Publications by authors named "Lawrence H Lin"

13 Publications

  • Page 1 of 1

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

Fetal-Maternal Hemorrhage in First-Trimester Intrauterine Hematoma.

Fetal Diagn Ther 2021 11;48(3):227-234. Epub 2021 Mar 11.

Department of Obstetrics and Gynecology/Faculdade de Medicina FMUSP/Universidade de Sao Paulo, Sao Paulo, Brazil,

Objective: The objective of this study was to compare the frequency and percentage of fetal hemoglobin (HbF%) by flow cytometry of (1) first-trimester asymptomatic patients with intrauterine hematoma (IUH), (2) first-trimester pregnant patients with vaginal bleeding (VB), and (3) first-trimester asymptomatic pregnant women without hematoma.

Methods: Prospective study involving pregnant women in the first trimester of pregnancy. Patients with ultrasound findings of asymptomatic hematoma and with VB were paired with asymptomatic pregnant women of same gestational age without hematoma (control group [CG]). Maternal blood HbF% was evaluated by flow cytometry. The groups were compared in terms of circulating fetal hemoglobin and HbF%.

Results: Sixty-six patients were selected, 22 with hematoma, 17 with bleeding, and 27 in the CG. Fetal hemoglobin was detected in 15 patients with hematoma (68.2%) and 13 with bleeding (76.5%) and in 20 of the control (74.1%) (p = 0.830). The mean HbF% of each group was 0.054, 0.012, and 0.042 for hematoma, bleeding, and control, respectively, and differences were not significant (p = 0.141). There was a moderate negative correlation between the volume of hematoma and HbF% (rSpearman = -0.527; p = 0.012).

Conclusions: The fetal-maternal hemorrhage expressed by Hbf% in first-trimester pregnancies did not seem to differ between patients with and without ultrasound findings of IUH.
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http://dx.doi.org/10.1159/000513747DOI Listing
March 2021

Analytical performance of lateral flow immunoassay for SARS-CoV-2 exposure screening on venous and capillary blood samples.

J Immunol Methods 2021 02 7;489:112909. Epub 2020 Nov 7.

Department of Pathology, NYU Langone Health, New York City, NY, United States of America. Electronic address:

Objectives: We validate the use of a lateral flow immunoassay (LFI) intended for rapid screening and qualitative detection of anti-SARS-CoV-2 IgM and IgG in serum, plasma, and whole blood, and compare results with ELISA. We also seek to establish the value of LFI testing on blood obtained from a capillary blood sample.

Methods: Samples collected by venous blood draw and finger stick were obtained from patients with SARS-CoV-2 detected by RT-qPCR and control patients. Samples were tested with Biolidics 2019-nCoV IgG/IgM Detection Kit lateral flow immunoassay, and antibody calls were compared with ELISA.

Results: Biolidics LFI showed clinical sensitivity of 92% with venous blood at 7 days after PCR diagnosis of SARS-CoV-2. Test specificity was 92% for IgM and 100% for IgG. There was no significant difference in detecting IgM and IgG with Biolidics LFI and ELISA at D0 and D7 (p = 1.00), except for detection of IgM at D7 (p = 0.04). Capillary blood of SARS-CoV-2 patients showed 93% sensitivity for antibody detection.

Conclusions: Clinical performance of Biolidics 2019-nCoV IgG/IgM Detection Kit is comparable to ELISA and was consistent across sample types. This provides an opportunity for decentralized rapid testing and may allow point-of-care and longitudinal self-testing for the presence of anti-SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1016/j.jim.2020.112909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647890PMC
February 2021

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City region.

Genome Res 2020 12 22;30(12):1781-1788. Epub 2020 Oct 22.

Department of Pathology, NYU Grossman School of Medicine, New York, New York 10016, USA.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.
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http://dx.doi.org/10.1101/gr.266676.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706732PMC
December 2020

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

Investigating the spectrum of dermatologic manifestations in COVID-19 infection in severely ill patients: A series of four cases.

J Cutan Pathol 2021 Jan 28;48(1):110-115. Epub 2020 Sep 28.

Department of Pathology, New York University Langone Health, New York, New York, USA.

