bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of markers of epithelial-mesenchymal transition in various forms of vulvar cancer.
Authors: Ulianova Elena P. , Busarova Angelina V. , Porkhanova Natalya V. , Sagakyants Aleksandr B. , Petrusenko Natalia A. , Shulgina Oksana G. , Chernikova Elena N. , Bakulina Svetlana M. , Pushkareva Tatiana F. , Verenikina Ekaterina V.
Published: June 2022

e17532

Background: Vulvar cancer is a rare gynecologic tumor accounting for 2–5% of all gynecologic cancers. The epithelial-mesenchymal transition (EMT) is considered one of the factors contributing to the aggressive behavior of vulvar squamous cell carcinoma. E- and N-cadherins are key regulators of this transition. The purpose of our study was to identify the features of the expression of EMT markers in vulvar cancer as prognostic factors. Methods: The study included 30 patients aged 39-70 years, mean age 52 years, with vulvar cancer: control group (n = 15) with vulvar cancer T1-2N0-M0 (G2); main group (n = 15) with vulvar cancer T1-2N1-M0 (G2) with metastases to inguinal lymph nodes. Immunohistochemical study was performed on sections from paraffin blocks of tumors using monoclonal mouse antibodies to E-cadherin (12#, Cloud-Clone Corp.) and N-cadherin (389, Invitrogen) and the UltraVision Quanto Detection System HRP DAB. Expression of E- and N-cadherin was semiquantitatively analyzed according to the cell percentage and stain intensity: 0 (0-10%); 1+ (11-30%); 2+ (31-70%); 3+ (> 70%). Expression was considered positive if the score was ≥2. Pearson's χ² test and Spearman's correlation coefficient were used for statistical analysis. Results: The maximum staining for E-cadherin was observed in the control group (in 73%), for N-cadherin - in the main group (in 59%). Median expressions of E- and N-cadherin differed: in the control group, 70 [40-78] and 26 [0-40]; in the main group, 47 [45-60] and 59 [27-65]. Pearson's chi-squared test showed that patients with E-cadherin+ tumors (p = 0.006) statistically significantly prevailed in the control group, and patients with N-cadherin+ tumors (p = 0.027) prevailed in the main group. However, when considering the correlation between E-cadherin and N-cadherin in the groups, no statistically significant differences were found (rs = -0.042 in the control group and rs = 0.250 in the main group at p > 0.05), apparently due to the limited sample. Conclusions: The immunohistochemical study revealed a tendency towards loss of E-cadherin and increased expression of N-cadherin, which is often associated with poor prognosis.
Phase I clinical safety and efficacy observation of αPD-1-mesoCAR-T cells in the treatment of advanced gynecologic cancer.
Authors: Xia Yong , Liu Zhuqing , Zhu Zhongzheng , Lin Zhicai , Xue Hui , Song Zongchang , Yu Yanyan , Guan Xinhong , Sun Yuying , Miao Zhifeng , Yang Yaping , Wang Sitong , Li Zhong , Lv Linjie , Xu Qing , Sun Yan , Lou Jin-xing , Qian Qijun
Published: June 2022

e17535

Background: Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death among women. Most of patients often have refractory or relapse. We have developed a CAR T cell secreting PD-1 nanoantibodies and targeting mesothelin (αPD-1-mesoCAR-T) and conducted a phase I clinical trial for evaluation of safety and efficacy of the αPD-1-mesoCAR-T cells in gynecologic tumors. Methods: This study is a single-arm, open, dose-increasing clinical study and two infusions (interval 14-35 days). Patients with advanced gynecological cancer were enrolled when immunohistochemical analysis for positive mesothelin over 70% and failed second-line treatment in Mengchao Cancer Hospital affiliated to Shanghai University and Shanghai Tenth People's Hospital affiliated to Tongji University. All patients underwent lymphodepletion before infusion at a dose of 1 to 15x106/kg. CAR copies, nanobody levels, cytokines, T lymphocyte subtypes were determined before and after infusion. Results: a total of 7 patients were enrolled so far and completed the first evaluation. After treatment, most symptoms of the patients were alleviated, two patients (#2, #3) had their lesions decreased. By RECIST 1.1, all 7 patients’ diseases became stable, and the disease control rate was 100%. The PFS of #3 patient with stable disease (SD) was 5.3 months, the patient #2 was 4.1 months. The frequent adverse events were fever, fatigue, nausea and pruritus. No sever adverse events above grade 3 occurred. The number of CAR-T cells in the peripheral blood increased significantly during day 4-14 after the infusion, and the PD-1 nanoantibody levels and the contents of INF-γ、IL-6、IL-2 and MCP-1 also increased at day 1-4. Conclusions: The preliminary clinical study showed that the aPD-1-mesoCAR-T cells are safe for the treatment of gynecologic cancer and stabilized the diseases. More data of the treatment is warrantied to continually follow up these patients.
Stochasticity in threshold of homologous recombination deficiency (HRD) score.
Authors: Xu Bai , Xu Bai , Kai Zhentian , Nguyen Thi Phuong Anh , Xia Chaoran , Shi Weiwei
Published: June 2022

