bluuebunny/crossref_metadata_2025 huggingface dataset:
Is prostate brachytherapy a dying art? Evidence of increasing utilization in Ontario, Canada.
Authors: Corkum Mark Thomas , Morton Gerard , Louie Alexander V. , Bauman Glenn , Mendez Lucas , D'Souza David , Dinniwell Robert Edward , Velker Vikram M. , Warner Andrew , Rodrigues George
Published: May 2020

e17608

Background: A worldwide decline in prostate brachytherapy (BT) utilization has been reported in multiple health care settings/jurisdictions, despite strong evidence for efficacy and safety compared to other alternatives. We sought to evaluate contemporary trends in BT, EBRT and prostatectomy utilization in a publicly funded healthcare system. Methods: Men with localized prostate cancer diagnosed and treated between 2007 and 2017 in Ontario, Canada were identified using administrative data from the Institute for Clinical Evaluative Sciences. Men were coded to have received EBRT, BT (monotherapy or boost) or prostatectomy as initial definitive management. Trends were evaluated using the Cochran-Armitage test. Multivariate logistic regression was used to evaluate patient-, tumour-, and provider-factors on treatment utilization over time. Results: 57,655 men were included in our study. Prostate BT use increased from 7.5% of all treatments in 2007 to 15.4% in 2017 ( p< 0.01), primarily due to increased use of BT boost (1.7% in 2007 to 10.4% in 2017, p < 0.01). Relative to EBRT, BT use increased from 17.9% in 2007 to 28.1% in 2017 ( p< 0.01). On multivariate analysis (MVA), BT boost use increased by 28% per year (OR 1.28, 95% CI 1.26–1.31, p< 0.01) and BT monotherapy use increased by 12% per year (OR 1.12, 95% CI 1.10–1.14, p< 0.01), offset by decreasing prostatectomy use (12% per year, OR 0.88, 95% CI 0.87–0.89, p< 0.01). Comparing BT to EBRT, the strongest predictors of receiving BT were geographic residence (OR 27.6, 95% CI: 20.3–37.6, p< 0.01 between highest/lowest Local Health Integration Networks) and whether the first consulting radiation oncologist performed BT (OR 3.46, 95% CI: 3.15–3.80, p< 0.01). Other significant factors predicting BT use vs. EBRT included lower age, lower PSA, lower Charlson comorbidity score and increasing neighborhood income quintile. Low-intermediate, high-intermediate and high-risk groups were predictive of receiving BT boost, whereas BT monotherapy was predominantly used in low-risk disease. Conclusions: Contrary to trends observed in other jurisdictions, utilization of prostate BT is increasing over time in Ontario. However, substantial variation in BT utilization was found, strongly driven by both geographic region and radiation oncologist BT practice patterns. To our knowledge, this is the first study to report increasing BT utilization in the era of dose-escalated EBRT, with Ontario potentially serving as a model to promote BT utilization elsewhere.
Expansion of germline genetic testing criteria for prostate cancer yields findings across all stages of disease.
Authors: Nielsen Sarah M. , Szmulewitz Russell Zelig , Yang Shan , Truty Rebecca , Michalski Scott T. , Das Kingshuk , Ngo Nhu , Pineda Alvarez Daniel Esteban , Lincoln Stephen E , Nussbaum Robert Luke , Esplin Edward D.
Published: May 2020

e17615

Background: Increasing evidence suggests criteria for germline testing of patients with prostate cancer (PCa) may miss potentially actionable pathogenic variants. A sponsored testing program with significantly broader criteria was initiated to increase access. Methods: We analyzed de-identified data from 2,252 men with PCa who received at least an 84 gene panel. Inclusion criteria were clinical stage ≥T2 and willingness of the patient and physician to participate. Positive results were categorized as: pathogenic (P), likely pathogenic (LP), or increased risk alleles (IRAs). Results: Clinical stage was available in 1825 men (81%): 541 (30%) were stage II, 228 (12%) stage III, and 1,056 (58%) stage IV (Demographics Table). Among all men, 297 (13%) had positive results, including 286 P/LP variants in 38 genes and 31 IRAs in APC and HOXB13. There was no statistically significant association between stage and positive rate. Of men with positive variants, only 30% reported a family history of prostate, breast, ovarian or pancreatic cancer. The most common positive variants were in BRCA1 (9) , BRCA2 (43) , PALB2 (11) , ATM (36) , CHEK2 (58) , HOXB13 (20) , and mismatch repair genes (8). With respect to ethnicity, the highest positive rate was observed in Ashkenazi Jews (23.8%) and the lowest in African Americans (5.4%). Overall, 190 (70%) of men had P/LP variants conferring eligibility for gene-specific precision therapies or clinical trials based on variants in homologous repair (182), or mismatch repair (8) genes. Conclusions: In a broad PCa patient population, we found overall germline positive rate of 13%, with no statistical difference in this rate with respect to stage. Overall, these data suggest that broader testing criteria and more access to testing could lead to better informed care for many additional patients and their families. [Table: see text]
Retrospective analysis of clinical characteristics and prognostic factors of neuroendocrine carcinoma of the gynecologic tract: A preliminary report of ten years follow-up.
Authors: Zhang Y , Yang J , Li Qy , Zhang Zg , Sun MJ , Shi Yg
Published: May 2020

