[The influence of lung metastasis on prognosis of previously untreated gestational trophoblastic neoplasia patients].

Objective: To investigate the impact of lung metastases on the prognosis of patients with gestational trophoblastic neoplasia (GTN). Methods: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage Ⅰ-Ⅲ GTN receiving primary chemotherapy in Peking Union Medical College Hospital between July 2014 and December 2018 were retrospectively analyzed and divided into group 1 with lung metastasis and group 2 without lung metastasis. The baseline characteristics and treatment outcomes of the two groups were compared. The optimal cut-off values of the diameter of largest lung nodule associated with recurrence were identified by receiver operating characteristic (ROC) curves. Logistic regression analyses were performed to identify risk factors for prognosis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Results: Of the 381 GTN patients enrolled (216 with lung metastases and 165 without lung metastases), the pretreatment ß human chorionic gonadotrophin [median: 12 572 IU/L (1 832-51 594 IU/L) vs. 5 614 IU/L (559-26 140 IU/L), P=0.001] and FIGO score [median: 3 (1-6) vs. 2 (1-4), P=0.038] were significantly higher in patients with lung metastases than those without lung metastases. In patients with FIGO score≥5, the emergence of resistance (26.76% vs. 10.26%, P=0.036) and median number of chemotherapy courses to achieve complete remission [6 (6-8) vs. 5 (4-6), P<0.001] were significantly higher than patients with lung metastases. In patients with FIGO score 0-4, no significant difference was found in the treatment outcomes between the two groups(P=0.833). Among all patients with lung metastases, the ROC curve showed a sensitivity and specificity of 62.5% and 78.8%, respectively, for predicting recurrence when the length of the largest lung nodule was 1.6 cm, with an area under the curve (AUC) of 0.711 (95% CI: 0.550, 0.871, P=0.044). Multivariate logistic regression analysis suggested a significantly higher recurrence rate when the largest lung nodule was ≥1.6 cm (OR=7.394, 95% CI: 1.003, 54.520, P=0.049). The 1-year disease-free survival rate was significantly lower in patients with the largest lung nodule ≥1.6 cm than in patients with the nodule <1.6 cm (98.2% vs. 82.4%, P=0.001). Conclusions: Lung metastasis is associated with increased first-line chemotherapy resistance in patients with FIGO scores≥5. The diameter of the largest lung metastatic nodule ≥1.6 cm is an effective factor for predicting recurrence.

[The affinity maturation, characteristics and application of HIV-1 broadly neutralizing antibodies].

Hundreds of broadly neutralizing antibodies(bNAbs) were successfully isolated from long-term nonprogression(LTNP) of human immunodeficiency virus type 1(HIV-1) infected individuals. Some bNAbs were illustrated could reduce the viral load and the risk of HIV-1 infection. Today, HIV-1 bNAbs are at the center of vaccine development and passive immunization treatment. Usually, the activity of neutralizing antibodies depends on the epitope. The affinity of neutralizing antibodies also plays a vital role in its inhibitory effect. Multiple affinity maturation in vivo actually provides the broad and potent neutralizing activity of HIV-1 bNAbs. When high affinity HIV-1 bNAbs applied in clinic, it can help immune system to remove virus with lower dosage and fewer side effect. While affinity maturation, HIV-1 bNAbs shows unique characteristics, such as extensive of somatic hypermutation(SHM), in-frame insertion and deletion and long CDR 3 region of heavy chain. The key points in the progress that HIV-1 bNAbs affinity maturation will help us understand the relationship between antibodies neutralizing capability and its characteristics.It also potentially provide a reference to design effective HIV-1 immunogen.

[Imaging features and clinical analysis of diffuse uterine leiomyomatosis cases].

Objective: To discuss the imaging, clinical features and management of diffuse uterine leiomyomatosis (DUL). Methods: Six cases of DUL confirmed in Peking Union Medical College Hospital from August 2009 to September 2019 were reviewed on their image and clinical data. Retrospective analysis was conducted on their perioperative and postoperative follow-up data. Results: The average age of the first diagnosis of DUL was (27±3) years old. All of the patients complained menorrhagia and three patients suffered moderate to severe anemia. Three patients were diagnosed infertility. Pelvic ultrasound and MRI showed symmetrical enlarged uterus with complete replacement of the myometrium by innumerable, confluent leiomyomas.Four patients were treated with GnRH-a before operation to reduce the volume of myoma and correct anemia. Among the six patients, five had undergone myomectomy because of DUL before visiting Peking Union Medical College Hospital. Three patients underwent open myomectomy. The number of resected myoma was 188-300 and the bleeding volume was 1 200-2 500 ml. Two of them suffered recurrence at 51 and 40 months after operation. One received sirolimus for 20 months without recurrence until now. Other three patients underwent hysterectomy. One patient underwent partial small bowel resection and partial omentum resection because of severe pelvic adhesion during hysterectomy, and the blood loss was 2 000 ml. Conclusions: Pelvic imaging especially MRI is helpful for early recognition and preoperative evaluation for DUL. Fertility preservation is a great challenge for DUL patients. The risk of recurrence after myomectomy is high. Hysterectomy is the last choice to completely cure DUL at present.