e17561

Background: HRD test from Myriad Inc. was approved by FDA as a biomarker for niraparib in ovarian cancer. Its threshold (as 42) was initially established by capturing 95% of tumors with BRCA1/2 mutation and BRCA1 promoter methylation in the training cohort. Here, we explored the stochasticity of such threshold, when the test noises themselves were concerned. Methods: We simulated HRD scores from figure 1 of Telli et al., 2016 by assigning the median from each histogram bin to the associated samples. The threshold was calculated, as described in the original paper, and the standard error (SE) and confidence interval (CI) for such threshold were estimated from bootstrapping the cohort. Furthermore, the entire cohort was down-sampled to determine the effect of sample size on the threshold. Results: The threshold of 42.5 was calculated from our simulated dataset, close to the original one, with SE of 1.62 and 95% CI of 40.75 - 47.5 for the bootstrap. As expected, SE steadily increased to 2.21, 2.84, 2.97 when the sample sizes decreased to 250, 230, and 210 respectively. When the dataset was further down-sampled to include only 200 BRCA deficient samples, SE increased to 3.76, and drastically, CI ranged between 36.5 and 51.2. Conclusions: We have showed there exists manifest stochasticity in the original threshold of 42 for the Myriad HRD test, which is likely close to platform noise in magnitude. The minimum size of BRCA deficient patients to obtain a stable threshold is 200, as shown in our study.
Exploring the value of intraoperative frozen section in the diagnosis and treatment of patients with early-stage ovarian cancer: A retrospective analysis of 421 patients.
Authors: Chen Jinghong , Gong Zhaolin , Zhang Mengpei , Yin Rutie
Published: June 2022

e17568

Background: Rapid and accurate judgment of the source and nature of tumors is conducive for surgeons to select the appropriate scope and method of surgery, and avoid unnecessary over-treatment or under-treatment. This study aimed to explore the diagnostic and treatment value of intraoperative frozen section pathology in patients with early-stage ovarian cancer (EOC) in the real world. Methods: We retrospectively collected the clinical and pathological data of EOC at West China Second University Hospital between January,2013 and December,2017, which diagnosed as stage ⅠA- IIA EOC according to the International Federation of Gynecology and Obstetrics (FIGO) 2014 standard of Ovarian cancer, fallopian tube cancer and peritoneal cancer. Results: There were totally 421 cases of EOC in the Second West China Hospital of Sichuan University from 2013 to 2017. The average age was 42.9 ± 13.5 years old. There were 395 patients who had finished the comprehensive staging surgeries. Group A consisted of 239 patients (60.5%) who had completed staging operation through only one surgery, while Group B consisted of 156 cases (39.5%) who had completed that through a second-time surgery. The frozen section submission rate of staging operation in the two groups were 99.2% (237/239) and 35.3% (55/156), respectively. Meanwhile, the coincidence rates of frozen and paraffin sections in the two groups were 98.3% (233/237) and 70.9% (39/55). The submission rate and coincidence rate of intraoperative frozen sections in Group A were higher than those in Group B (the submission rate: X2= 199.983, P< 0.05; the coincidence rate: X2= 52.541, P < 0.05). Conclusions: Our results confirm that increasing the submission rate of intraoperative frozen section and improving the accuracy of frozen section attach great importance to the diagnosis and treatment of EOC. Once identified, timely and comprehensive staging surgery can help improve patient outcomes for those who do not take fertility preservation into consideration.[Table: see text]
Interim analysis from a phase II study of olaparib maintenance with pembrolizumab and bevacizumab in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer: APGOT-ov4/ OPEB-01.
Authors: LEE Jung-Yun , Kim Jae-Weon , Kim Byoung-Gie , Kim Sang Wun , Kim Hee Seung , Kim Se Ik , Lim Myong Cheol , Choi Chel Hun , Ngoi Natalie , Tan David Shao Peng , Kim Yoo Na
Published: June 2022

e17579

Background: The optimal treatment of BRCA wild-type patients with platinum-sensitive recurrent (PSR) ovarian cancer remains controversial. This single arm phase 2 study (OPEB-01) evaluated a triple combination regimen with olaparib, bevacizumab, and pembrolizumab as 2nd-line maintenance treatment in BRCA non-mutated, PSR ovarian cancer. Methods: Women with PSR ovarian cancer who had a partial or complete response to their most recent platinum-based regimen were eligible. Patients received olaparib 300mg PO bid daily, bevacizumab 15mg/kg IV q3w, and pembrolizumab 200mg IV q3w until progressive disease or unacceptable toxicity. The primary endpoint of the study was 6-month PFS rate. A simon 2-stage design was utilized. Target accrual was 22 patients in the first stage; 13 or more patients with non-progressive disease at 6 months was required to proceed to second stage. Results: 22 patients were enrolled at the first stage. Median age was 60 years old and most of the patients (90.9%) had high-grade serous carcinoma. Secondary cytoreductive surgery was performed in 6 (27.3%) patients. The objective response rate (ORR) was 68.2% and the disease control rate (DCR) was 90.9%. At the time of data analysis (data cutoff Jan 19 2022), 20 (90.9%) had non-progressive disease at 6 months. No grade 4 adverse events were reported and no treatment related adverse events leading to treatment discontinuation was observed. Additional correlative data regarding homologous recombination deficiency and PD-L1 will be presented at the meeting. Conclusions: OPEB-01 is the first trial to suggest the potential benefit of triple combination maintenance in BRCA wild-type patients. These combinations showed a manageable safety profile. Accrual is ongoing in the second stage. Clinical trial information: NCT4361370.
POSTCare-O: A survivorship care transition for women with ovarian cancer.
Authors: Kvale Elizabeth Ann , Phillips Farya
Published: June 2022