e18001

Background: To investigate the clinical characteristics and prognostic factors of neuroendocrine carcinoma of the gynecologic tract (NECGT). Methods: Patients with NECGT diagnosed during 2010 to 2019 were enrolled in this retrospective study. Clinical parameters were calculated, including age, childbearing history, initial symptoms, blood indexs, International Federation of Gynaecology and Obstetrics (FIGO) stages, treatment modalities and survival data. The cut-off values of parameters were screened by receiver-operating characteristic (ROC) curves and their significance was assessed by multivariate logistic regression. Results: We indentified forty five NECGT patients available with the median follow-up time of 5.5 months (9.7±1.98 months). 42 cases (93.3%) originated from cervix uteri, 2 cases (4.4%) from vagina and 1 case (2.2%) from fallopian tube. Irregular vaginal bleeding was the most frequent symptom at the first visit accounting for 75.6%. FIGO stages I to IV distributions were 16 (35.6%), 15 (33.3%), 6 (13.3%), and 8 patients (17.8%). Squamous carcinoma (16.7%) and adenocarcinoma (11.9%) were the common mixed pathological types. 66.7% patients underwent radical surgery, almost all of which received 4-6 cycles adjuvant chemotherapy and half followed by radiation therapy. While data analysis showed that adjuvant radiotherapy could not bring additional survival benefits (p = 0.523). The median PFS of enrolled patients was 14 months (1-78months). Pelvic recurrence (66.7%) and lymphatic metastasis (52.6%) were the main failure patterns. In multivariate analysis, leukocyte count (HR = 0.068, 95%CI: 0.007-0.673, p = 0.021), neutrophil-to-leukocyte ratio (HR = 0.151, 95%CI: 0.024-0.95, p = 0.044), lactic dehydrogenase (LDH) (HR = 6.632, 95%CI: 1.31-33.569, p = 0.022) and carbohydrate antigen-ca 125 (CA-125) (HR = 7.173, 95%CI: 1.25-41.06, p = 0.027) were the independent prognostic factors of PFS. In addition, age at natural menopause (ANM) later than 51.5years (p = 0.009) and an optimal maximum diameter > 62.1mm (p = 0.002) were closely related with poor survival. Conclusions: NECGT is a rare malignant tumor of female genital system. Surgery combined with chemotherapy is the essential treatment, addition of adjuvant radiotherapy did not improve survival. More high-quality clinical trials are needed to provide powerful evidence.
The efficacy and safety of pembrolizumab in advanced cervical cancer—A real world treatment study in an irish healthcare setting.
Authors: Browne Iseult , Fennelly David William , Crown John , Murray Hazel
Published: May 2020

e18007

Background: Pembrolizumab is a monoclonal antibody that binds to the PD1 receptor blocking its interaction with PDL1 and PDL2, releasing PD1 pathway-mediated inhibition of the immune response. Pembrolizumab is not currently licensed for use in cervical cancer anywhere in Europe. Pembrolizumab was granted approval by the FDA in 2018 for treatment of patients with recurrent or metastatic cervical cancer with progression on or after chemotherapy whose tumours express PDL1 CPS ≥1, based on the interim results from Keynote 158. This showed an ORR of 14.6% in PDL1+ population. The aim of this project was to assess our experience with pembrolizumab in patients with advanced cervical cancer in an Irish Healthcare Setting. Methods: Patients with advanced cervical cancer treated with pembrolizumab at 3 hospitals in Ireland were included. Patients’ clinical data was collected from hard copy and electronic medical records. All patients had recurrent or metastatic cervical cancer. Patients received Pembrolizumab 200mg IV once every three weeks. To enable us to compare our results with the reported outcomes from Keynote 158 we analysed PFS, OS and ORR. Results: Data collection was between April 2018 and December 2019. Patient baseline characteristics include: median age 41 (27-77yrs), 95% FIGO stage IVB, 5% stage IIIB. Histology: 70% SCC, 20% adenocarcinoma, 5% mixed large/small cell, 5% unknown. PDL1 status: 50% positive, 30% unknown, 20% negative. 90% had received previous systemic treatment in the metastatic setting. The ORR was 25% with a DCR of 30%. All responses were in patients with PDL1+ or of unknown PDL1 status. mOS was 8.9months in total population (11.2months in PDL1+), and mPFS was 6.4months (8.3months in PDL1+). 45% of patients experienced all grade toxicity with 10% experiencing grade 3-4. At the time of our analysis 70% had discontinued treatment and 65% of patients had died. Conclusions: The observed activity in our patient population is superior to the interim results from Keynote 158. There are limited therapeutic options in these symptomatic and often terminally ill patients. Additionally all of these alternate treatments create a significant toxicity profile impacting hugely on the patients’ quality of life. Therefore, in our real life experience, pembrolizumab provides an effective and much improved toxicity profile alternative in this patient population. We believe, based on our findings, pembrolizumab should be considered as a standard option for those with advanced PDL1+ cervical cancer.
A new perspective of different schemes of neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy for locally advanced cervical cancer.
Authors: Tian Xue , Li Fenghu , Li Ran , Yang Feiyue , Chang Jianying , Li Jiehui , Hu Lili , Du Yanjun , Mei Fan , Zuo Kai , Chen Shuying
Published: May 2020

