Publications by authors named "Kevin M Elias"

82 Publications

Synthetic Lethality in Ovarian Cancer.

Mol Cancer Ther 2021 Sep 13. Epub 2021 Sep 13.

Gynecologic Oncology, Brigham and Women's Hospital

Ovarian cancers include several distinct malignancies which differ with respect to clinicopathological features and prognosis. High-grade serous cancer is the most common histological subtype and accounts for most ovarian cancer deaths. HGSOC is treated with surgery and platinum-based chemotherapy, but most patients relapse and succumb to chemoresistant disease. The genetic concept of synthetic lethality, in which the synergy of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to overcome chemoresistance in ovarian cancer. Recent progress in understanding the genomic architecture and hereditary drivers of ovarian cancer has shown potential for synthetic lethality strategies designed around homologous DNA repair. Clinical trials have validated high response rates for poly (ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA1 or BRCA2 mutations. Here we discuss the biological rationale behind targeting BRCA-PARP synthetic lethality based on genetic context in ovarian cancer and how this approach is being assessed in the clinic. Applying the concept of synthetic lethality to target non-BRCA-mutant cancers is an ongoing challenge, and we discuss novel approaches to target ovarian cancer using synthetic lethality in combination with and beyond PARP inhibitors. This review will also describe obstacles for synthetic lethality in ovarian cancer and new opportunities to develop potent targeted drugs for ovarian cancer patients.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0500DOI Listing
September 2021

Challenges in the Treatment of Low-risk Gestational Trophoblastic Neoplasia.

Rev Bras Ginecol Obstet 2021 Jul 30;43(7):503-506. Epub 2021 Aug 30.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, New England Trophoblastic Disease Centre, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.

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http://dx.doi.org/10.1055/s-0041-1735177DOI Listing
July 2021

Folinic acid rescue during methotrexate treatment for low-risk gestational trophoblastic neoplasia - How much is just right?

Gynecol Oncol 2021 Sep 13;162(3):638-644. Epub 2021 Jul 13.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To compare the outcomes of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with 8-day methotrexate (MTX) with two different regimens of folinic acid (FA).

Methods: Retrospective cohort study of low-risk GTN followed at Rio de Janeiro Federal University, from January/2000-December/2019 with 8-day MTX with FA at 0.1 mg/kg versus 15 mg fixed dose.

Results: Among 667 patients with low-risk GTN, 323 were treated with FA at 0.1 mg/kg and 142 with FA at 15 mg fixed dose. The weight-based and fixed dose groups were comparable in terms of clinical profile but did differ in the hCG pretreatment level (8883 versus 5127 IU/L, p < 0.01) and FIGO risk score 5/6 (3.4% versus 18.3%, p < 0.01), respectively. Despite this, there was no difference in the remission rate in first-line treatment (76.8 versus 81%, p = 0.33), although FA at 0.1 mg/kg had a significantly higher number of chemotherapy cycles to remission (5 versus 4, p < 0.01), need to delay chemotherapy due to toxicity (6.8 versus 2.8%, p < 0.01) and time to remission, (12 versus 8 weeks, p < 0.01), respectively. A logistic regression analysis showed that the different FA rescue regimens appeared comparable in terms of achieving remission in first-line chemotherapy for low-risk GTN (OR:5.16, CI95%:0.84-31.64, p = 0.08).

Conclusion: FA with 15 mg fixed dose as compared to 0.1 mg/kg of FA was associated with similar primary remission rate, relapse or death among low-risk GTN treated with 8-day MTX. This regimen is highly practical, reduces visits to health facilities, appears equally safe and may be preferable with the 8-day MTX regimen in the treatment of low-risk GTN.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.013DOI Listing
September 2021

Dissection of Aberration for Cervical Adenocarcinoma Outcomes.

Cancers (Basel) 2021 Jun 28;13(13). Epub 2021 Jun 28.

Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in E542K, E545K, or H1047R were detected in 41.7% of tumors. mutation detected in the patient's circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women's cancer.
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http://dx.doi.org/10.3390/cancers13133218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269188PMC
June 2021

Predictors for single-agent resistance in FIGO score 5 or 6 gestational trophoblastic neoplasia: a multicentre, retrospective, cohort study.

Lancet Oncol 2021 08 25;22(8):1188-1198. Epub 2021 Jun 25.

Trophoblastic Tumour Screening and Treatment Centre, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

Background: Patients with gestational trophoblastic neoplasia who have an International Federation of Gynaecology and Obstetrics (FIGO) risk score of 5 or 6 usually receive non-toxic single-agent chemotherapy as a first-line treatment. Previous studies suggest that only a third of patients have complete remission, with the remaining patients requiring toxic multiagent chemotherapy to attain remission. As stratification factors are unknown, some centres offer multiagent therapy upfront, resulting in overtreatment of many patients. We aimed to identify predictive factors for resistance to single-agent therapy to inform clinicians on which patients presenting with a FIGO score of 5 or 6 are likely to benefit from upfront multiagent chemotherapy.

Methods: We did a multicentre, retrospective, cohort study of patients with gestational trophoblastic neoplasia presenting with a FIGO score of 5 or 6, who received treatment at three gestational trophoblastic neoplasia reference centres in the UK, Brazil, and the USA between Jan 1, 1964, and Dec 31, 2018. All patients who had been followed up for at least 12 months after remission were included. Patients were excluded if they had received a non-standard single-agent treatment (eg, etoposide); had been given a previously established first-line multiagent chemotherapy regimen; or had incomplete data for our analyses. Patient data were retrieved from medical records. The primary outcome was the incidence of chemoresistance after first-line or second-line single-agent chemotherapy. Variables associated with chemoresistance to single-agent therapies were identified by logistic regression analysis. In patient subgroups defined by choriocarcinoma histology and metastatic disease status, we did bootstrap modelling to define thresholds of pretreatment human chorionic gonadotropin concentrations and identify groups of patients with a greater than 80% risk (ie, a positive predictive value [PPV] of 0·8) of resistance to single-agent chemotherapy.