e17583

Background: The POSTCare survivorship care transition is efficacious as a quality-of-life intervention for patients diagnosed with breast cancer but has not been studied in women with ovarian cancer. Ovarian cancer patients who complete treatment face unprecedented uncertainty regarding survivorship including life expectancy, and the balance of healthcare demands with living well. The routine provision of automated survivorship care plans (SCPs) by advanced practice providers (APPs) is a standardized approach which does not consider the unique needs of ovarian cancer survivors. Aim: To adapt the POSTCare intervention for ovary cancer patients by incorporating a component of concurrent palliative care and tailoring the skills of an existing workforce. Methods: We provided web-based training to APPs from Gyn Oncology programs. Qualitative methods explored the POSTCare protocol, ideas for adapting the intervention, and training preferences. We conducted semi-structured interviews with nurses who completed the POSTCare-O web-based training and utilized components of the POSTCare model in clinical care. The goal was to discover the elements of the model that worked well in their setting, which elements they can utilize routinely to meet the needs of patients, and which elements they find most satisfying. Results: Nine advanced practice providers completed online training and follow up assessment. All participants passed the final competency assessment (role play skills check). Exit interview data revealed four areas where participants reported changes in their own perceptions and skills related to survivorship care that they attributed to the POSTCare-O training program. APPs reported the training increased their competency in palliative care skills and left them better able to support survivors in the face of uncertainty. Specifically, the training; (1) enhanced their communication skills; (2) developed their understanding of survivorship care as more than just surveillance; and (3) demonstrated how to implement patient driven goal setting. Conclusions: POSTCare intervention can serve as a platform for delivery of components of early concurrent palliative care that is acceptable to ovarian cancer patients who remain focused on life-prolonging treatments. POSTCare-O web based training improved APPs appreciation of the scope of survivorship care beyond just surveillance and management of physical effects. This training provided the tools necessary for clinicians to provide whole person care while implementing patient driven survivorship care planning.
Evaluating the utility of ctDNA in detecting residual cancer and predicting recurrence in patients with serous ovarian cancer.
Authors: Akbari Mohammad R. , Zhu Jie Wei , Wong Fabian , Szymiczek Agata , Ene Gabrielle , Zhang Shiyu , May Taymaa , Narod Steven A , Kotsopoulos Joanne
Published: June 2022

e17588

Background: Ovarian cancer remains the most fatal gynecological malignancy. Patients who have no visible residual disease after surgical resection have a relatively good prognosis. Among these patients, those who later succumb to their cancer are believed to harbour non-detectable cancer cells in the peritoneal cavity after treatment which later lead to recurrence. Analyzing circulating tumour DNA (ctDNA) in the blood may offer a sensitive method to detect occult (non-visible) residual disease after surgery and to predict disease recurrence. We proposed to determine the proportion of ovarian cancer patients with and without visible residual disease documented after surgery who had detectable ctDNA from their primary tumour in their blood and to evaluate if the presence of ctDNA is associated with survival. Methods: We included biological samples and clinical information from 48 women diagnosed with high-grade serous ovarian cancer. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue, and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. The plasma sample was collected after surgery and before initiating chemotherapy. We sequenced DNA samples for a panel of 59 breast and ovarian cancer driver genes. DNA variants in matched germline and tumour DNAs were compared to determine tumour specific variants (TSVs) and cfDNA was searched for TSVs to identify the presence of ctDNA in the plasma. The Kaplan-Meier method was used to estimate overall and recurrence-free survival according to the presence or absence of ctDNA. Results: We found TSVs in 47 patients that were used for detecting ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Among the 31 (68.1%) pateints with no visible residual disease, 24 (77.4%) patients had detectable ctDNA. Of those with no visible residual disease, those patients with detectable ctDNA in post-surgery samples had a higher mortality risk compared to those without detectable ctDNA (HR 2.32; 95% CI: 0.67-8.05), although this difference was not statistically significant (p = 0.18). Conclusions: These findings suggest potential clinical utility in ctDNA to improve upon surgical classification of the residual disease status and a potential predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings.
Patterns and prevalence of pathogenic germline mutations using multi-gene panel testing in patients with ovarian cancer: The Jordanian Exploratory Cancer Genetics (Jo-ECAG) Ovarian Study.
Authors: Al-Azzam Khansa , Abu-Fares Hala , Abu Sheikha Areej , Abujamous Lama , Alkyam Mais , Bani Hani Hira , Bater Rayan , Heald Brandie , Esplin Edward D. , Abdel-Razeq Hikmat
Published: June 2022