e18011

Background: To observe the clinical effect, survival time and toxicity and side effects in unoperated cervical cancer patients treated with different schemes of neoadjuvant chemotherapy (NACT) followed by concurrent chemotherapy and radiotherapy (CCRT). Methods: A retrospective analysis was performed in 120 patients who were followed up until they died or being followed up at least 5 years. The treatment schedules consisted of 2 cycles of intravenous paclitaxel 135-175 mg/m2 plus cisplatin 60-80mg/m2 (TP group, 62 patients) or lobaplatin 30mg/m2 (TL group, 58 patients) every 21 days. Patients were then submitted to CCRT. Chemotherapy regimen of CCRT was cisplatin 40 mg/m2 (TP group) or lobaplatin 30mg/m2 (TL group) weekly. External beam radiation therapy (total 50.4-56.35Gy, 28 fractions, 180-215cGy per fraction daily) was administered using the3D-CRT or IMRT followed by intracavitary brachytherapy (5Gy per fractions, mostly 5 fractions, Ir192 based). Results: The proportion who had a complete/partial response was 81.7% after NACT, and 99.2% after all treatment. In all patients, the one-year, three-year and five-year survival rates were 99.2%, 81.7% and 69.2% respectively. In TP group vs. TL group, the 3-yr and 5-yr survival rates were 85.5% vs.77.6% (χ2= 1.248, p = 0.264) and 75.8% vs. 63.8% (χ2= 2.059, p = 0.151) with no significant difference. In mass size ≥ 5cm group vs. <5cm group, 3-yr survival rates were 88.0% vs.77.1% with no significant difference (χ2= 2.296, p = 0.130), but 5-yr survival rates were 82.0% vs.61.4% (χ2= 5.878, p = 0.015) with significant difference. The 3-yr and 5-yr OS rates between stage IIB and stage IIIB were not significantly different, respectively 83.1% vs. 70.6% (χ2= 2.083, p = 0.149) and 67.7% vs. 64.7% (χ2= 0.090, p = 0.765) . In TP group, grade 3 or 4 digestive reaction was obviously more frequent than TL group, respectively 54.3% vs. 1.8%(p = 0.000). Neutropenia and thrombocytopenia are more common in TL group than TP group, respectively 48.3% vs. 30.6%(p = 0.0.048) and 44.8% vs. 1.6%(p = 0.000). Conclusions: For patients with severe digestive system reaction or contraindications of cisplatin, lobaplatin was might be used as an alternative drug. A prospective research is undergoing in our hospital. NACT may improve the prognosis of patients with large-scale mass. A undergoing prospective study protocol was approved by the Ethics Committee of hospital number 2017-02 and was registered in ClinicalTrial.gov as ChiCTR-IIR-17011559.
Opportunities and challenges in cervical cancer screening program in Kazakhstan: Results after imPACT review.
Authors: Kaidarova Dilyara , Bolatbekova Raikhan , Zhylkaidarova Alma , Sadykova Tolkyn , Kukubassov Yerlan , Aidarov Askar , Satanova Alima
Published: May 2020

e18020

Background: Cervical cancer is the second most common cancer in women worldwide, where the majority of registered patients are in developing countries. Screening programs in developed countries have reduced morbidity and mortality from cervical cancer by more than 2 times. Cervical cancer (CC) is the most common gynecological cancer in Kazakhstan (KZ). Standardized incidence rate of CC was 18.2 per 100,000, while the mortality rate was 6.2 per 100,000, in 2019. The National Cervical Screening program in KZ uses cytology (Pap test) from 2008. Screening program funded by the State budget. In 2016, Experts of imPACT Mission analyzed the CC screening and made recommendations for improvement. Since 2018 target age of CC screening expanded to 30-70 years and shortened the interval to 4 years, strengthened the control of patients with pre-cancerous pathology. Until 2018, people came to a fixed age; today we start CC screening within the target age at any age at the time of the first visit. The purpose of this study is to analyze cytological screening results in KZ after imPACT recommendations. Methods: Coverage, the number of screened women, the level of pre-cancer detection and cervical cancer during screening have been obtained from specific reports (form № 025, № 08) for 2008-2019. Results: The total number of screened women was in 6.775.975. There is a decrease in the number of screened women by 32% from 2008 to 2017. Since improvement of CC screening we increased coverage from 49.9% in 2017 (abs. number 409.124) to 89% in 2019 (abs. number 954.322). According to the results of screening, 2603 cases of CC were registered in 12 years. Analysis of screening results showed a marked increase in the detection of CC with an increasing by 67%. The persentage of registered cases of ASH+HSIL increased from 0.136% to 0.673%. Conclusions: there has been an increase in the coverage by screening of the target population since the screening update. During the study period, there has been an improvement in the detection of precancerous pathology and cancer in the early stage. Despite the positive results of screening, sufficient coverage by screening, certain successes in detecting the initial stage of CC, mortality rate from CC remain high, which makes it necessary to improve the screening of CC in KZ through the introduction of HPV-screening.
Non-brachytherapy approach for locally advanced cervical cancer treatment.
Authors: Salim Nidal , Nosov Vladimir , Zvereva Daria , Novikova Olga , Tedeeva Anna , Trofimenko Irina , Gromova Nadezhda , Koposov Pavel
Published: May 2020

e18023

Background: Concomitant chemoradiation therapy (CRT) that includes both external beam radiotherapy (EBRT) and brachytherapy (BT) is the current standard of care in treatment of locally advanced cervical cancer (LACC). Adaptive EBRT using volumetric modulated arc technology without BT allows dose escalation and decreases toxicities. Non-brachytherapy treatment is an evolving alternative approach provides geographical radiation accuracy but the oncological outcomes still to be evaluated. Methods: Patients with LACC (stages 1B3–IVA) who underwent non-brachytherapy CRT using adaptive EBRT with simultaneous integrated boost at our institution were evaluated prospectively from May 2015 to December 2019. All patients were initially assessed by a gynecologic oncologist, pelvic MRI and 18FDG-PET/CT scan were conducted. Follow-up pelvic examinations with cytology every 3 months and PET/CT at 3 and 12 months after completion of treatment were performed. Oncological outcomes and toxicities were assessed. Results: Twenty-one patients were analyzed: median age was 54 years (30–76 years); 19 patients had squamous cell histology and 2 had adenocarcinoma. Median follow-up was 32 months (8–56). The average dose administered to the gross tumor volume was 90.2 Gy (79.5–96.6), 79.8 Gy to all PET/MRI positive lymph nodes (63.0–89.7). No patents received BT; all but 3 received chemotherapy. Three-year local control was 100% (PFS = 90.4% and OS = 100%). There were 2 recurrences: a solitary skull lesion 18 months following CRT in a patient with mesonephric adenocarcinoma and a metastasis to a transposed ovary 15 months after CRT. No grade 3–4 toxicities were seen. Only 1 patient (4.7%) had late rectal grade II toxicity. Conclusions: Non-brachytherapy adaptive CRT for LACC is feasible. It allows for a significant dose escalation, thus providing better local control and likely increases PFS and OS at no cost of serious toxicity. Randomized studies comparing this approach to the current standard of care are needed.
Uncovering the immune-modulating role of anti-RANKL therapy for cervical cancer: Preliminary results.
Authors: Van Dam Peter , Verhoeven Yannick , De Waele Jorrit , Jacobs Julie , Van Dam Pieter-Jan , Kockx Mark , Van de Vijver Koen , Lammens Martin , Wouters An , Smits Evelien , Lardon Filip , Trinh Xuan Bich
Published: May 2020