[Preliminary study of PD-1 inhibitor in the treatment of drug-resistant recurrent gestational trophoblastic neoplasia].

Objective: To investigate the therapeutic effect of programmed cell death receptor 1 (PD-1) inhibitor in drug-resistant recurrent gestational trophoblastic neoplasia (GTN). Methods: Clinicopathological features, previous treatments, PD-1 inhibitor treatment and prognosis of 8 patients with drug-resistant recurrent GTN treated with PD-1 inhibitor pembrolizumab， in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from August 2018 to June 2019 were collected and retrospectively analyzed. Results: (1) Clinicopathological features: the average age of onset of 8 GTN patients was 32.9 years old (31-39 years old); pathological types: choriocarcinoma in 7 cases, epithelioid trophoblastic tumor in 1 case. International Federation of Gynecology and Obstetrics (FIGO) stages: stage Ⅲ in 5 cases, stage Ⅳ in 3 cases; FIGO score: 4 patients with 7-12 points (high-risk group) and 4 patients with ≥13 points (ultra high-risk group). All the 8 patients had lung metastasis, 2 patients with brain metastasis, 1 patient with kidney and 1 patient with intestinal metastasis. (2) Previous treatments: ① Chemotherapy: 8 patients with GTN received an average of 21.1 courses (5-30 courses) of chemotherapy; the main route was systemic intravenous chemotherapy. One patient received intrathecal methotrexate chemotherapy due to brain metastasis. ② Surgery: 7 of 8 patients with GTN received surgical treatment, including 5 cases of pelvic surgury, 6 cases of pulmonary lobectomy and 1 case of right hemicolectomy. ③ Radiotherapy: 2 of 8 patients with GTN received radiotherapy, among which 1 patient received radiotherapy for lung for 8 times due to lung metastasis, and the other one received radiotherapy for lung, right sacroiliac joint and skull for a total of 22 times. (3) PD-1 inhibitor treatment: 8 patients with GTN received PD-1 inhibitor treatment with a mean course of 9 (2-12 courses). Six patients appeared Ⅰ-Ⅱ grade of immune related adverse events (AE), and no severe AE occurred. (4) Prognosis: after 2-3 courses of PD-1 inhibitor treatment, serum ß-hCG level came to normalization in 4 patients. They were followed up for 2-7 months without any recurrence after 0-9 courses of consolidation treatment. One patient received 12 courses of PD-1 inhibitor treatment. The serum ß-hCG level normalized after the 6th courses but increased 1 months later, and then received bevacizumab treatment due to the progression of the disease. The remaining 3 patients received other chemotherapy regiments due to disease progression during PD-1 inhibitor treatment. Conclusions: PD-1 could be used as a remedial treatment for drug-resistant recurrent GTN, with a high effective rate and relatively mild AE. However, more cases need to be accumulated clinically and efficacy should be comprehensively evaluated in combination with pathology and immunohistochemical examination.

[Impact of chemotherapy on ovarian function and quality of life of patients with gestational trophoblastic neoplasia].