e17593

Background: Ovarian cancer is one of the most common gynecological malignancies. Because of the absence of effective screening methods, ovarian cancer is usually diagnosed at late stages contributing to high mortality rates. Patients with BRCA1 and BRCA2 pathogenic germline variants (PGVs) harbor elevated risk of developing both ovarian and breast cancer. Identifying PGVs may help optimize management options and improve outcomes. The worldwide prevalence of gene mutations is variable. Multiple series have demonstrated differences in PGVs according to ethnicity and geographic area. Data about prevalence of the aforementioned PGVs among Arab patients with ovarian cancer is not well understood. Methods: Patients with epithelial ovarian, fallopian tube or primary peritoneal carcinomatosis were referred for 20 or 84-multi-gene panel testing (MGPT). All patients had their diagnosis, treatment and follow up at a single cancer center. Following detailed counselling, MGPT was performed at no-cost to all patients at two reference laboratories. Descriptive statistics were performed, groups outcome was determined by two-tailed Fisher’s exact test and unpaired t-test. The study was approved by the Institutional Review Board (IRB) at King Hussein Cancer Center and all patients signed informed consent. Results: During the study period, 152 patients, median age (range): 50 (18-79) years were tested. Two patients had fallopian tube cancer, while all others had epithelial ovarian cancer. The majority (n = 100, 65.8%) had high-grade serous carcinoma, and 106 patients (69.7%) had metastatic disease on presentation. In total, 38 (25.0%) had PGVs while 47 (30.9%) others had variants of uncertain significance (VUS). PGVs were mostly in BRCA1 (n = 21, 13.8%) and in BRCA2 (n = 12, 7.9%), while only 5 (3.3%) had PGVs in non- BRCA1/2 genes ( CHECK2, MUTYH, PMS2, RAD51D, and RB1) . Age (< 50 versus ≥50) at diagnosis, histological tumor subtype, and disease stage had no impact on pathogenic variant rates. However, PGVt rates were significantly higher (60.0%, p = 0.022) among patients with positive family history of ovarian cancer and 40.4% (p = 0.017) among patients with positive family history of breast cancer. The two patients with fallopian tube cancer were both positive for BRCA1 PGVs. Only one patient underwent prophylactic bilateral mastectomies. Conclusions: PGVs in patients with ovarian cancer are common among Arabs and mostly in BRCA1/2 and rates are significantly higher among patients with family history of ovarian or breast cancers.
Clinical experience with rucaparib after prior PARPi treatment: A subanalysis from the rucaparib access program in Spain by GEICO.
Authors: Yubero-Esteban Alfonso , Reche-Molina Piedad , Salvador Coloma Carmen , Estévez-García Purificación , Manso Luis , Iglesias Campos Marcos , Barquin Arantzazu , Marquez Raul , Santaballa Ana , Calzas Julia , Herrero Ana , Casado Victoria , Madani Julia , Merino Maria , Marquina Gloria , Alarcon Company Jesus , Gaba Lydia , Fuentes Pradera Jose , Gonzalez Martin Antonio , Sanchez Lorenzo Maria Luisa
Published: June 2022

e17598

Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients’ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/ 2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ≥3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure. [Table: see text]
Multi-omics analysis reveals spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer.
Authors: Chen Gang , Yang Bin , Li Xiong , Zhang Wei , Fan Junpeng , Sun Chaoyang
Published: June 2022