e18028

Background: Conventional treatments for cervical cancer (CC) have reached a plateau and only limited progress for targeted therapy has been made over the last decades, resulting in a meager five-year survival rate of only 17% for the advanced stages. To improve long-term benefits for the patient, a promising hot field of research in oncology that opens new perspectives is immunotherapy. Even though CC has shown to be immunogenic, only a minority of patients respond to this type of treatment. In recent years, the RANKL/RANK signaling pathway has been implicated as a key immune modulating factor in the tumor microenvironment, allowing the cancer cells to evade the immune response by disrupting the immune-intrinsic crosstalk. Both RANKL and RANK are highly co-expressed in CC, which correlates with inferior clinicopathological parameters and an increased risk of death. Targeting this pathway may therefore be of great value in the treatment of CC and the quest to release the brakes on the immune system, thereby reinvigorating the tumors’ susceptibility to immunotherapy. Hence, we aim to elucidate the effects of anti-RANKL therapy on the tumor-immune microenvironment in CC. Methods: Two cervical biopsies were taken before and after anti-RANKL therapy in CC patients. One fresh biopsy was immediately processed to a single cell suspension for flow cytometry (FCM) using enzymatic digestion, while the other was formalin-fixed and paraffin-embedded for immunohistochemistry (IHC) and RNA sequencing. For FCM and IHC, the samples were stained with different markers for RANK/L signaling, the immune infiltrate and immune checkpoints. FCM was performed on a BD FACSAria IIä cytometer and analyzed with FlowJo. IHC staining was performed on a Ventana Benchmark Ultra and Ventana Discovery Ultra and scored by a pathologist or by HistoScientist using Visiopharm, while RNA sequencing was performed with the Truseq RNA exome panel on the NextSeq 500 system. Results: Our preliminary results show a relative increase of the CD8+ population, while a trend is observed in increased lymphocyte activation after anti-RANKL therapy. Updated results will be presented in more detail at the conference, including RNA sequencing data. Conclusions: Preliminary findings indicate that anti-RANKL therapy modifies the tumor-immune microenvironment in CC. Higher patient accrual will allow to dissect targets for combination therapy with anti-RANKL to further optimize this treatment strategy.
Open label phase I trial using SPL-108 in combination with weekly paclitaxel final report with molecular correlates.
Authors: Girda Eugenia , Hou June YiJuan , Buckley De Meritens Alexandre , Stephenson Ruth , Leiser Aliza L. , Song Mihae , Finlayson Malcolm , Nelson David M , Rodriguez-Rodriguez Lorna
Published: May 2020

e18040

Background: Therapeutic options for patients with recurrent platinum resistant ovarian cancer are scarce and represent an unmet need in ovarian cancer. Chemotherapy resistance has been linked to many CD44 pathways including P-glycoprotein mediated efflux of chemotherapeutic agents. Our working hypothesis was that chemotherapy resistant ovarian tumors that expressed CD44 would revert drug resistance by using a CD44 inhibitor SPL-108, that had proven safe as a single agent. Methods: Patients with platinum refractory or resistant CD44+ ovarian tumors were eligible. We used a standard 3+3 phase I design, open-label, 2-arm trial of the combination of SPL-108 and IV paclitaxel (PTX): Arm 1 (2 cohorts) Safety Phase: Cohort 1: SPL-108 150 mg SQ Daily +80 mg PTX weekly Cohort 2: SPL-108 300mg daily +80 mg PTX weekly Arm 2 (1 cohort) Exploratory Phase: Cohort 3: SPL-108 daily dose 300 mg +80 mg PTX weekly Days 1-15 in 28 day cycles Primary end points were safety and tolerability. Secondary endpoints included determining molecular signatures of response using NGS. Tumors were sequenced at the time of recurrence or initial diagnosis. Results: Fourteen patients were enrolled in the study. Prior number of treatments ranged from 2-6, except for one patient with platinum refractory disease that progressed during first line of therapy. There was no DLT and all cohorts were completed as designed. The treatment was well tolerated. There was one instance of a bowel micro-perforation that was treated medically. This patient had platinum refractory disease and eventually underwent an interval cytoreduction. There was one patient with grade 3 neurotoxicity. Sixty-two% of the patients had clinical benefit with 36% having a PR. Forty-three % of patient had a PFS of more than 6 months. Two patients enjoyed a PR of 12 months. Molecular profiling of the tumors revealed that all tumors had TP53 alterations and the 4 patients that did not have a response had tumors with TP53 truncations or a lack of function alteration. Conclusions: Daily SPL-108 300mg SQ in combination with weekly PTX is safe and feasible. The promising clinical activity on drug resistant ovarian tumors warrants further investigation. Resistance to SPL-108 are characterized by lack of function of TP53, mostly early truncations. It is possible that SPL-108 may be reactivating TP53 by promoting its active conformation. Once TP53 is active CD44 expression is abrogated at the promoter. Therefore SPL-108 is effectively acting on CD44 through 2 different mechanisms to promote chemotherapy sensitivity. Clinical trial information: NCT03078400.
Results of a deep-dive survey on practice patterns of oncologists and advanced practice providers utilizing PARP inhibitors as maintenance therapy for patients with ovarian cancer.
Authors: Turell Wendy , Ackbarali Tariqa , Coleman Robert L. , Westin Shannon Neville , Smith Judith Ann
Published: May 2020