Findings: Of 5025 patients with low-risk gestational trophoblastic neoplasia, we identified 431 patients with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6. All patients were followed up for a minimum of 2 years. 141 (40%) of 351 patients developed resistance to single-agent treatments and required multiagent chemotherapy to achieve remission. Univariable and multivariable logistic regression revealed metastatic disease status (multivariable logistic regression analysis, odds ratio [OR] 1·9 [95% CI 1·1-3·2], p=0·018), choriocarcinoma histology (3·7 [1·9-7·4], p=0·0002), and pretreatment human chorionic gonadotropin concentration (2·8 [1·9-4·1], p<0·0001) as significant predictors of resistance to single-agent therapies. In patients with no metastatic disease and without choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 411 000 IU/L or higher yielded a PPV of 0·8, whereas in patients with either metastases or choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 149 000 IU/L or higher yielded the same PPV for resistance to single-agent therapy.

Interpretation: Approximately 60% of women with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6 achieve remission with single-agent therapy; almost all remaining patients have complete remission with subsequent multiagent chemotherapy. Primary multiagent chemotherapy should only be given to patients with metastatic disease and choriocarcinoma, regardless of pretreatment human chorionic gonadotropin concentration, or to those defined by our new predictors.

Funding: None.

Translation: For the Portuguese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00262-XDOI Listing
August 2021

Loss of Selenoprotein Iodothyronine Deiodinase 3 Expression Correlates with Progression of Complete Hydatidiform Mole to Gestational Trophoblastic Neoplasia.

Reprod Sci 2021 Jun 15. Epub 2021 Jun 15.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02115, USA.

To investigate if differences in imprinting at tropho-microRNA (miRNA) genomic clusters can distinguish between pre-gestational trophoblastic neoplasia cases (pre-GTN) and benign complete hydatidiform mole (CHM) cases at the time of initial uterine evacuation. miRNA sequencing was performed on frozen tissue from 39 CHM cases including 9 GTN cases. DIO3, DLK1, RTL1, and MEG 3 mRNA levels were assessed by qRT-PCR. Protein abundance was assessed by Western blot for DIO3, DLK1, and RTL1. qRT-PCR and Western blot were performed for selenoproteins and markers of oxidative stress. Immunohistochemistry (IHC) was performed for DIO3 on an independent validation set of clinical samples (n = 42) and compared to normal placenta controls across gestational ages. Relative expression of the 14q32 miRNA cluster was lower in pre-GTN cases. There were no differences in protein abundance of DLK1 or RTL1. Notably, there was lower protein expression of DIO3 in pre-GTN cases (5-fold, p < 0.03). There were no differences in mRNA levels of DIO3, DLK1, RTL1 or MEG 3. mRNA levels were higher in all CHM cases compared to normal placenta. IHC showed syncytiotrophoblast-specific DIO3 immunostaining in benign CHM cases and normal placenta, while pre-GTN cases of CHM lacked DIO3 expression. We describe two new biomarkers of pre-GTN CHM cases: decreased 14q32 miRNA expression and loss of DIO3 expression by IHC. Differences in imprinting between benign CHM and pre-GTN cases may provide insight into the fundamental development of CHM.
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http://dx.doi.org/10.1007/s43032-021-00634-yDOI Listing
June 2021

Risk of venous thromboembolism for ovarian cancer patients during first-line therapy after implementation of an Enhanced Recovery After Surgery (ERAS) protocol.

Gynecol Oncol 2021 Aug 3;162(2):353-359. Epub 2021 Jun 3.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, United States; Dana-Farber Cancer Institute, Boston, MA, United States. Electronic address:

Objective: To determine incidence and risk factors for VTE for patients with advanced epithelial ovarian cancer undergoing first-line therapy, including cytoreductive surgery, on an Enhanced Recovery After Surgery (ERAS) protocol.

Methods: Medical records were reviewed for patients with FIGO stage IIIA-IVB epithelial ovarian, fallopian tube, or primary peritoneal cancer undergoing primary or interval cytoreductive surgery from March 2017 through September 2019. All patients were enrolled on an ERAS protocol, including 28-day postoperative VTE prophylaxis. Demographic information, medical history, perioperative characteristics, and ERAS compliance were evaluated using univariate and multivariate models.

Results: Of 230 patients undergoing cytoreductive surgery via laparotomy, 155 received neoadjuvant chemotherapy and 75 received primary cytoreduction. 38 patients had a VTE during the study period. 13 events (5.7%) were identified at time of diagnosis, 6 (3.9%) during neoadjuvant chemotherapy, 5 (2.2%) within 30 days after surgery, 5 (2.2%) between 30 days and 6 months after surgery, and 9 (3.9%) after the 6-month window. The cumulative incidence of VTE was 6.1% (95% CI, 4.3-8.8%) within 6 months after diagnosis and 8.5% (6.2-11.4%) within 1 year after diagnosis. Estimated blood loss (adjusted HR 1.22 [95% CI, 1.09-1.36], p = 0.001) and history of VTE (7.06 [2.34-21.29], p = 0.001) were independently associated with VTE.

Conclusion: With implementation of an ERAS protocol, only 1 in 46 patients experienced a VTE within 30 days after surgery. However, overall VTE occurred in 1 in 16 patients during first-line therapy. Strategies to further reduce VTE risk, especially during neoadjuvant chemotherapy and surveillance, should be investigated.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.032DOI Listing
August 2021

Enhanced recovery after surgery protocols improve time to return to intended oncology treatment following interval cytoreductive surgery for advanced gynecologic cancers.

Int J Gynecol Cancer 2021 08 15;31(8):1145-1153. Epub 2021 Apr 15.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA

Objective: The objective of this study was to determine whether the implementation of an enhanced recovery after surgery (ERAS) protocol is associated with earlier return to intended oncology treatment following interval cytoreductive surgery for advanced gynecologic cancers.

Methods: Participants comprised consecutive patients (n=278) with a preoperative diagnosis of stage IIIC or IV ovarian cancer, divided into those that received treatment before versus after implementation of an ERAS protocol at our institution. All patients received at least three cycles of neoadjuvant chemotherapy with a platinum based regimen and underwent interval cytoreduction via laparotomy with the intent to deliver additional cycles of chemotherapy postoperatively. The primary outcome was defined as the timely return to intended oncologic treatment, defined as the percentage of patients initiating adjuvant chemotherapy within 28 days postoperatively.