e17603

Background: The effect of spatial immunologic variation, especially in T cell infiltration, recognition and expansion, across various tumor foci in the ovary (primary) and distant metastatic foci in the peritoneal cavity and their contribution to the limited response to immune therapy in High-Grade Serous Ovarian Cancer(HGSOC) remains unexplored. We aim to provide a detailed analysis of the landscape of heterogeneity of infiltrating T cells in primary and metastatic lesions and their differential characteristics in HGSOC. Methods: We performed multi-site sampling and simultaneous RNA sequencing (RNA-seq), whole-genome sequencing (WGS) and bulk T cell receptor (TCR) sequencing as well as single cell RNA sequencing (scRNA-seq) and paired TCR sequencing (scTCR-seq) in 9 patients (48 sites, including 19 ovarian, 11 omental, 18 other metastasis lesions) with untreated primary HGSOC. Validation by IHC, flow cytometry, another scRNA-seq data from 7 patients (32 sites, including 9 ovarian, 6 omental, 6 ascites and 11 other metastasis lesions) and spatial transcriptomics. Results: CD8 exhausted clusters that are enriched in ovarian tumors exhibited high exhaustion, tumor-specific score and low bystander score, whereas CD8 transition and NK-like clusters that are enriched in omental tumors exhibited the opposite characteristics, which was confirmed by flow cytometry. Of note, the exhausted CD8+ T cells exhibited GZMB, PRF1, FASLG and IFNG effector genes despite the expression of exhaustion markers, developing from an early differentiation state with high proliferative capacity and the process preferentially occurs in primary ovarian sites. Besides, T cells corresponding to the selected TCRs that had the same distribution as neoantigens were enriched in ovarian lesions, while the virus-specific TCR preferentially enriched in omentum samples. The association of TMB, HRD score, and COSMIC mutational signatures with antigen-engaged T cell subsets was not observed at the site level within individual patients. STARTRAC-migration analysis showed that T cell clusters in blood or other sites migrating to ovarian was extremely low or vice versa. The expression of MHC-I processing and presentation genes and MHC-I protein were higher in omental lesions, along with T cells were preferentially located in tumor region of ovarian tumors. Conclusions: We identify two different immune patterns in ovarian cancer: 1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells. These exhausted CD8 T cells with cytotoxic function are clonal expanded; 2) omental lesions infiltrated with non-tumor-specific bystander cells. Decreased major histocompatibility complex (MHC)-I antigen presentation ability and failure of T cell infiltration into omental tumors may contribute to lack of tumor-specific T cells in omental metastasis.
Diagnosis of first relapse and its impact on quality of life in patients with advanced ovarian cancer (AGO-OVAR 19/II).
Authors: Harter Philipp , Ataseven Beyhan , Burges Alexander , Reuss Alexander , Kommoss Stefan , Sehouli Jalid , Lampe Bjoern , Schmalfeldt Barbara , Wimberger Pauline , Witteler Ralf , Buderath Paul , Herwig Uwe , Bronger Holger , Emons Guenter , Klar Maximillian , Hasenburg Annette , de Gregorio Nikolaus , Hilpert Felix , Du Bois Andreas , Mahner Sven
Published: June 2022

e17609

Background: Maintenance or improvement of health-related quality of life (QoL) is one of the major goals for patients with advanced ovarian cancer (OC). QoL is influenced by symptoms of disease on the one and beneficial or adverse effects of surgical and systemic treatment on the other side. In addition, QoL is also an important patient centered endpoint in clinical trials to support primary endpoints such as progression-free survival (PFS). This analysis evaluates the impact of the diagnosis of first relapse on QoL. Methods: Patients with primary OC were included before start of treatment. QoL was assessed by the cancer-specific questionnaires EORTC QLQ‐C30 and QLQ‐OV28 and the generic EQ‐5D 3L at baseline and every 3 months thereafter, to describe the influence of treatment and course of disease on QoL. QoL data within 100 days before and after the first relapse were compared (part 2 of NCT02828618). QoL scales were analyzed by repeated measures regression. We report model-based pre- and post-recurrence means and p-values for the difference in means. Results: In total, 269 had a PFS event with a median PFS of 20.3 months. This analysis includes 186 patients; 122 with QoL assessment before and after relapse and 50 and 14 with assessment only before or after relapse. Median age was 62.5 years (range 31 – 90). The number of evaluable answers for each domain ranged between 166 and 172 before recurrence and 135 and 137 after recurrence. Global QoL decreased from 61.4 to 48.4 points (p < 0.001) with the diagnosis of recurrence. The following scales showed a deterioration of at least 10 points: Social functioning (65.7- > 52.6), fatigue (55.8 - > 44.5), appetite loss (22.5 - > 33.4), emotional functioning (65.2 - > 54.9), role functioning (56.5 - > 46.4); (all p < 0.001). EQ-5D 3L visual analogue scale showed a deterioration from 66.4 to 55.0 (p < 0.001). Conclusions: The event of first relapse is associated with a significant and clinically relevant deterioration of global QoL including several subscales. Therefore, prolongation of PFS preserves QoL, which supports the role of PFS as meaningful primary endpoint in ovarian cancer trials. Clinical trial information: NCT02828618.
End-of-life care for patients with advanced ovarian cancer in the Netherlands: A retrospective registry-based analysis.
Authors: Broekman Esther , Van Der Aa Maaike , Nijman Hans , Jalving Mathilde , Reyners An K.L
Published: June 2022

e17612

Background: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating abdominal symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration, and emergency room and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe and between European countries. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. Methods: All patients with ovarian cancer that died in 2016 and 2017 were identified from the database of the foundation Dutch Hospital Data (DHD). For the last six months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. Data were analysed for the cohort as a whole and separately for three age categories: < 60, 60-75 and > 75 years of age. The intensity of inpatient care was compared to previously reported European and US data. Results: A total of 2172 patients died with ovarian cancer in 2016 and 2017 in the Netherlands. Data on medical care use was available for 1775 patients. During the last 6 months of life, chemotherapy was given to half of the ovarian cancer patients and the same percentage of patients was admitted to hospital. Chemotherapy administration near the end-of-life was infrequent, with only 12% of patients receiving chemotherapy in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (< 10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. The use of chemotherapy in the six months prior to death was highest in patients 60-75 years of age compared to younger or older patients. ER visits and hospital admissions were less frequent in patients > 75 years of age compared to the younger age groups. Conclusions: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts.
Cancer-associated fibroblasts in uterine corpus endometrial carcinoma.
Authors: Li Yingqiang , Zhou Jie , Zhang Jing , Liu Ming , Chen Shifu , Liu Yaqiong
Published: June 2022