e18044

Background: Often diagnosed at an advanced stage, most patients with ovarian cancer will relapse. As several PARP inhibitors (PARPi) have recently been approved as maintenance, patients are presented with treatment options that extend the interval of disease remission. However, novel challenges exist as oncology teams are apprehensive of integrating PARPi in practice. Emphasis on building this competence is essential for patients to obtain the maximum benefit of maintenance PARP therapy. Methods: Oncology teams were invited to participate in a 1-hour live and online education activity broadcast from 2018-2019 at OMedLive.com for 12 months. The activity addressed clinical data on the use of PARPi as maintenance therapy, management of adverse events, and emerging strategies utilizing PARP inhibition. A deep-dive survey, including structured and open-ended questions, was conducted 2 to 4 months after participation and focused on changes in practice, barriers to change, and observed patient outcomes. Results: In total, 915 clinicians participated in the video-based activity. Sixty physicians and advanced practitioners opted to complete the deep-dive survey, 70% of whom have used PARP inhibitors as maintenance therapy. Practice improvements were reported for identifying patients likely to benefit from PARPi (90%), differentiating among approved PARPi (86%), counseling patients (85%), and team-based side effect management (95%). The top 3 barriers to utilization of PARPi were lack of reimbursement (23%), inability to anticipate patient outcomes (15%), and unfamiliarity with clinical guidelines (15%). Variations in responses to open-ended questions included persistent questions (n = 47) in need of responses before adopting PARPi, data needed to better inform decision-making (n = 49), major concerns about PARPi (n = 55), and the most challenging aspects of current patient management with PARPi (n = 39). Conclusions: Patient education yielded improvements in practical application and management of PARP inhibitors for patients with ovarian cancer. The thematic variations in open-ended responses may inform the design of tailored interventions to improve clinical integration of PARP inhibitors as maintenance therapy and different lines of treatment.
Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancer undergoing cytoreductive surgery.
Authors: Mullany Sally Anne , Miller David S. , Robison Katina , Levinson Kimberly , Lee Yi-Chun , Yamada Seiko Diane , Walker Joan L. , Markman Maurie , Marin Alyson , Mast Peter , Dizerega Gere
Published: May 2020

e18046

Background: Although advances in chemotherapy, cytoreductive surgery, and maintenance therapy (SOC) improved PFS for high grade epithelial ovarian cancer, > 20% of patients relapse during the first 6 months and 60% relapse after 6 months. Submicron particles (~800 nm) of paclitaxel (SPP) contain 1-2 billion molecules of pure drug that release tumoricidal levels of paclitaxel over many weeks. In a previous trial, percutaneous instillations of SPP in nonsurgical patients with intraperitoneal cancer were associated with reduced systemic and local toxicity as compared to standard chemotherapy regimens. (Williamson et al Cancer Chemo Pharm (2015) 75:1075). Methods: This study compared two dose-levels of IP SPP instilled in 200 ml of saline post-cytoreductive surgery. Eligible patients with primary (n = 6) or recurrent (n = 4) epithelial ovarian cancer who underwent complete cytoreductive surgery were enrolled to receive a single instillation of IP SPP followed by standard IV carboplatin and paclitaxel. Endpoints were PFS and evaluation of treatment-emergent adverse events. Clinical response was determined by CT scans and serum CA-125 measurements. Results: Of the 24 subjects screened, 10 were enrolled and received treatment: seven patients received 100 mg/m2 and three received 200 mg/m2. For analysis purposes, 7 out of 10 subjects were evaluable (1 withdrew, 1 died unrelated to study drug during IV treatment and 1 was unevaluable). Upon completion of planned chemotherapy post-SPP instillation, the PFS at 6 months was 66% (4/6) and at 12-months 66% (4/6) using RECIST 1.1. One subject had a complete response at the end of IV treatment, but died (unrelated to study treatment) before PFS evaluation. There was one case of incision dehiscence and one case of vaginal cuff leakage after surgery. Conclusions: This pilot study supports further evaluation of IP SPP to treat peritoneal carcinomas. Clinical trial information: NCT03029585.
Factors affecting recurrence rates in women with borderline ovarian tumors.
Authors: Scanlon Lauren , Goldberg Gary L.
Published: May 2020