Results: The study cohorts included 150 pre-ERAS patients and 128 post-ERAS patients. Median age was 65 years (range 58-71). Most patients (211; 75.9%) had an American Society of Anesthesiologists score of 3, and the median operative time was 174 min (range 137-219). Median length of stay was 4 days (range 3-5 days) in the pre-ERAS cohort versus 3 days (range 3-4) in the post-ERAS cohort (p<0.0001). At 28 days after operation, 80% of patients had resumed chemotherapy in the post-ERAS cohort compared with 64% in the pre-ERAS cohort (odds ratio (OR) 2.29, 95% confidence interval (CI) 1.36 to 3.84; p=0.002). In multivariate logistic regression analysis, the ERAS protocol was the strongest predictor of timely return to intended oncology treatment (OR 10.18, 95% CI 5.35 to 20.32).

Conclusion: An ERAS protocol for gynecologic oncology patients undergoing interval cytoreductive surgery is associated with earlier resumption of adjuvant chemotherapy.
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http://dx.doi.org/10.1136/ijgc-2021-002495DOI Listing
August 2021

Treatment of high-risk gestational trophoblastic neoplasia and chemoresistance/relapsed disease.

Best Pract Res Clin Obstet Gynaecol 2021 Jul 2;74:81-96. Epub 2021 Feb 2.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

High-risk gestational trophoblastic neoplasia (GTN) has an increased risk of developing chemoresistance to single-agent chemotherapy; therefore, the primary treatment should be a multiagent etoposide-based regimen, preferably EMA/CO. After remission (normalization of human chorionic gonadotropin - hCG), at least three consolidation courses of EMA-CO are needed to reduce the risk of relapse. Chemoresistance is diagnosed during treatment if hCG levels plateau/increase, in two consecutive values over a two-week period. When this occurs after remission, in the absence of a new pregnancy, there is a relapse. In both cases, after re-assessment of the extent of disease, EMA-EP is the most common chemotherapy choice. Even in these cases, remission rates are high. After remission is achieved, hCG should be measured monthly for a year. Pregnancy can be allowed after 12 months from remission. The follow-up of these patients in referral centers minimizes the chance of death from this disease and should be encouraged.
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http://dx.doi.org/10.1016/j.bpobgyn.2021.01.005DOI Listing
July 2021

Video Hysteroscopy in the Diagnosis of Molar Pregnancy in two Challenging Situations: Complete Mole with Normal hCG and Partial Mole with Early Gestational Age.

J Minim Invasive Gynecol 2021 Aug 6;28(8):1448-1449. Epub 2021 Feb 6.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Drs. Elias, Horowitz, and Berkowitz).

Study Objective: To present the first hysteroscopic findings of 2 cases of complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) within the context of the patients' clinical histories.

Design: Presentation of 2 hysteroscopic videos with narration of the intrauterine findings of molar pregnancy (MP) from Rio de Janeiro Gestational Trophoblastic Disease Reference Center.

Setting: MP is characterized by abnormal fertilization that generates 2 clinical syndromes: CHM and PHM [1].

Interventions: In the first case, the patient was aged 50 years, and hysteroscopy was indicated to assess abnormal uterine bleeding in the presence of normal serum human chorionic gonadotropin (hCG) and transvaginal ultrassonography showing an endometrial cavity with heterogeneous content. Hysteroscopy found translucent hydropic structures diagnosed as CHM. The negative hCG value was due to the hook effect (hCG after dilution: 2 240 000 IU/L). In the second case, an 18-year-old patient underwent hysteroscopy to assess the endometrial cavity with retained abortion at 7 weeks in which, during conservative management, the hCG level increased over 4 weeks from 25 000 IU/L to 58 000 IU/L. Hysteroscopy visualized the embryo with its umbilical cord and hydatidiform vesicles diagnosed as PHM.

Conclusion: MP can be an incidental finding during hysteroscopy for abnormal uterine bleeding or retained abortion [2-4]. Knowing its morphology during hysteroscopy is helpful for the correct management of this uncommon clinical situation. Hysteroscopy as an adjunct diagnostic tool (not as first-line treatment for MP) can be of significant benefit in challenging clinical scenarios. Further studies should assess the possible risk of spreading molar cells into the peritoneal cavity owing to hysteroscopic fluid.
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http://dx.doi.org/10.1016/j.jmig.2021.02.001DOI Listing
August 2021

Triaging abnormal cervical cancer screening tests using p16INK4a detection by ELISA on fresh cervical samples.

Am J Reprod Immunol 2021 07 20;86(1):e13394. Epub 2021 Feb 20.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Problem: Cervical cancer screening strategies in the United States include cotesting (human papillomavirus (HPV) with cytology), primary HPV with genotyping and reflex cytology, and cytology alone. An ongoing challenge is the appropriate triage of patients to colposcopy to those at highest risk. We investigated whether incorporation of p16INK4a immunodetection by enzyme-linked immunosorbent assay (ELISA) on fresh cervical samples obtained at the time of screening could improve appropriate referral to colposcopy.

Method Of Study: A derivation group comprised of cervical swabs collected from subjects with high-grade dysplasia or cancer (positive control) and from subjects with negative screening history (negative control). Samples collected from colposcopy were used to evaluate the existing screening strategies individually and with incorporation of p16INK4a ELISA. Histology was used as the gold standard.

Results: Among 163 subjects recruited, 138 were included. In the derivation group, mean p16INK4a level was 2.86 ng/mL (n = 31) and 0.58 ng/mL (n = 20) among positive and negative controls respectively (p = 0.002) with an area under the receiver operator characteristic curve of 0.79 (p < 0.001). Among colposcopy subjects, sensitivity/specificity for cotesting, primary HPV, and cytology were 94%/42%, 88%/45%, and 88%/49%, respectively. Incorporation of p16INK4a resulted in similar sensitivity and improved specificity (cotesting+p16 88%/58%, primary HPV+p16 88%/57%, cytology+p16 81%/62%; p = 0.23/p = 0.008) with decrease in colposcopy referrals by 15% to 22% (p = 0.01).