e17618

Background: The general role of cancer-associated fibroblasts (CAFs) and their invasive characteristics in Uterine Corpus Endometrial Carcinoma (UCEC) remain unknown. CAFs serve as an important component of the tumor microenvironment and promote tumorigenesis and cancer aggressiveness. Methods: UCEC mRNA data were downloaded from TCGA cBioPortal ( http://www.cbioportal.org/ ). CAF levels were estimated by three algorithms: MCPCOUNTER, XCELL, and EPIC, so three CAF scores were gotten and ranked. Then, the data of CAF scores in each cohort were divided into quarters, and we labeled the sample by upper quartile and lower quartile with “high”, “medium”, and “low”. To mitigate the possible classification error from each estimation method, we defined samples as “high” by at least two methods consistently labeling “high”. Samples labeled with “low” by at least two methods were assigned to the consensual low CAF group. The high and low group were analysis using GSEA software, Survival analysis was performed using the R package “survival”. Results: There were 129, 118 and 280 samples in the high, low and middle CAFs group, respectively. GSEA results showed extensive gene expression differences between the high and low CAF groups. 193 gene sets were significantly enriched at nominal p value < 0.01 in the low group, 869 gene sets were significantly enriched at nominal p value < 0.01 in the high group. In the low group, obvious differences, included lim mammary stem cell up, reactome degradation of the extracellular matrix, bertucci medullary vs ductal breast cancer dn etc. are enriched in the high group. xu akt1 targets 6hr, OUELLET (Gene Set) ovarian cancer invasive vs lmp up etc. are enriched in the low group. OS and PFS survival analysis showed there was no significant difference between these two groups. Conclusions: Our study analyzed the relationship between CAFs with UCEC, CAFs were associated with an immunosuppressive microenvironment. Larger transcriptomic alterations occurred in UCECs with high CAF infiltration, and with AKT, ALCALA APOPTOSIS and SPLICEOSOME pathways prominent in this process. But Survival analysis showed no difference between the two groups.
DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort.
Authors: Riggs McKayla J , Lin Nan , Miller Rachel W. , Piecoro Dava West , Schneider Bryan P. , Chon Hye Sook , Carpten John D. , Churchman Michelle L. , Corr Bradley , Washington Christina , Dood Robert , Edge Stephen B. , Leiser Aliza L. , Siegel Erin M. , Ueland Frederick West , Kolesar Jill
Published: June 2022

e17634

Background: DACH1 is a novel transcriptional repressor and tumor suppressor gene. DACH1 mutations are associated with poor prognostic features and reduced overall survival in endometrial cancer, with an increased prevalence in the Appalachian region of Kentucky. Preliminary studies have suggested an association with an increase in tumor mutation burden. In this follow up study, we utilized the nationwide Oncology Research Information Exchange Network (ORIEN) to determine the frequency of DACH1 mutations in patients with endometrial cancer through a multi-institution analysis and evaluate its impact on RNA expression, clinical correlates, and outcomes. Methods: We obtained clinical and genomic data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN collaborative. We examined the clinical attributes of the cancers with DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (6/41 patients, 15%) compared to the non-Appalachian endometrial cancer population (24/581 patients, 4.1%) with p-value = 0.010, with the non-Appalachian DACH1 mutation frequency mirroring the rate of DACH1 gene mutation seen in TCGA at 3.8%. DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (32.2 vs. 4.62, p-value = 0.001) though no differences in microsatellite instability between DACH1 mutated and wild-type were present (p-value = 0.350). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, MSH2, MSH6 and PMS2. Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer, particularly those from the Appalachian region. These results were again reflected in the TCGA PanCancer Atlas as well as the ORIEN multi-institution cohort. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 as a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.
Apatinib in recurrent or metastatic head and neck cancer patients.
Authors: WU Qiuji , Liu Jia , Li Shaojie , Wang Juan , Zhong Yahua
Published: June 2022

