p < 0.02). The mean OS was 7.6 months (95% CI: 2.4-11.3 months) for the recurrent group, while in the metastatic group the mean OS was 13.7 months (95% CI: 5.7-16 months). Conclusions: As a second-line therapy, PD-L1 inhibitors were associated with longer overall survival in metastatic compared to recurrent HNSCC.
Safety/efficacy of a phase I/II study of SNS-301 added to pembrolizumab in patients with ASPH+ locally advanced unresectable or metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN).
Authors: Smith William , Celebi John , Pierce Robert , Drumheller Alice , Csiki Ildiko , Algazi Alain Patrick
Published: May 2020

e18510

Background: SNS-301 is a first-in-class immune activating agent targeting human aspartyl (asparaginyl) β-hydroxylase (ASPH). ASPH is overexpressed in +20 tumor types. SNS-301 is an inactivated λ-bacteriophage, engineered to express a highly immunogenic fragment of ASPH fused to the phage gpD coat protein, previously shown to safely and effectively generate CD4, CD8 and B cell responses in a Phase I study (NCT04034225). Anti-PD-1 antibodies such as pembrolizumab and nivolumab can induce durable clinical responses in 13-16% SCCHN patients. While ASPH is frequently expressed in SCCHN, effective de novo responses to this tumor-specific antigen may be limited due to immune tolerance. Our hypothesis is that SNS-301 will break tolerance and trigger a significant anti-ASPH T-cell immune response, which in combination with anti-PD-1 blockade, will result in improved anti-tumor responses in this difficult-to-treat patient population. Methods: This is a Phase I/II study of SNS-301 delivered intradermally in combination with pembrolizumab. The population consists of 30 patients with ASPH+ locally advanced unresectable or metastatic/recurrent SCCHN who are actively receiving pembrolizumab or nivolumab for ≥12 weeks and have a best response of stable disease (SD) or first evidence of progressive disease (PD). A safety run-in will be performed for safety and any dose limiting toxicities (DLT) using a modified rolling six design prior to proceeding to full enrollment. Patients will provide a pre-SNS-301 tumor sample, an on-treatment tumor biopsy and an optional biopsy at PD to characterize the tumor microenvironment and correlate with clinical outcomes. SNS-301 in combination with pembrolizumab is given until confirmed PD or unacceptable toxicity. Study Objectives: Safety, tolerability and anti-tumor activity such as objective response rate, duration of response, progression-free and overall survival, immune responses, tumor/immune biomarkers and their associated treatment outcome. Results: Three patients have been enrolled. There have been no DLTs. Emerging safety data includes G1 adverse events with one G1 injection site pain. Patient status includes 1 PD and 2 patients with SD of at least six weeks duration. Immunological analyses will be presented. Conclusions: Early safety/efficacy warrant further evaluation of this combination therapy. Trial will be proceeding to full enrollment after the safety run-in is completed. Clinical trial information: NCT04034225.