Conclusions: These results demonstrate the feasibility of quantifying p16INK4a by ELISA in fresh cervical samples, and its potential as an adjunct to existing screening strategies in the identification of high grade-dysplasia while reducing the number of colposcopic referrals.
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http://dx.doi.org/10.1111/aji.13394DOI Listing
July 2021

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.

Cancer Res 2021 01 6;81(1):158-173. Epub 2020 Nov 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes and demonstrated efficacy , validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878408PMC
January 2021

Distinct microRNA profiles for complete hydatidiform moles at risk of malignant progression.

Am J Obstet Gynecol 2021 04 5;224(4):372.e1-372.e30. Epub 2020 Oct 5.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, New England Trophoblastic Disease Center, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address:

Background: MicroRNAs are small noncoding RNAs with important regulatory functions. Although well-studied in cancer, little is known about the role of microRNAs in premalignant disease. Complete hydatidiform moles are benign forms of gestational trophoblastic disease that progress to gestational trophoblastic neoplasia in up to 20% of cases; however, there is no well-established biomarker that can predict the development of gestational trophoblastic neoplasia.

Objective: This study aimed to investigate possible differences in microRNA expression between complete moles progressing to gestational trophoblastic neoplasia and those regressing after surgical evacuation.

Study Design: Total RNA was extracted from fresh frozen tissues from 39 complete moles collected at the time of uterine evacuation in Brazil. In the study, 39 cases achieved human chorionic gonadotropin normalization without further therapy, and 9 cases developed gestational trophoblastic neoplasia requiring chemotherapy. Total RNA was also extracted from 2 choriocarcinoma cell lines, JEG-3 and JAR, and an immortalized normal placenta cell line, 3A-subE. MicroRNA expression in all samples was quantified using microRNA sequencing. Hits from the sequencing data were validated using a quantitative probe-based assay. Significantly altered microRNAs were then subjected to target prediction and gene ontology analyses to search for alterations in key signaling pathways. Expression of potential microRNA targets was assessed by quantitative real-time polymerase chain reaction and western blot. Finally, potential prognostic protein biomarkers were validated in an independent set of formalin-fixed paraffin-embedded patient samples from the United States (15 complete moles progressing to gestational trophoblastic neoplasia and 12 that spontaneously regressed) using quantitative immunohistochemistry.

Results: In total, 462 microRNAs were identified in all samples at a threshold of <1 tag per million. MicroRNA sequencing revealed a distinct set of microRNAs associated with gestational trophoblastic neoplasia. Gene ontology analysis of the most altered transcripts showed that the leading pathway was related to response to ischemia (P<.001). Here, 2 of the top 3 most significantly altered microRNAs were mir-181b-5p (1.65-fold; adjusted P=.014) and mir-181d-5p (1.85-fold; adjusted P=.014), both of which have been shown to regulate expression of BCL2. By quantitative real-time polymerase chain reaction, BCL2 messenger RNA expression was significantly lower in the complete moles progressing to gestational trophoblastic neoplasia than the regressing complete moles (-4.69-fold; P=.018). Reduced expression of BCL2 was confirmed in tissue samples by western blot. Immunohistochemistry in the independent patient samples revealed significantly lower cytoplasmic expression of BCL2 in the villous trophoblasts from cases destined for progression to gestational trophoblastic neoplasia compared with those that regressed, both with respect to staining intensity (optic density 0.110±0.102 vs 0.212±0.036; P<.001) and to the percentage of positive cells (16%±28% vs 49.4%±28.05%; P=.003).

Conclusion: Complete moles progressing to gestational trophoblastic neoplasia are associated with a distinct microRNA profile. miR-181 family members and BCL2 may be prognostic biomarkers for predicting gestational trophoblastic neoplasia risk.
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http://dx.doi.org/10.1016/j.ajog.2020.09.048DOI Listing
April 2021

Outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia following single-agent chemotherapy.

Gynecol Oncol 2020 12 3;159(3):751-757. Epub 2020 Oct 3.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Dana-Farber Cancer Institute, Boston, MA, United States; New England Trophoblastic Disease Center, Boston, MA, United States. Electronic address:

Objective: To compare outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia (GTN) following single-agent chemotherapy.

Methods: This was a single center retrospective study of low risk GTN. Cases failing to achieve a normal hCG with first-line therapy were defined as chemotherapy resistance. Cases achieving hCG remission, but recurring, were defined as relapse. Primary endpoints were remission rate with second-line therapy and time to remission. Univariate and multivariate analyses were performed to define prognostic factors.

Results: Among 877 low risk GTN patients there were 124 (14.8%) chemotherapy resistant and 22 (2.6%) relapse cases. Complete remission rates with second-line therapy were similar between relapse (77.3%) and resistant (76.6%) cases (p = 0.95), but resistance was associated with a longer time to reach complete remission with second-line therapy (median 8.3 vs 4.9 weeks; p = 0.024). In multivariate analysis, the significant prognostic factors for second-line therapy remission and time to second-line therapy remission were use of multi-agent chemotherapy (OR of 9.45; 95%CI, 2.13-41.97; p = 0.003) and primary chemo-resistance (HR of 0.27; 95%CI, 0.12-0.59; p = 0.001), respectively. With additional therapies, sustained remission rates rose to 90% (18/20) for relapse and 99.2% (120/121) for chemo-resistance (p = 0.053).

Conclusions: Although second-line therapy for resistant or relapsed low risk GTN is able to achieve complete remission in most cases, time to complete remission for relapsed disease was shorter than for resistant disease. Further studies on the biologic differences between resistant and relapsed disease may clarify the optimal treatment for these clinical situations.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.046DOI Listing
December 2020

Uterine artery pulsatility index and serum BMP-9 predict resistance to methotrexate therapy in gestational trophoblastic neoplasia: A cohort study.

Curr Probl Cancer 2021 02 4;45(1):100622. Epub 2020 Aug 4.

Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Campus of Imperial College Healthcare NHS Trust, London, UK; Molecular Oncology, Department of Surgery and Cancer, Hammersmith Hospital Campus of Imperial College London, London, UK.

Background: Methotrexate is the most common first-line chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Uterine artery pulsatility index (UAPI) is an ultrasound marker for tumor vascularity that has been associated with an increased risk of methotrexate resistance. The combination of circulating angiogenic factor levels with UAPI data may improve the capacity of this model to predict chemoresistance.