COVID-19, an infectious disease caused by the novel coronavirus, was initially identified in Wuhan, China, in December 2019. By March 2020, it was declared a pandemic by the World Health Organization. Although most findings have been reported in the lungs, primarily due to catastrophic respiratory decline, other organs, including the skin, are affected. Recent reports have been published describing the clinical spectrum of COVID-19-related lesions. In addition, recent case series have described a subset of these lesions having underlying thrombotic microangiopathy with increased complement activation characterized by increased C4d deposition within the blood vessel walls. Herein, we describe a series of COVID-19-related cutaneous manifestations found at autopsy examination and their underlying histopathologic findings. Although the clinical manifestations seen in these lesions vary widely, the underlying etiology of thrombotic microangiopathy remains consistent and reproducible.
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http://dx.doi.org/10.1111/cup.13867DOI Listing
January 2021

Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease.

Circ Res 2020 09 6;127(7):945-947. Epub 2020 Aug 6.

Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478197PMC
September 2020

Association of Initial Viral Load in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Patients with Outcome and Symptoms.

Am J Pathol 2020 09 3;190(9):1881-1887. Epub 2020 Jul 3.

Department of Pathology, NYU Langone Health, New York, New York; Department of Dermatology, NYU Langone Health, New York, New York. Electronic address:

The dynamics of viral load (VL) of the severe acute respiratory syndrome coronavirus 2 and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of oxygen support, and overall survival in 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization. Associations were tested with univariate and multivariate regression models. Diagnostic VL was significantly lower in hospitalized patients than in patients not hospitalized (log10 VL = 3.3 versus 4.0; P = 0.018) after adjusting for age, sex, race, body mass index, and comorbidities. Higher VL was associated with shorter duration of the symptoms in all patients and hospitalized patients only and shorter hospital stay (coefficient = -2.02, -2.61, and -2.18; P < 0.001, P = 0.002, and P = 0.013, respectively). No significant association was noted between VL, admission to intensive care unit, length of oxygen support, and overall survival. Our findings suggest a higher shedding risk in less symptomatic patients, an important consideration for containment strategies. Furthermore, we identify a novel association between VL and history of cancer. Larger studies are warranted to validate our findings.
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http://dx.doi.org/10.1016/j.ajpath.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332909PMC
September 2020

Sequencing identifies multiple, early introductions of SARS-CoV2 to New York City Region.

medRxiv 2020 Apr 21. Epub 2020 Apr 21.

Department of Pathology, NYU Grossman School of Medicine, New York, USA.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 236 SARS-CoV2 sequences from cases in the New York City metropolitan area during the initial stages of the 2020 COVID-19 outbreak. The majority of cases throughout the region had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that the majority were most related to cases from Europe. Our data are consistent with numerous seed transmissions from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of real-time genomic surveillance in addition to traditional epidemiological indicators.
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http://dx.doi.org/10.1101/2020.04.15.20064931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276014PMC
April 2020

Is chemotherapy always necessary for patients with nonmetastatic gestational trophoblastic neoplasia with histopathological diagnosis of choriocarcinoma?

Gynecol Oncol 2018 02 13;148(2):239-246. Epub 2017 Dec 13.

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

Objective: To evaluate expectant management versus immediate chemotherapy following pathological diagnosis of gestational choriocarcinoma (GCC) in patients with nonmetastatic disease.

Methods: Multicenter retrospective cohort that included patients with histological diagnosis of GCC with nonmetastatic disease followed at one of thirteen Brazilian referral centers for gestational trophoblastic disease from January 2000 to December 2016.

Results: Among 3191 patients with gestational trophoblastic neoplasia, 199 patients with nonmetastatic GCC were identified. Chemotherapy was initiated immediately in 152 (76.4%) patients per FIGO 2000 guideline, while 47 (23.6%) were managed expectantly. Both groups presented with similar characteristics and outcomes. All patients (n=12) who had normal human chorionic gonadotropin (hCG) in the first 2-3weeks of expectant management achieved complete sustained remission with no chemotherapy. Only 44.7% (21 patients) of patients who were expectantly managed needed to receive chemotherapy due to plateauing or rising hCG level in the first 2-3weeks of follow up. The outcome of patients receiving chemotherapy after initial expectant management was similar to those who received chemotherapy immediately after the diagnosis in terms of need for multi-agent chemotherapy or number of cycles of chemotherapy. There was no case of relapse or death in either group. Logistic regression analysis showed that age≥40years and hCG≥92,428IU/L at GCC diagnosis were risk factors for needing chemotherapy after initial expectant management of nonmetastatic GCC.