e18055

Background: Borderline or low malignant potential tumors of the ovary (BOTs) make up approximately 15-20% of all ovarian neoplasms. These tumors are considered indolent and usually confer an excellent overall survival in women who are treated utilizing a conservative surgical approach. However, recurrence rates can approach 30%. The aim of this study was to compare the type and mode of surgery and its impact on outcomes in patients with BOTs. Methods: An Institutional Review Board approved, retrospective cohort study identified all patients at Long Island Jewish Medical Center, North Shore University Hospital and USC Medical Center with BOTs who underwent surgery between January 2008 and May 2018. Demographics and outcome measures were obtained from the medical records. Prognostic factors for disease recurrence were studied including histological subtypes type of surgical procedure, including minimally invasive or open ovarian cystectomy and oophorectomy. Results: 260 patients were identified. 226 of these women (88%) had stage I disease at the time of diagnosis. There were 26 recurrences noted in the cohort, a recurrence rate of 10 percent. The median age was 50 years old (range 16-86). 145 patients (56%) underwent minimally invasive surgical procedures compared to 115 (44%) who had open laparotomy. 30 (12%) of the women underwent an ovarian cystectomy and 230 (88%) had an oophorectomy. The median time to disease recurrence was 25 months (range 4-94 months). There was significant difference in the recurrence free survival between the patients who had minimally invasive procedures and those who had open laparotomy (hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.11-6.52). There was also significant difference in Recurrence Free Survival (RFS) and in those who underwent ovarian cystectomy and oophorectomy (HR 7.32, 95%CI 3.34-16.06). No difference in recurrence rates were noted between those with serous and mucinous histology. Conclusions: In this cohort of women with BOTs, the risk of recurrence was associated with minimally invasive surgery versus open laparotomy as well as ovarian cystectomy compared with oophorectomy. Conservative surgery for BOTs in young patients plays an important role for fertility preservation in these young women and can be curative. This study allows us to present additional information to address surgical approach and risk for disease recurrence in young women having fertility sparing and conservative surgery for BOTs.
Evaluation of adaptive NK cells in ovarian cancer patients with cytomegalovirus (CMV) reactivation and systemic inflammation.
Authors: Wesley Erin , Uppendahl Locke , Felices Martin , Messelt Audrey , Hunter-Schlichting Devon , Nelson Heather , Bendzick Laura , Geller Melissa Ann
Published: May 2020

e18062

Background: Cytomegalovirus (CMV) is a common infection associated with increased inflammation (c-reactive protein (CRP) upon reactivation during immunosuppression. CMV infection has been associated with a subset of NK cells (adaptive) that are long-lived, have enhanced cytotoxicity, and thought to contribute to cancer control. Previous evaluation of a retrospective study showed CMV+CRP+ patients had significantly worse RFS and OS compared to CMV+ CRP− patients who had the longest OS. These findings suggest CMV may be immunomodulatory and, without immunosuppressive effects of inflammation, may be protective. We are further evaluating for the presence of adaptive NK cells in the patients to evaluate if these populations of cells are drivers for the changes in outcomes. Methods: Serum and ascites (22 samples each) collected in a prospective study at the time of surgery for HGSOC were evaluated for CMV and inflammation. CMV status and systemic inflammation were measured by immunoassay for CMV immunoglobulin G (IgG), dPCR for CMV DNA and C-reactive protein (CRP). Samples were categorized as reactive or non-reactive for CMV and positive or negative for CRP (≤10, > 10 mg/L). Adaptive NK cell percentages were analyzed using GraphPad Prims 8 and p-values ≤ 0.05 were considered statistically significant. Proteomic techniques to quantify adaptive NK cells, differences in NK cell maturation and cytotoxicity are in process for an additional 80 samples. Results: CMV reactive patients showed increased percentages of adaptive NK cells (NKG2C+CD57+) in the blood and peritoneal cavity compared to CMV negative patients. There is a trend in the presence of adaptive NK cells in patient samples that are CMV reactive and CRP positive compared to CMV nonreactive and CRP positive. Conclusions: Preliminary analysis shows a trend in presence of adaptive NK cells in both the blood and peritoneal cavity of these patients but analysis is ongoing.
The impact of obesity on treatment and outcomes in ovarian cancer by race/ethnicity.
Authors: Martin Alexandra , Mallen Adrianne Rose , Sinha Sweta , Wells Ali , Cline Kathryn , Lam Clarissa , Peres Lauren , Chern Jing-Yi
Published: May 2020

e18067

Background: Concern for toxicities in obese ovarian cancer patients may limit weight-based chemotherapy dosing, which has been associated with poor survival. We sought to evaluate the impact of obesity on treatment and outcomes by race/ethnicity at a National Cancer Institute (NCI)-designated Comprehensive Cancer Center (CCC). Methods: 66 minority (non-Hispanic black, Hispanic) epithelial ovarian cancer patients diagnosed 2006 and treated with frontline chemotherapy were frequency matched to two non-Hispanic white (NHW) patients by 5-year age group and stage (n = 198). For frontline carboplatin, relative dose intensity (RDI) was calculated by dividing the dose received by the expected dose, with an RDI < 0.85 indicating carboplatin dose reduction. Patient characteristics and RDI were compared by obesity and race/ethnicity. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between obesity, race/ethnicity and RDI with mortality, adjusting for confounders. Results: Minorities were more likely to be obese, underinsured, and to experience delays in chemotherapy compared to NHW. Compared to normal/overweight patients, obese patients were more likely to experience carboplatin under dosing in the neoadjuvant (p = 0.004) and adjuvant (p < 0.0001) setting, but there were no differences in RDI by race/ethnicity or toxicities. No association with survival was observed for dose reduction and BMI. Compared to NHW, minorities had similar survival in the first 4 years after diagnosis (HR = 0.99, 95% CI = 0.60-1.63), but an increased risk of mortality > 4 years after diagnosis (HR = 4.07, 95% CI = 1.92, 8.60). Conclusions: Even though minorities were more likely to be obese, there were no differences in dosing by race/ethnicity at an NCI CCC. Minorities had similar survival to NHW in the first 4 years after diagnosis, likely due to similar access to quality care at an NCI CCC. However, > 4 years after diagnosis, the racial/ethnic survival disparity persisted after adjustment for clinical and pathologic characteristics. Expansion of this work to other patient populations may help determine if findings are similar outside of a tertiary care center.
The role of imaging in early detection of patients at risk for neuropathy during primary chemotherapy for ovarian carcinoma.
Authors: Bell Sarah , Dalton Liam , Derstine Brian , Ross Brian , Sullivan June , Wang Stewart , Uppal Shitanshu , Siedel Jean
Published: May 2020