Methods: This was a single-center cohort study of women newly diagnosed between January 2008 and June 2012 with low-risk GTN during postmolar surveillance and treated with single-agent methotrexate at Charing Cross Hospital, a UK national center for treatment of gestational trophoblastic disease. Two hundred seventeen women underwent an ultrasound for UAPI measurement prior to initiation of chemotherapy. To examine serologic markers of methotrexate resistance among this cohort, we performed a case-control study using archived serum from 76 patients who could be matched based on prognostic risk score. Serum samples were examined by immunoassay to measure 8 different angiogenic factors (VEGF-A, FGF-basic, PLGF-1, PDGF-BB, EGF, ANGPT2, BMP-9, and ENG). Receiver-operator characteristic area under the curve (AUC) values were calculated for the ability of each analyte to correctly classify patients as methotrexate sensitive (MTX-S) or resistant (MTX-R).

Results: Total human chorionic gonadotropin levels were similar between the MTX-S and MTX-R groups. UAPI values were significantly higher in MTX-S (median 1.30 [interquartile range {IQR} = 0.80-1.90]) compared to MTX-R patients (median 0.875 [IQR = 0.60-1.30]; P < 0.0001) with AUC 0.68 (95% confidence interval 0.61-0.76; P < 0.0001). In univariate analysis, only BMP-9 concentrations were significantly different between groups, lower among MTX-S (median of 225 ng/L, IQR = 170-287) compared to MTX-R patients (median 280 ng/L [IQR = 200-339]; P= 0.03). Combining UAPI with BMP-9 concentration improved prediction for chemoresistance with AUC 0.77 (95% confidence interval 0.66-0.88; P < 0.0001).

Conclusion: Circulating levels of BMP-9 are elevated in newly diagnosed women with low-risk GTN destined to fail primary methotrexate therapy. A combined test using serum BMP-9 plus UAPI might improve prediction of MTX-R in low-risk GTN.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100622DOI Listing
February 2021

Association between antioxidant vitamins and oxidative stress among patients with a complete hydatidiform mole.

Clinics (Sao Paulo) 2020 6;75:e1724. Epub 2020 Jul 6.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, New England Trophoblastic Disease Center, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.

Objectives: This study aimed to evaluate the potential relationship between oxidative stress, dietary intake, and serum levels of antioxidants in patients with a complete hydatidiform mole (CHM) compared with controls.

Methods: This was an observational cross-sectional study conducted in Rio de Janeiro, Brazil. A total of 140 women were enrolled in this study and divided into four groups: 43 patients with CHM, 33 women who had had an abortion, 32 healthy pregnant women, and 32 healthy non-pregnant women. All participants underwent blood sampling, assessment using a semiquantitative food frequency questionnaire, and anthropometric measurement. Blood samples were collected after overnight fasting (10-12 h). Vitamin levels (A, C, and E) were determined by ultra-performance liquid chromatography, and gamma-glutamyl transferase levels were assessed using an automated quantitative analysis system (Dimension®, Siemens).

Results: Although all groups showed sufficient serum vitamin A and E levels, the participants had inadequate dietary intake of these vitamins. Conversely, all groups had an insufficient serum level of vitamin C, despite adequate intake. The gamma-glutamyl transferase values did not differ significantly among the groups. However, elevated serum levels of this enzyme were observed in several patients.

Conclusions: All groups exhibited high levels of oxidative stress, as evaluated by gamma-glutamyl transferase levels, and had inadequate intake of antioxidant vitamins. Therefore, the high exposure to oxidative stress found in our study, even in healthy pregnant and non-pregnant women, may increase the incidence of CHM in this region.
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http://dx.doi.org/10.6061/clinics/2020/e1724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330716PMC
September 2020

How to optimize the management of gestational trophoblastic disease during the coronavirus disease era?

Am J Obstet Gynecol 2020 10 29;223(4):604-605. Epub 2020 May 29.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA.

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http://dx.doi.org/10.1016/j.ajog.2020.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256512PMC
October 2020

EMA vs EMACO in the treatment of gestational trophoblastic neoplasia.

Gynecol Oncol 2020 07 11;158(1):99-104. Epub 2020 May 11.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Dana-Farber Cancer Institute, Boston, MA, United States; New England Trophoblastic Disease Center, Boston, MA, United States. Electronic address:

Objective: To compare experiences with EMA versus EMACO in the treatment of gestational trophoblastic neoplasia.

Methods: The medical records of women diagnosed with GTN at the New England Trophoblastic Disease Center from 1986 to 2019 were reviewed, and women receiving EMA or EMACO as their first multiagent regimen were eligible. Clinical characteristics, treatment, outcomes, and adverse events were compared between the two groups.

Results: We identified 44 and 39 patients who received EMA and EMACO, respectively. The complete remission rate was significantly higher in the EMA group (97.7%) than in the EMACO group (71.8%) (p = 0.001). However, patients receiving EMACO were more likely to have adverse prognostic factors such as higher median prognostic risk score (8 vs 4, p < 0.001), non-molar antecedent pregnancy (59 vs 27.3%, p = 0.014) and distant metastasis (64.1 vs 47.7%, p = 0.017). Time to complete remission was also similar (p = 0.947) with a median of 12 weeks with EMA and 13.1 weeks with EMACO. There was no significant difference in treatment delays or use of adjuvant surgery. After multivariate analysis, chemotherapy regimen (EMA or EMACO) did not retain prognostic significance for remission. Overall toxicities were more frequent in EMA (60.2 vs 32.7%, p < 0.001), especially neutropenia, but this did not delay treatment and likely resulted from less growth factor support (18.2 vs 48.7%, p = 0.003).

Conclusions: When controlling for other prognostic factors, outcomes with EMA appear similar to EMACO. It may be worthwhile to investigate whether EMA, a simpler and less costly regimen, may be as effective as EMACO in the treatment of GTN.
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http://dx.doi.org/10.1016/j.ygyno.2020.04.699DOI Listing
July 2020

Gestational trophoblastic neoplasia lethality among Brazilian women: A retrospective national cohort study.