e18010

Background: Apatinib is a small tyrosine kinase inhibitor targeting the vascular endogenous growth receptor 2 (VEGFR-2) that shows potent antitumor activities in various advanced cancers via the inhibition of neo-angiogenesis. The effect of apatinib in recurrent or metastatic head and neck cancers has not been fully demonstrated. Methods: Patients with recurrent or metastatic head and neck cancers consecutively treated in our institute by apatinib from January 2015 to December 2020 were enrolled. Daily 250 mg or 500 mg apatinib was given with or without chemotherapy according to patients' tolerance. A part of the patients also received palliative radiotherapy. Disease response, treatment-related toxicities and patient survival were analyzed. Toxicity was assessed by CTCAE v4.0. Kaplan-Meier analysis was used to estimate patients' overall survival. The R software (version 3.6.3) were used for statistical analysis. Results: A total of 73 patients were enrolled in this study. There were 59 males and 14 females with the median age of 55 (range: 27-80) years. Most patients had a performance status of 0 (15/73, 20.5%) and 1 (51/73, 69.9%). There were 29 oral cavity cancers, 20 nasopharyngeal carcinomas, 8 salivary gland cancers, 7 nasal and paranasal sinus cancers and 9 other malignancies. Pathologically, 47 were squamous cell carcinoma, 18 were adenoid cystic carcinoma, and the rest 8 were adenocarcinoma, sarcoma and melanoma. The majority of patients were with metastatic diseases (57/74, 78.1%). Nine of the 73 (12.3%) received apatinib as first-line treatment, 22 (30.1%) as second-line and 42 (57.5%) as more than second-line treatments. Forty patients received S-1 or capecitabine chemotherapy, 2 received nab-paclitaxel and 1 received gemcitabine. Ten patients received palliative radiotherapy. The most frequent toxicities were anemia (37/73, 50.7%), leucopenia (27/73, 37.0%), thrombocytopenia (20/73, 27.4%), proteinuria (20/73, 27.4%), arterial hypertension (17/73, 23.3%), hand-foot syndrome (17/73, 23.3%). Hemorrhage occurred in 10 (13.7%) patients. No treatment-associated death was noted. The median follow-up was 29.9 months. Fifty-six patients had evaluable tumor response. Complete response occurred in 1 patients. Partial response was seen in 3 patients. Most patients had stable disease (29/56, 51.8%) or progressive disease (23/56, 41.1%). By the end of the last follow-up, 33 patients died of disease progression. The median overall survival was 29.6 months. Conclusions: Apatinib showed modest antitumor activities in recurrent or metastatic head and neck cancers. The side effects were manageable. The effect of apatinib in recurrent or metastatic head and neck cancers warrants further studies in larger-scale randomized studies.
Long-term toxicity and tolerance of concurrent docetaxel with radiotherapy in cisplatin ineligible head and neck cancer patients.
Authors: Kolkur Manali , Patil Vijay Maruti , Menon Nandini Sharrel , Noronha Vanita , Prabhash Kumar , Simha Vijai , Talreja Vikas , Chandrasekharan Arun , Dhumal Sachin
Published: June 2022

e18037

Background: Docetaxel can be administered in several situations like low creatinine clearance or pre-existing grade 3-4 ototoxicity, where cisplatin is contraindicated. In this analysis, we present our data on toxicity and tolerance to docetaxel-based chemoradiation in cisplatin-ineligible patients. Methods: Patients who underwent docetaxel-based chemoradiation between January 2015 to December 2017 for locally advanced head and neck cancer, either in the radical or adjuvant setting were selected for this analysis. SPSS version 16 was used for analysis. Results: Nineteen patients were identified and the median age of the cohort was 58 years (range 41-71 years). The most common site of the primary was the oral cavity (n = 9, 47.4%). Sixteen patients (84.2%) had stage IV disease and 3 patients (15.8%) had stage 3 disease. The intent of chemoradiation was radical in 12 (63.9%) patients and adjuvant in 7 (36.1%) patients. Any grade 3 or above adverse events were seen in 12 patients (63.2%). The most common grade 3 or above adverse events observed were mucositis and hyponatremia in 9 patients (47.4%) each. At a median follow up of 5.3 years, the 2-year and 5-year PFS were 26.3% (Standard error-10.1) and 15.8% (Standard error- 8.4) while 2-year and 5-year OS were 36.8% (Standard error-11.1) and 15.8% (Standard error- 8.4). Conclusions: Docetaxel based chemoradiation is a feasible and tolerated option in cisplatin unfit patients and needs further testing in large randomized studies to prove its worth.
Human papillomavirus DNA resides in surgical drain fluid exosomes from HPV+ oropharyngeal squamous cell carcinoma patients and can be spread to neighboring HPV-negative cells.
Authors: Xu Zhongping , Earland Noah , Harris Peter K. , Gerndt Sophie P. , Ramirez Ricardo J. , Hearn Andrew I. , Semenkovich Nicholas P. , Chaudhuri Aadel A , Zevallos Jose P.
Published: June 2022