e18071

Background: Neuropathy is a common adverse event requiring dose reduction or regimen change in patients receiving platinum-taxane chemotherapy for ovarian cancer. Our aim was to determine whether specific biomarkers, such as skeletal muscle, visceral and subcutaneous fat cross-sectional areas, measured using computerized tomography (CT), were associated with the development of neuropathy. Analytic Morphomics, a semi-automated image analysis method, has been used to predict oncologic outcomes with immunotherapy and to identify patients at higher risk for postoperative complications from major cancer surgeries. We hypothesized that patients who required dose reductions or regimen changes would have CT imaging findings that distinguished them from their counterparts who did not require dose reduction or regimen change. Methods: All patients at our institution diagnosed with high-grade ovarian carcinoma between January 1, 2014 and December 31, 2018 were identified retrospectively. Analytic Morphomics was used to extract measures of body composition from CT images at the level of the third lumbar vertebra. Demographic and clinical characteristics were abstracted from the electronic medical record. We analyzed several binary outcomes (neuropathy, delay in chemotherapy, or dose reduction by cycle 1, 3 or 6) and used unpaired, two-tailed t-tests to compare means between each outcome group at each timepoint. Results: Of 156 patients screened for the study, 138 patients were included and had pre-treatment CT scans available and completed six cycles of platinum-taxane chemotherapy. Patients who developed neuropathy in any of the six cycles, or had a change in their chemotherapy regimen by cycle six, had higher mean visceral fat area than those who did not develop neuropathy. This finding was statistically significant throughout three cycles (p = 0.023) and six cycles (p = 0.030). Conclusions: Increased visceral fat on CT imaging was significantly associated with a higher incidence of neuropathy and change in chemotherapy regimen in patients undergoing primary platinum-taxane chemotherapy for ovarian carcinoma. Weight and BMI did not have a significant association with development of neuropathy, dose reduction, or treatment delay. Further study is needed to determine if dose reductions or regimen changes due to neuropathy can be better predicted using morphomics.
Defining the tumor cell: CA-MSC interactions which mediate ovarian cancer metastasis.
Authors: Goldfeld Ester , Atiya Huda , Frisbie Leonard , Coffman Lan Gardner
Published: May 2020

e18072

Background: Carcinoma-associated mesenchymal stem cells (CA-MSCs) are mesenchymal stem cells (MSCs) within the tumor microenvironment (TME). We demonstrated that CA-MSCs promote ovarian cancer chemotherapy resistance through paracrine signaling with ovarian cancer cells, interact with ovarian cancer cells to form mixed-cellularity complexes which enhance metastasis, and arise from cancer cell and TME reprogramming of normal tissue MSCs. To identify mediators of the CA-MSC:tumor cell interaction, we investigated the role of tetraspanins, which are membrane-spanning proteins that have been implicated in cancer development and metastasis by influencing cell adhesion and cell-cell interactions. The tetraspanins CD9, CD81, CD151, and CD63 were identified as potential mediators of cell surface interactions between ovarian cancer cells and CA-MSCs through homo- and heterodimerization. Methods: Td-labeled OVCAR3 cancer cells were co-cultured with 3 patient-derived MSC (derived from normal tissue) and 3 patient-derived CA-MSC (derived from malignant tissue) cell lines. Flow cytometry was performed to measure surface protein expression of the tetraspanins CD9, CD81, CD151, and CD63, and was compared to control cells (not co-cultured) and their median fluorescence intensity (MFI). We next separated OVCAR3 cells co-cultured with MSCs or CA-MSCs using fluorescent activated cell sorting (FACS) based on Td expression. Following FACS, tetraspanin expression in OVCAR3 cells, MSCs, and CA-MSCs was assessed via qRT-PCR and western blotting, and compared to cell lines that were not co-cultured. Results: Flow cytometric analysis revealed an increase in MFI of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs when compared to non-co-cultured matched cells. Increased RNA expression of CD9, CD151, and CD63 was seen in OVCAR3 cells that were co-cultured with CA-MSCs or MSCs when compared to non-co-cultured OVCAR3 cells. Increased RNA expression of CD81 and CD63 was noted in both co-cultured CA-MSCs and MSCs compared to non-co-cultured cells. Lastly, western blotting demonstrated increased protein expression of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs compared to non-co-cultured matched cells. Conclusions: These results indicate that direct interactions between OVCAR3 cells and CA-MSCs or MSCs lead to overexpression of specific tetraspanins at the RNA and protein levels, implying that they may be facilitating tumor cell:CA-MSC and tumor cell:MSC binding.
Biomarker lead time for predicting progression in women with ovarian cancer compared to imaging.
Authors: Samborski Alexandra , Blackman Alexandra Michelle , Miller Michael Craig , Eklund Elizabeth , Messerlian Geralyn , Moore Richard G.
Published: May 2020