Gynecol Oncol 2020 08 8;158(2):452-459. Epub 2020 May 8.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To investigate GTN lethality among Brazilian women comparing cases of death by GTN with those who survived, thereby identifying factors associated with GTN lethality.

Methods: We retrospectively reviewed medical records of women with GTN treated at ten Brazilian GTN Reference Centers, from January 1960 to December 2017. We evaluated factors associated with death from GTN and used Cox proportional hazards regression models to identify independent variables with significant influence on the risk of death.

Results: From 2186 patients with GTN included in this study, 2092 (95.7%) survived and 89 (4%) died due to GTN. When analyzing the relative risk (RR), adjusted for WHO/FIGO score, patients with low risk disease had a significantly higher risk of death if they had choriocarcinoma (RR: 12.40), metastatic disease (RR: 12.57), chemoresistance (RR: 3.18) or initial treatment outside the Reference Center (RR: 12.22). In relation to patients with high-risk GTN, these factors were significantly associated with death due to GTN: the time between the end of antecedent pregnancy and the initiation of chemotherapy (RR: 4.10), metastatic disease (RR: 14.66), especially in brain (RR: 8.73) and liver (RR: 5.76); absence of chemotherapy or initial treatment with single agent chemotherapy (RR: 10.58 and RR: 1.81, respectively), chemoresistance (RR: 3.20) and the initial treatment outside the Reference Center (RR: 28.30).

Conclusion: The risk of mortality from low and high-risk GTN can be reduced by referral of these patients to a Reference Center or, if not possible, to involve clinicians in a Reference Center with consultation regarding management.
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http://dx.doi.org/10.1016/j.ygyno.2020.04.704DOI Listing
August 2020

Effectiveness and toxicity of second-line actinomycin D in patients with methotrexate-resistant postmolar low-risk gestational trophoblastic neoplasia.

Gynecol Oncol 2020 05 7;157(2):372-378. Epub 2020 Feb 7.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, MA, USA; Harvard Medical School, Boston, MA, USA.

Objectives: The purpose of this study was to evaluate both the outcomes and toxicity of second-line actinomycin D (ActD) chemotherapy in methotrexate (MTX) - resistant low-risk postmolar gestational trophoblastic neoplasia (GTN) with 5-day ActD versus pulsed ActD.

Methods: This retrospective cohort study included patients with MTX-resistant low-risk postmolar GTN from 1974 to 2016. Second-line chemotherapy consisted of 5-day ActD (10-12 μg/kg per day for 5 days every 14 days) or biweekly ActD (1.25 mg/m every 2 weeks). Data on patient characteristics, disease presentation, treatment outcome, and toxicity were collected.

Results: Sixty-eight MTX-resistant patients receiving ActD as second-line chemotherapy were identified (5-day ActD, 53 patients; pulsed ActD, 15 patients). No significant differences were observed in patient/disease characteristics and sustained remission (overall rate 72%) between second-line ActD regimens. Time to hCG remission was significantly faster (median 21 vs 47 days, p = .04) and required fewer treatment cycles (median 1 vs 2, p < .001) with 5-day ActD. Thrombocytopenia was only observed with 5-day ActD (64.6 vs 0%, p < .001). The frequency (60.4 vs 16.7%, p = .009) and severity (grade 3: 37.9 vs 0%, p = .045) of oral mucositis was significantly higher with 5-day ActD. Grade 2 alopecia was significantly more frequent (70.6 vs 16.7%, p = .02) with 5-day ActD.

Conclusions: While 5-day ActD and pulsed ActD achieve comparable remission rates, due to its reduced toxicity, ease of administration, and patient convenience, pulsed ActD should be the treatment of choice for MTX-resistant postmolar low-risk GTN.
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http://dx.doi.org/10.1016/j.ygyno.2020.02.001DOI Listing
May 2020

Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.

Gynecol Oncol 2020 03 10;156(3):598-605. Epub 2020 Jan 10.

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To compare the outcomes of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with standard 8-day methotrexate/folinic acid (MTX/FA) versus modified regimen.

Methods: Retrospective cohort study of patients with low-risk GTN followed at Rio de Janeiro Federal University, from January/1990-December/2017 with standard 8-day MTX/FA or modified regimen (MTX administered on the 8th day rather than 7th) to avoid treatment on the weekend.

Results: From 937 patients with low-risk GTN, 538 were treated with standard MTX/FA and 98 patients received modified regimen. Both groups were comparable in age (p = .749), antecedent pregnancy (p = .221), time to initiate chemotherapy (p = .926), hCG pretreatment level (p = .112) and WHO/FIGO prognostic risk score (p = .723). Patients treated with modified MTX/FA had twice of cases of metastatic lung disease compared with the standard regimen (22.5% vs 10.6%; p = .002). The rate of remission (p = .999), number of cycles to remission in the first-line (p = .966), chemoresistance (p = .500), time to switch to second-line therapy (p = .176), need for multiagent chemotherapy (p = .084), relapse (p = .122) or death (p = .475) was the same for both MTX/FA regimen. However, although patients receiving modified MTX/FA required a higher total number of remission cycles (6 vs 5 cycles; p = .004) and longer time to remission (19 vs 16 weeks; p < .001) when compared with the standard regimen, these variables showed no significant differences after multivariate logistic regression adjusted for lung metastasis.

Conclusion: The modified 8-day MTX/FA regimen didn't compromise oncologic outcomes for women with low-risk GTN. This regimen appears to be an acceptable alternative to standard 8-day MTX/FA when treatment on weekend isn't an option.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.044DOI Listing
March 2020

Considering Changes in the Recommended Human Chorionic Gonadotropin Monitoring After Molar Evacuation.

Obstet Gynecol 2020 01;135(1):9-11

From the New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; email:

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http://dx.doi.org/10.1097/AOG.0000000000003625DOI Listing
January 2020

State-of-the-Art Workup and Initial Management of Newly Diagnosed Molar Pregnancy and Postmolar Gestational Trophoblastic Neoplasia.