Conclusion: In order to avoid exposing patients unnecessarily to chemotherapy, close surveillance of women with pathological diagnosis of nonmetastatic GCC seems to be a safe practice, particularly for those who have a normal hCG at the time of diagnosis. If confirmed by other studies, the FIGO guidelines may need to be revised.
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http://dx.doi.org/10.1016/j.ygyno.2017.12.007DOI Listing
February 2018

Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review.

Gynecol Oncol 2017 Apr 26;145(1):88-95. Epub 2017 Jan 26.

New England Trophoblastic Disease Center, Donald P. Goldstein MD, Trophoblastic Tumor Registry, Boston, MA, USA; Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA; Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA. Electronic address:

Objective: To determine the clinical characteristics of multiple gestation with complete mole and coexisting fetus (CHMCF) in North and South America.

Methods: Retrospective non-concurrent cohorts compromised of CHMCF from New England Trophoblastic Disease Center (NETDC) (1966-2015) and four Brazilian Trophoblastic Disease Centers (BTDC) (1990-2015).

Results: From a total of 12,455 cases of gestational trophoblastic disease seen, 72 CHMCF were identified. Clinical characteristics were similar between BTDC (n=46) and NETDC (n=13) from 1990 to 2015, apart from a much higher frequency of potentially life-threatening conditions in Brazil (p=0.046). There were no significant changes in the clinical presentation or outcomes over the past 5 decades in NETDC (13 cases in 1966-1989 vs 13 cases in 1990-2015). Ten pregnancies were electively terminated and 35 cases resulted in viable live births (60% of 60 continued pregnancies). The overall rate of gestational trophoblastic neoplasia (GTN) was 46%; the cases which progressed to GTN presented with higher chorionic gonadotropin levels (p=0.026) and higher frequency of termination of pregnancy due to medical complications (p=0.006) when compared to those with spontaneous remission.

Conclusions: The main regional difference in CHMCF presentation is related to a higher rate of potentially life-threatening conditions in South America. Sixty percent of the expectantly managed CHMCF delivered a viable infant, and the overall rate of GTN in this study was 46%. Elective termination of pregnancy did not influence the risk for GTN; however the need for termination due to complications and higher hCG levels were associated with development of GTN in CHMCF.
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http://dx.doi.org/10.1016/j.ygyno.2017.01.021DOI Listing
April 2017

Is Doppler ultrasound useful for evaluating gestational trophoblastic disease?

Clinics (Sao Paulo) 2015 Dec;70(12):810-5

Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.

Unlabelled: Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia. The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: "Gestational trophoblastic disease AND Ultrasonography, Doppler." Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. (1) Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. (2) There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. (3) Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. (4) Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis.

Conclusion: Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia.
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http://dx.doi.org/10.6061/clinics/2015(12)08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676324PMC
December 2015

Androgen receptor gene polymorphism and polycystic ovary syndrome.

Int J Gynaecol Obstet 2013 Feb 24;120(2):115-8. Epub 2012 Nov 24.

Gynecology Division, Department of Obstetrics and Gynecology, Clinics Hospital, School of Medicine, University of São Paulo, Sao Paulo, Brazil.

Background: Polycystic ovary syndrome (PCOS) is characterized by ovulatory dysfunction and hyperandrogenism. Its etiopathology is not well understood but genetic factors seem to have a role. Polymorphism of the androgen receptor (AR) gene has been associated with different androgen pattern diseases.

Objective: To review the association between AR gene polymorphism and PCOS.

Search Strategy: A systematic review was performed via PUBMED, EMBASE, and LILACS (up to May 31, 2011).

Selection Criteria: Studies assessing the presence of the (CAG)(n) polymorphism of the AR gene in at least 2 comparison groups (PCOS and control). Studies that did not contain adequate information were excluded.

Data Collection And Analysis: Study characteristics and results were analyzed. Meta-analysis could not be performed because only 2 articles provided odds ratios.

Main Results: Ten studies met the inclusion criteria. Three studies reported a correlation between the polymorphism and PCOS; 2 studies linked the disorder to shorter repeats, whereas the other associated it with longer repeats.

Conclusion: Polymorphism of the AR gene seems to be a promising biomarker for PCOS because shorter repeats may be linked to the disorder. However, further studies are needed to understand the association fully.
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http://dx.doi.org/10.1016/j.ijgo.2012.08.016DOI Listing
February 2013
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