Publications by authors named "Ross S Berkowitz"

226 Publications

Impact of clinical characteristics on human chorionic gonadotropin regression after molar pregnancy.

Clinics (Sao Paulo) 2021 27;76:e2830. Epub 2021 Aug 27.

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

Objectives: This study aimed to determine the effects of age, race/ethnicity, body mass index, and contraception on human chorionic gonadotropin (hCG) regression following the evacuation of a molar pregnancy.

Methods: This was a retrospective cohort study of 277 patients with molar pregnancies between January 1, 1994 and December 31, 2015. The rate of hCG regression was estimated using mixed-effects linear regression models on daily log-transformed serum hCG levels after evacuation.

Results: There were no differences in hCG half-lives among age (p=0.13) or race/ethnicity (p=0.16) groups. Women with obesity and hormonal contraceptive use demonstrated faster hCG regression than their counterparts (3.2 versus. 3.7 days, p=0.02 and 3.4 versus. 4.0 days, p=0.002, respectively).

Conclusion: Age and race/ethnicity were not associated with hCG regression rates. Hormonal contraceptive use and obesity were associated with shorter hCG half-lives, but with unlikely clinical significance. It is important to understand whether the clinical characteristics of patients may influence the hCG regression curve, as it has been proposed as a way to predict the risk of gestational trophoblastic neoplasia.
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http://dx.doi.org/10.6061/clinics/2021/e2830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366901PMC
August 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

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.

Cancers (Basel) 2021 May 3;13(9). Epub 2021 May 3.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of mutations in UC. We functionally profiled targetable dependent DNA damage repair and cell cycle control pathways in a panel of mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
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http://dx.doi.org/10.3390/cancers13092195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125555PMC
May 2021

Disease Distribution at Presentation Impacts Benefit of IP Chemotherapy Among Patients with Advanced-Stage Ovarian Cancer.

Ann Surg Oncol 2021 Mar 8. Epub 2021 Mar 8.

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

Background: Ovarian cancer with miliary disease spread is an aggressive phenotype lacking targeted management strategies. We sought to determine whether adjuvant intravenous/intraperitoneal (IV/IP) chemotherapy is beneficial in this disease setting.

Methods: Patient/tumor characteristics and survival data of patients with stage IIIC epithelial ovarian cancer who underwent optimal primary debulking surgery from 01/2010 to 11/2014 were abstracted from records. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables. The Kaplan-Meier method was used to estimate survival curves, and outcomes were compared using log-rank tests. Factors significant on univariate analysis were combined into multivariate logistic regression survival models.

Results: Among 90 patients with miliary disease spread, 41 (46%) received IV/IP chemotherapy and 49 (54%) received IV chemotherapy. IV/IP chemotherapy, compared with IV chemotherapy, resulted in improved progression-free survival (PFS; 23.0 versus 12.0 months; p = 0.0002) and overall survival (OS; 52 versus 36 months; p = 0.002) in patients with miliary disease. Among 78 patients with nonmiliary disease spread, 23 (29%) underwent IV/IP chemotherapy and 55 (71%) underwent IV chemotherapy. There was no PFS or OS benefit associated with IV/IP chemotherapy over IV chemotherapy in these patients. On multivariate analysis, IV/IP chemotherapy was associated with improved PFS (HR, 0.28; 95% CI 0.15-0.53) and OS (HR, 0.33; 95% CI 0.18-0.61) in patients with miliary disease compared with those with nonmiliary disease (PFS [HR, 1.53; 95% CI 0.74-3.19]; OS [HR, 1.47; 95% CI 0.70-3.09]).

Conclusions: Adjuvant IV/IP chemotherapy was associated with oncologic benefit in miliary disease spread. This survival benefit was not observed in nonmiliary disease.
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http://dx.doi.org/10.1245/s10434-021-09746-wDOI Listing
March 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

Characterization of miR-200 family members as blood biomarkers for human and laying hen ovarian cancer.

Sci Rep 2020 11 18;10(1):20071. Epub 2020 Nov 18.

Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. We evaluated the levels of family members relative to the internal control miR-103a in ovarian cancer and control blood specimens collected from American and Hong Kong Chinese institutions, as well as from a laying hen spontaneous ovarian cancer model. The levels of miR-200a, miR-200b and miR-200c were significantly elevated in all human cancer versus all control blood samples. Further analyses showed significantly higher miR-200 levels in Chinese control (except miR-429) and cancer (except miR-200a and miR141) samples than their respective American counterparts. Subtype-specific analysis showed that miR-200b had an overall elevated level in serous cancer compared with controls, whereas miR-429 was significantly elevated in clear cell and endometrioid cancer versus controls. MiR-429 was also significantly elevated in cancer versus control in laying hen plasma samples, consistent with the fact that endometrioid tumor is the prevalent type in this species. A neural network model consisting of miR-200a/200b/429/141 showed an area under the curve (AUC) value of 0.904 for American ovarian cancer prediction, whereas a model consisting of miR-200b/200c/429/141 showed an AUC value of 0.901 for Chinese women. Hence, miR-200 is informative as blood biomarkers for both human and laying hen ovarian cancer.
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http://dx.doi.org/10.1038/s41598-020-77068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674435PMC
November 2020

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

MicroRNA-200 family governs ovarian inclusion cyst formation and mode of ovarian cancer spread.

Oncogene 2020 05 25;39(20):4045-4060. Epub 2020 Mar 25.

Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Epidemiologic and histopathologic findings and the laying hen model support the long-standing incessant ovulation hypothesis and cortical inclusion cyst involvement in sporadic ovarian cancer development. MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. Herewith, we show that ovarian surface epithelial (OSE) cells with ectopic miR-200 expression formed stabilized cysts in three-dimensional (3D) organotypic culture with E-cadherin fragment expression and steroid hormone pathway activation, whereas ovarian cancer 3D cultures with miR-200 knockdown showed elevated TGF-β expression, mitotic spindle disorientation, increased lumenization, disruption of ROCK-mediated myosin II phosphorylation, and SRC signaling, which led to histotype-dependent loss of collective movement in tumor spread. Gene expression profiling revealed that epithelial-mesenchymal transition and hypoxia were the top enriched gene sets regulated by miR-200 in both OSE and ovarian cancer cells. The molecular changes uncovered by the in vitro studies were verified in both human and laying hen ovarian cysts and tumor specimens. As miR-200 is also essential for ovulation, our results of estrogen pathway activation in miR-200-expressing OSE cells add another intriguing link between incessant ovulation and ovarian carcinogenesis.
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http://dx.doi.org/10.1038/s41388-020-1264-xDOI Listing
May 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

A novel classification of residual disease after interval debulking surgery for advanced-stage ovarian cancer to better distinguish oncologic outcome.

Am J Obstet Gynecol 2019 10 10;221(4):326.e1-326.e7. Epub 2019 May 10.

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

Background: Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease.

Objective: To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes.

Study Design: Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated.

Results: Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001).

Conclusion: Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.
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http://dx.doi.org/10.1016/j.ajog.2019.05.006DOI Listing
October 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

Can carboplatin or etoposide replace actinomycin-d for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia?

Gynecol Oncol 2019 05 8;153(2):277-285. Epub 2019 Mar 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 evaluate the impact of periodic shortage of actinomycin-d (Act-d) in the treatment of Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN) after methotrexate and folinic acid rescue (MTX/FA) resistance, treated alternately with carboplatin or etoposide as a second-line regimen.

Methods: Retrospective cohort that included patients with failure of first-line MTX/FA regimen for low-risk GTN treated at Rio de Janeiro Federal University, Universidade Federal de São Paulo and Irmandade da Santa Casa de Misericórdia de Porto Alegre, from January/2010- December/2017.

Results: From 356 patients with low-risk GTN treated with MTX/FA, 75 (21.1%) developed resistance, of which 40 (53.3%) received Act-d, 23 (30.7%) carboplatin and 7 (9.3%) etoposide. Although patients treated with single-agent chemotherapy as a second-line regimen had comparable clinical and primary treatment characteristics, those treated with Act-d (80%, p = 0.033) or etoposide (71.4%, p = 0.025) had higher remission rates when compared with carboplatin (47.8%). Only 29% of patients treated with carboplatin received the chemotherapy cycles without delay compared to Act-d (98%, p < 0.001) or etoposide (85%, p = 0.009). Patients treated with carboplatin had significantly more hematological toxicity, notably anemia (30.4%, p = 0.008), lymphopenia (47.7%, p < 0.001) and thrombocytopenia (43.4%, p < 0.001), as well as a higher occurrence of febrile neutropenia (14.4%, p = 0.044) and vomiting (60%, p < 0.001) than those receiving Act-d (5%, none, 2.5%, none, 10%, respectively).

Conclusion: Carboplatin did not have a satisfactory clinical response rate, likely due to severe hematological toxicity, which postponed chemotherapy. Our results reinforce the preference for Act-d as a second-line agent in patients with low-risk GTN after MTX/FA resistance.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.005DOI Listing
May 2019

Infection, thrombosis, and oncologic outcome after interval debulking surgery: Does perioperative blood transfusion matter?

Gynecol Oncol 2019 04 8;153(1):63-67. Epub 2019 Jan 8.

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

Objectives: To determine whether perioperative red blood cell transfusion (PRBCT) affects infection, thrombosis, or survival rates in epithelial ovarian cancer (EOC) patients undergoing neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS).

Methods: Demographics, operative characteristics, and outcome data were abstracted from records of stage IIIC-IV EOC patients managed with NACT-IDS from 01/2010-07/2015. Associations of PRBCT with morbidity and oncologic outcomes were evaluated.

Results: Of 270 patients, 136 (50.4%) received PRBCT. Patients with preoperative anemia and higher estimated blood loss (EBL) were more likely to undergo PRBCT (OR,95%CI 1.80, 1.02-3.17) and (OR,95%CI 1.00, 1.002-1.004), respectively. There were no significant differences in PRBCT based on patient age, Charlson Comorbidity Index, or stage. When compared to low complexity operations, patients with moderate and high complexity surgeries were more likely to receive PRBCT (OR,95%CI 1.81, 1.05-3.09) and (OR,95%CI 2.25, 1.13-4.50), respectively. On univariate analysis, PRBCT was associated with intraabdominal infection (OR,95%CI 8.31, 1.03-67.41), but not wound complications (OR,95%CI 1.57, 0.76-3.23) or venous thromboembolism/pulmonary embolism (VTE/PE) (OR,95%CI 2.02, 0.49-8.23). After adjusting for surgical complexity and preoperative anemia, PRBCT was not independently associated with intraabdominal infection (OR,95%CI 7.66, 0.92-63.66), wound complications (OR,95%CI 1.70, 0.80-3.64), or VTE/PE (OR,95%CI 2.15, 0.51-9.09). When comparing patients undergoing PRBCT versus those who did not, there were no significant differences in median progression-free survival (PFS) or median overall survival (OS) on univariate analysis after adjusting for age, stage and residual disease.

Conclusions: Among patients undergoing NACT-IDS, intraabdominal infection, wound complication and VTE/PE rates are similar, regardless of PRBCT. PRBCT does not impact PFS or OS.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.001DOI Listing
April 2019
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