e18074

Background: Both CA125 and HE4 are biomarkers used to monitor women diagnosed with epithelial ovarian cancer (EOC). When these biomarkers increase and suggest progression of disease, imaging is frequently obtained for further assessment and confirmation. This study aims to assess how far in advance these biomarkers begin to trend upwards in comparison to the radiographic evidence of disease progression. Methods: This was an IRB approved retrospective trial. Residual longitudinal serum samples drawn for serum CA125 levels during treatment and monitoring from women with EOC were obtained. The samples were drawn every 3-5-weeks for patients on chemotherapy and every 3 months while monitoring. Serum CA125 and HE4 levels in the residual sera were analyzed at each time point. Imaging data was collected for each patient. Patients were included if either HE4 or CA125 was a marker for their disease. For each patient, the date of time point when the biomarker started to trend upward was identified and the date of radiographic evidence of progression was determined. The lead time (in days) for elevation of both CA125 and HE4 prior to evidence of radiographic progression was determined for each patient. Results: A total of 48 patients undergoing 58 treatment and monitoring events were identified. Each had evidence of disease progression by CA125 levels, HE4 levels, and computed tomography (CT). CA125 was the first biomarker to trend upward for 9 events (15.5%), HE4 was the first biomarker for 10 events (17.2%), and both increased simultaneously for 39 events (67.2%). Mean lead time for CA125 elevation prior to progression on imaging was 60 days (95% CI: 43 - 78, median = 44, range = 0 - 386). For HE4, mean lead time was 66 days (95% CI: 48 – 83, median = 46, range = 0 - 386). There was no significant difference in the average lead times between the two biomarkers (p < 0.01). Conclusions: When used for EOC monitoring both CA125 and HE4 have similar average lead times (~2 months) prior to the detection of progressive or recurrent disease by CT imaging.
Malignant MIXED mullerian tumors and serous endometrial cancer: Molecular targets the need of the hour.
Authors: Shah Manan , Jain Sanjay R , Oprea Gabriela , Shafi Saba
Published: May 2020

e18106

Background: Malignant Mixed Mullerian Tumors (carcinosarcomas) and serous variants are rare but aggressive endometrial cancers which constitute less than 5 percent of uterine tumors. Our aim was to understand the clinical and molecular features of these variants which could aid us in further management. Methods: We retrospectively reviewed cases of carcinosarcomas and serous endometrial cancers at our institution over a period of 5 years. A total number of 28 cases were identified. Baseline clinical characteristics, treatment parameters including adjuvant chemo-radiotherapy and disease status at one year follow up were noted. Molecular markers included hormone receptor status (ER/PR), p16, p53, Her-2/neu, and the MMR gene panel (MLH1, PMS2, MSH2, MSH6). Results: The mean age for carcinosarcomas was 66 ± 12 years and for serous tumors 71± 8 years. The mean BMI of patients with carcinosarcoma was 32±7 kg/m2and serous tumors was 32±4 kg/m2. African American and Hispanic females were the predominant race. FIGO stage 1 at presentation constituted 75% in patients with carcinosarcomas while FIGO stage 3 and 4 constituted 62 % in serous variants. All our patients underwent surgery (TAH/BSO or debulking) followed by adjuvant chemotherapy/radiation or both. At 1 year follow up post treatment only 33% patients with carcinosarcomas and 12% with serous tumors had stable disease. Remaining patients showed progression or new metastasis to lung, peritoneum, retroperitoneum and vaginal vault. Molecular studies revealed ER+ in 41% and PR + in 33% with carcinosarcomas and 43% and 31% with serous tumors respectively. All patients with carcinosarcomas were Her-2/neu negative while 25 % were positive in serous tumors. 88% cases were strongly positive for both p53 and p16 in the serous variant. All patients showed an intact MMR gene panel. An interesting observation was that all patients with stable disease at 1 year follow up were ER/PR+ and Her-2/neu negative. Conclusions: Overall survival of these variants remains poor. Biomarkers such as p16, p53, Her-2, MMR panel and hormone receptors have become indices for individualization of treatment and further studies using targeted agents are warranted.
Clinicopathologic and protein markers distinguishing POLE and copy-number low group in endometrial cancer.
Authors: Kim Kidong , Hwangbo Suhyun , Park Taesung , Kim Hyojin , Kim Yong Beom , No Jae Hong , Suh Dong-Hoon , Kim Ju-Hyun
Published: May 2020

e18110

Background: Requirement of DNA sequencing to diagnose POLE group is a barrier for adoption of molecular subtyping in endometrial cancer. We aimed to identify clinicopathologic and protein markers distinguishing POLE and copy-number (CN) low group in endometrial cancer. Methods: Ninety-one samples (POLE: 15, CN low 76) classified as POLE or CN low groups by integrative clustering were selected from The Cancer Genome Atlas endometrial cancer dataset. Clinicopathologic variables and normalized reverse phase protein array expression data were extracted. We first selected clinicopathologic variables associated with group (POLE vs CN low) via univariate analysis. Then, we identified protein makers using the logistic regression model with significant clinicopathologic variables as adjusting covariates. The differentially expressed proteins were selected based on q-value of the false discovery rate for multiple comparison. With various q-value cut-off ( < 5%, 10%, 20%), several logistic models including differentially expressed markers were constructed by stepwise selection method using the area under curve (AUC) from 5-fold cross-validation (CV). Results: Among clinicopathologic variables, body mass index (BMI) and tumor grade were associated with group (p = 0.02 and p < 0.01, respectively). Being adjusted for BMI and tumor grade, 5 proteins were associated with group in q-value cut-off of < 5%. The model including clinicopathologic variables and 5 proteins identified BMI, Cyclin B1, Caspase 8, and XBP1 as markers distinguishing POLE and CN low groups. The mean of CV AUC, sensitivity and specificity of the selected model were 0.97, 0.97, and 0.60, respectively. Conclusions: BMI and expression levels of Cyclin B1, Caspase 8, XBP1 are candidate markers distinguishing POLE and CN low group. A further validation study using immunohistochemical staining is necessary to facilitate the adoption of molecular subtyping as daily practice.