J Natl Compr Canc Netw 2019 11;17(11):1396-1401

Gestational trophoblastic disease refers to a series of interrelated tumors arising from the placenta, including benign molar pregnancies as well as the malignant conditions termed gestational trophoblastic neoplasia (GTN). GTN most commonly follows a molar pregnancy but may develop after any gestation. The wide availability of first trimester ultrasound and serum human chorionic gonadotropin (hCG) measurement has changed the presentation of molar pregnancy in recent decades from a second trimester to a first trimester disease, such that most patients have few symptoms at diagnosis. With identification of molar pregnancy at earlier gestations, accurate diagnosis increasingly relies on expert histopathology coupled with ancillary molecular and genetic techniques. However, earlier diagnosis has not changed the risk of postmolar GTN. Although most molar pregnancies are treated with dilation and curettage, hysterectomy may be appropriate in select cases when future fertility is not desired. After treatment of molar pregnancy, close surveillance with serial hCG monitoring is essential to diagnose GTN and identify the need for chemotherapy. Physicians following hCG levels should understand the performance characteristics of the test, including common causes of false-positive and false-negative results. After a diagnosis of postmolar GTN is made, selection of single-agent or multiagent chemotherapy depends on accurate assignment of the clinical stage and risk stratification by the International Federation of Gynecology and Obstetrics (FIGO) prognostic scoring system. Surgical treatment of postmolar low-risk GTN, including both second uterine curettage and hysterectomy, may decrease subsequent need for or duration of chemotherapy. Cure rates for postmolar low-risk GTN approach 100%, and subsequent pregnancy outcomes for patients reflect those of the general population.
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http://dx.doi.org/10.6004/jnccn.2019.7364DOI Listing
November 2019

Continued hCG surveillance following chemotherapy for gestational trophoblastic neoplasia: When is enough enough?

Gynecol Oncol 2019 10;155(1):1-2

New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115 USA.

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http://dx.doi.org/10.1016/j.ygyno.2019.09.006DOI Listing
October 2019

Defining fallopian tube-derived miRNA cancer signatures.

Cancer Med 2019 11 10;8(15):6709-6716. Epub 2019 Sep 10.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: MicroRNAs have recently emerged as promising circulating biomarkers in diverse cancer types, including ovarian cancer. We utilized conditional, doxycycline-induced fallopian tube (FT)-derived cancer models to identify changes in miRNA expression in tumors and plasma, and further validated the murine findings in high-grade ovarian cancer patient samples.

Methods: We analyzed 566 biologically informative miRNAs in doxycycline-induced FT and metastatic tumors as well as plasma samples derived from murine models bearing inactivation of Brca, Tp53, and Pten genes. We identified miRNAs that showed a consistent pattern of dysregulated expression and validated our results in human patient serum samples.

Results: We identified six miRNAs that were significantly dysregulated in doxycycline-induced FTs (P < .05) and 130 miRNAs differentially regulated in metastases compared to normal fallopian tissues (P < .05). Furthermore, we validated miR-21a-5p, miR-146a-5p, and miR-126a-3p as dysregulated in both murine doxycycline-induced FT and metastatic tumors, as well as in murine plasma and patient serum samples.

Conclusions: In summary, we identified changes in miRNA expression that potentially accompany tumor development in murine models driven by commonly found genetic alterations in cancer patients. Further studies are required to test both the function of these miRNAs in driving the disease and their utility as potential biomarkers for diagnosis and/or disease progression.
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http://dx.doi.org/10.1002/cam4.2416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825987PMC
November 2019

Educating healthcare providers to increase Human Papillomavirus (HPV) vaccination rates: A Qualitative Systematic Review.

Vaccine X 2019 Dec 5;3:100037. Epub 2019 Aug 5.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States.

Objectives: HPV vaccination rates in the United States lag behind other developed countries. Educational interventions are primarily directed at patients and parents rather than healthcare providers (HCPs), despite evidence that provider recommendation is a key determinant of vaccine uptake. The objectives for this review are to synthesize the available evidence related to the knowledge, attitudes, and beliefs of HCPs surrounding HPV vaccination, to summarize provider-specific educational interventions which have been evaluated, and to review existing provider-specific educational resources from national organizations and whether they align with the gaps identified.

Methods: A systematic search was performed using PubMed, Web of Science, CINAHL, and ERIC with MeSH terms human papillomavirus, vaccine, education, workshop, training, knowledge, attitude, belief, intention, and healthcare provider. Full text articles were obtained for studies that described the knowledge and attitudes of providers and/or impact of educational interventions. Data extraction was performed by four independent reviewers. Websites of American organizations with an interest in HPV vaccination were manually searched for provider resources.

Results: 1066 publications were identified, and 98 articles were fully reviewed with 40 ultimately included. Providers' knowledge on HPV was generally low with a correspondingly low vaccine recommendation rate. Provider-specific education (e.g., didactic session and communication training) with complimentary interventions demonstrated increased knowledge and vaccine series initiation and completion. Themes identified in descriptive studies highlighted providers' lack of general HPV and vaccine knowledge, low self-confidence in counselling and addressing parental concerns, and discomfort in discussing sexual issues related to vaccination. Many American organizations have provider-specific resources; however, the effectiveness of these materials has not been established.

Conclusions: HPV knowledge among providers remains low. Educational interventions to improve knowledge and communication appear to be effective. A breadth of resources from national organizations are available but their efficacy and level of utilization is largely unknown. Coordinated efforts are needed to evaluate provider-specific educational resources to improve vaccine uptake in the US.
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http://dx.doi.org/10.1016/j.jvacx.2019.100037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708991PMC
December 2019

Racial disparities in brachytherapy administration and survival in women with locally advanced cervical cancer.

Gynecol Oncol 2019 09 7;154(3):595-601. Epub 2019 Jul 7.

Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States of America; Dana-Farber Cancer Institute, Boston, MA, United States of America. Electronic address:

Objective: Black women have the highest incidence and mortality from cervical cancer in the United States. This study evaluated whether racial disparities in the receipt of brachytherapy (BT) for locally advanced cervical cancer mediate survival differences by race using the National Cancer Database.

Methods: A retrospective cohort study was performed using 16,116 women with stage IB2-IVA cervical cancer treated from 2004 to 2014. Women who did not receive external beam radiation therapy, those with unknown survival data or stage, and those status post hysterectomy or pelvic exenteration were excluded. Multivariate logistic regression was performed to evaluate factors associated with BT use. Using a propensity score adjusted model with inverse probability treatment weighting, adjusted hazard ratios for overall survival were calculated, including an interaction term between BT and race.