e18050

Background: Human papillomavirus (HPV) is the primary driver of oropharyngeal squamous cell carcinoma (OPC) in the US. Previous studies have investigated the role of plasma and saliva-based cell-free HPV DNA in OPC, yet the pathophysiological impact of exosomes in HPV+ OPC remains unknown. Exosomes are nanometer-sized membrane vesicles of endocytic origin carrying DNA, RNA and proteins, and have been shown to exist in blood, plasma, and in urine. We hypothesize that serosanguinous fluid drained from the postoperative bed, which we call “surgical drain fluid” (SDF) also contains exosomes. We further hypothesize that exosomes derived from SDF in HPV+ OPC patients contain HPV DNA that can be directly transmitted into HPV-negative cells. Methods: Twenty-six 5-mL SDF samples were collected following surgical neck dissections directly from the surgical drain; 21 from HPV+ and 5 from HPV- OPC patients. Exosomes were isolated from SDF using the Qiagen exoEasy kit. Exosome structure was characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Western blotting (WB) targeted known exosomal surface markers. Exosomes were pretreated with DNase (New England Biolabs) to cleave the surface DNA, then exosomal DNA was extracted using a cell-free DNA isolation kit (Sigma). TaqMan real-time PCR was employed to detect HPV16 copy numbers. Lastly, exosomes isolated from 3 HPV+ patients’ SDF and 1 HPV- patient’s SDF were incubated with HPV- cell lines, SCC22A and SCC25, in order to query exosome-mediated HPV transmission. Results: TEM identified exosomes as round/oval-shaped vesicles measuring between 70 and 150 nm. NTA enumerated an average of 1.5 x 1011 particles per mL of SDF. WB further confirmed exosomal identity with strong CD63, CD9, and TSG101 signal detected. Among SDF exosomes from HPV+ OPC, 81% (n = 17) had detectable HPV16 DNA by real-time PCR, while all HPV- SDF exosomes (n = 5) showed undetectable HPV16. Paired comparison of HPV16 levels within exosomes to total HPV16 in SDF revealed an average of 90% of HPV16 in SDF was contained within exosomes. In an in vitro assay, SCC22A and SCC25 cells treated with HPV16 + exosomes became real-time PCR-positive for HPV16, while cells treated with HPV16- exosomes remained HPV16 negative. Conclusions: This study demonstrates that SDF, a novel post-surgical biofluid analyte, is enriched for HPV-containing exosomes in HPV+ OPC patients. We also found that exosomes from HPV+ OPC patients can transmit HPV to HPV-negative cells, suggesting a novel mode of virus-mediated spread of disease.
Risk of second primary malignancies among patients with nasopharyngeal cancer in the United States: A population-based study.
Authors: Chamarti Karthik , Bakhati Bibek , Rudraraju Vasudha , Mannem Maneesh , Rajput Maryam , Garza John , Bajaj Kelash
Published: June 2022

e18056

Background: Nasopharyngeal cancers (NPCs) have an estimated incidence of 0.5 to 2 cases per 100,000 in the United States. Treatment of NPC with combination chemoradiotherapy has resulted in an 18% increase in 5-year overall survival in the US. It is essential to focus on the developments of second primary malignancies (SPMs) with improved survival. We aim to analyze the risk of SPMs among NPC survivors in this study. Methods: We estimated the incidence of SPMs among two-month survivors of NPC using the Surveillance, Epidemiology, and End Results (SEER)-18 registries between 2006 to 2018. The risk of SPMs was calculated using standardized incidence ratios (SIRs). Results: We included 7,560 patients with NPC in this study. The median age of diagnosis was 56 yrs (range 0 to 85 yrs). The median follow-up duration was 33 months (range 0 to 155 months). The median time for SPM development from initial diagnosis was 41 months (range 2 to 140 months). A total of 367 (5%) patients developed 398 SPMs at the last follow-up, of which 89% were solid organ malignancies, and 11% were hematologic neoplasms. The SPM risk for cohort was significantly elevated (SIR = 1.88, 95% confidence interval [CI] = 1.7 to 2.07) compared with the general population. The SIR was slightly higher in males (SIR = 1.90, 95% CI = 1.69 to 2.13) compared to females (SIR = 1.81, 95% CI = 1.48 to 2.20). The SIR according to age groups were as follows: age < 65 years (SIR = 2.03, 95% CI = 1.79 to 2.29), age > 65 years (SIR = 1.65, 95% CI = 1.38 to 1.94). Sites with highest risk included the nose, nasal cavity, and middle ear (SIR = 22.98, 95% CI = 9.92 to 45.27), nasopharynx (SIR = 17.28, 95% CI = 8.93 to 30.19), oral cavity and pharynx (SIR = 10.07, 95% CI = 7.81 to 12.79), esophagus (SIR = 3.97, 95% CI = 1.9 to 7.29), lung and bronchus (SIR = 3.53, 95% CI = 2.86 to 4.32), and liver (SIR = 3.05, 95% CI = 1.86 to 4.71) (Table). The risk of malignancies of the esophagus and lung were higher within the first year of diagnosis of NPC. The risk of malignancies of the nasopharynx, oral and nasal cavity, and liver was higher after one year of latency and remained statistically significantly elevated throughout the follow-up period. Conclusions: Our study reveals that patients with NPC are at higher risk of SPMs than the general population, most notably in the oral and nasal cavity, nasopharynx, esophagus, and lungs. These patients may benefit from cancer-specific screening during follow-up.[Table: see text]