Results: Of 16,116 patients, 19.2% were black and 55.8% received BT. Black women were significantly less likely to receive BT (AOR 0.87, 95% confidence interval [CI] 0.79-0.96, p = 0.007) and had worse all-cause mortality (median survival 3.9 years [95% CI 3.6-4.6] versus 5.2 years [95% CI 4.9-5.5] for non-black women, p < 0.001). In the adjusted model, black patients had an increased risk of death compared to non-black patients (AHR 1.14, 95% CI 1.05-1.24; p = 0.002) among women who did not receive BT. However, there was no difference in survival by race when both groups received BT (AHR 1.04, 95% CI 0.95-1.13, p = 0.42; p-interaction = 0.005).

Conclusions: Black women with locally advanced cervical cancer are less likely to receive brachytherapy, which mediates survival differences by race. Improving access to brachytherapy may improve overall survival.
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http://dx.doi.org/10.1016/j.ygyno.2019.06.022DOI Listing
September 2019

Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

Bioeng Transl Med 2019 May 14;4(2):e10131. Epub 2019 Jun 14.

The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology (MIT) Cambridge MA, 02142.

Advanced staged high-grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5-year survival rates of only 25-30% due to late-stage diagnosis and the shortcomings of platinum-based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP-ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum-based therapy by developing a targeted delivery approach. Novel electrostatic layer-by-layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP-encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44-expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half-life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.
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http://dx.doi.org/10.1002/btm2.10131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584097PMC
May 2019

International validation of Enhanced Recovery After Surgery Society guidelines on enhanced recovery for gynecologic surgery.

Am J Obstet Gynecol 2019 09 30;221(3):237.e1-237.e11. Epub 2019 Apr 30.

Division of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada.

Background: Enhanced Recovery After Surgery Society publishes guidelines on perioperative care, but these guidelines should be validated prospectively.

Objective: To evaluate the association between compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guideline elements and postoperative outcomes in an international cohort.

Study Design: The study comprised 2101 patients undergoing elective gynecologic/oncology surgery between January 2011 and November 2017 in 10 hospitals across Canada, the United States, and Europe. Patient demographics, surgical/anesthesia details, and Enhanced Recovery After Surgery protocol compliance elements (pre-, intra-, and postoperative phases) were entered into the Enhanced Recovery After Surgery Interactive Audit System. Surgical complexity was stratified according to the Aletti scoring system (low vs medium/high). The following covariates were accounted for in the analysis: age, body mass index, smoking status, presence of diabetes, American Society of Anesthesiologists class, International Federation of Gynecology and Obstetrics stage, preoperative chemotherapy, radiotherapy, operating time, surgical approach (open vs minimally invasive), intraoperative blood loss, hospital, and Enhanced Recovery After Surgery implementation status. The primary end points were primary hospital length of stay and complications. Negative binomial regression was used to model length of stay, and logistic regression to model complications, as a function of compliance score and covariates.

Results: Patient demographics included a median age 56 years, 35.5% obese, 15% smokers, and 26.7% American Society of Anesthesiologists Class III-IV. Final diagnosis was malignant in 49% of patients. Laparotomy was used in 75.9% of cases, and the remainder minimally invasive surgery. The majority of cases (86%) were of low complexity (Aletti score ≤3). In patients with ovarian cancer, 69.5% had a medium/high complexity surgery (Aletti score 4-11). Median length of stay was 2 days in the low- and 5 days in the medium/high-complexity group. Every unit increase in Enhanced Recovery After Surgery guideline score was associated with 8% (IRR, 0.92; 95% confidence interval, 0.90-0.95; P<.001) decrease in days in hospital among low-complexity, and 12% (IRR, 0.88; 95% confidence interval, 0.82-0.93; P<.001) decrease among patients with medium/high-complexity scores. For every unit increase in Enhanced Recovery After Surgery guideline score, the odds of total complications were estimated to be 12% lower (P<.05) among low-complexity patients.

Conclusion: Audit of surgical practices demonstrates that improved compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guidelines is associated with an improvement in clinical outcomes, including length of stay, highlighting the importance of Enhanced Recovery After Surgery implementation.
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http://dx.doi.org/10.1016/j.ajog.2019.04.028DOI Listing
September 2019

Liquid biopsy of HPV DNA in cervical cancer.

J Clin Virol 2019 05 12;114:32-36. Epub 2019 Mar 12.

Department of Microbiology, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Background: A blood test to serve as a tumor marker for cervical cancer would be useful to clinicians to guide treatment and provide an early signal for recurrence. The development of droplet digital PCR has enabled the detection of HPV DNA in patient serum, providing a potential marker for cervical cancer.

Objectives: To report on a blood-based test for HPV-specific E7 and L1 genes, which may serve as a tumor marker to guide treatment and detect early recurrence in cervical cancer.

Study Design: Pre-treatment plasma samples were investigated from 138 Hong Kong Chinese women with primary invasive squamous cell carcinoma and adenocarcinoma of the cervix with tumor samples expressing HPV16 or HPV18. Two genes specific to the human papillomavirus, E7 and L1, were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. Analysis of detectable E7 and L1 levels was performed to investigate the potential of liquid biopsy of E7 and L1 as a clinically useful molecular biomarker.

Results: The majority of patients had HPV16 (71.7%), squamous cell carcinoma (78.3%) and stage IB-II disease (82.6%). HPV E7 and L1 sequences were detected in plasma cfDNA from 61.6% (85/138) of patients. Patients with high viral load (defined as ≥20 E7 or L1 copies per 20 μL reaction volume) had increased risk of recurrence and death at 5 years on univariate analysis but not multivariate analysis.

Conclusions: HPV DNA can be quantitatively detected with the use of cfDNA. This has the potential to provide a clinically useful tumor marker for patients with cervical cancer that can aid in post-treatment surveillance and estimating the risk of disease relapse.
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http://dx.doi.org/10.1016/j.jcv.2019.03.005DOI Listing
May 2019
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