Objective: Using a questionnaire to evaluate different regimens of chemotherapy on ovarian function and quality of life of patients with gestational trophoblastic neoplasia (GTN) . Methods: At least 6 months after completion of chemotherapy, 200 patients with GTN treated in Peking Union Medical College Hospital from January 2010 to June 2017 were randomly selected to fill up the questionnaire. The questionnaire items were included the patient's menstrual cycles, sexual life, gestational issues and common health. The patients were divided into 3 groups by chemotherapy regimens: actinomycin D (Act-D) group, floxuridine+Act-D+vincristine (FAV) or floxuridine+Act-D+etoposide+vincristine (FAEV) group (FAV-FAEV group) , and etoposide+methotrexate+Act-D (EMA) /vincristine+cyclophosphamide (CO) or EMA/ etoposide+cisplatin (EP) group (EMA/CO-EMA/EP group) . Chi-square test was used with a significance level of P-value less than 0.05. Results: One hundred and seventy-three (86.5%,173/200) of the patients completed the questionnaire. Forty three point two percent (43.2%, 19/44) in the EMA/CO-EMA/EP group had a normal menstrual cycle, which were significantly lower than those of Act-D group (84.6%,22/26) and FAV-FAEV group (71.2%, 37/52; all P<0.05) . Amenorrhea rate was also significantly higher in EMA/CO-EMA/EP group (25.0%, 11/44) than in Act-D group (0) and FAV-FAEV group (17.3%, 9/52; all P<0.05) . The sexual life parameters were comparable among 3 groups. Ten out of thirty-two patients conceived after chemotherapy, 2 had miscarriages and 8 had full-term delivery of healthy babies. The common health and labor capacity were significantly decreased after chemotherapy (all P<0.05) . Conclusions: EMA/CO or EMA/EP regimen have a worse impact on ovarian function than Act-D and FAV or FAEV regimen. Gynecologic oncologist should be concerned about the ovarian function and quality of life of GTN patients.

[Clinical outcome of patients with gestational trophoblastic neoplasia receiving primary treatment at Peking Union Medical College Hospital: a 30-year retrospective cohort study].

Objective: To summarize and analyze the clinical outcomes of gestational trophoblastic neoplasia (GTN) patients receiving primary treatment at Peking Union Medical College Hospital from 1985 to 2015, and investigate the changes in treatment efficacy between the first and the second 15 years. Methods: Clinical data of GTN patient receiving primary chemotherapy at Peking Union Medical College Hospital from January 1985 to December 2015 were retrospectively analyzed. It further compared the therapeutic results and chemotherapy cycles given to GTN patients, according to International Federation of Gynecology and Obstetrics (FIGO, 2000) prognostic score system, who were classified to different stages and low- or high-risk groups. Results: In total, 1 711 GTN patients were included in this study. Comparing the 1985-2000 group and the 2001-2015 group, the results showed that: (1) while the overall complete remission (CR) rate was 93.7% (1 603/1 711) , the CR rate of 2001-2015 group was significantly higher than that of 1985-2000 group [98.4% (1 155/1 174) vs 83.4% (448/537) , χ(2)=139.353, P<0.01]. This difference was significant between stage Ⅲ and Ⅳ patients, but nonexistent between stage Ⅰ and Ⅱ patients, including low- and high-risk groups. (2) The relapse rate of patients who had been in CR was 2.7% (43/1 603) , with no significant differences between the groups of 1985-2001 and 2001-2015 [3.6% (16/448) vs 2.3% (27/1 155) , χ(2)=6.867, P=0.142]. (3) The overall mortality rate was 2.6% (44/1 711) , which significantly decreased in 2001-2015 group compared to 1985-2000 group [1.6% (19/1 174) vs 4.7% (25/537) , χ(2)=13.830, P<0.01]. This difference appeared only in high-risk patients with stage Ⅲ disease (χ(2)=9.505, P<0.01) . (4) Fluorouracil was gradually replaced by floxridine in chemotherapy regimens. The total cycles of chemotherapy regimens given to low-risk patients with stage Ⅲ disease significantly decreased in 2001-2015 group, but no statistical difference was shown with patients at other stages. Moreover, the cycles of consolidation treatment were significantly reduced in patients with stage Ⅲ patients. Conclusions: GTN patients could obtain satisfactory curative results after appropriate and standard treatment. Peking Union Medical College Hospital has achieved better curative effect in the latest 15 years than before.

[Effects of prophylactic chemotherapy on outcomes and prognosis of patients older than 40 years with invasive mole].

Objective: To discuss the effects of prophylactic chemotherapy on the outcomes and prognosis of invasive mole patients. Methods: One hundred and fifteen invasive mole (IM) patients older than 40 years were registered in Peking Union Medical Collage Hospital.Eleven of them were treated with prophylactic chemotherapy before diagnosed as IM prophylactic chemotherapy group, while the other 104 cases received therapeutic chemotherapy after diagnosed as IM (non-prophylactic chemotherapy group). The general clinical data (including age, clinical stage, risk factor score), treatment, outcomes and relapse of patients were retrospectively compared between two groups. Results: (1) The age of prophylactic chemotherapy group and non-prophylactic chemotherapy group were (47±5) versus (46±4) years old. Ratio of clinical stageⅠ-Ⅱ were 3/11 versus 29.8% (31/104), clinical stage Ⅲ-Ⅳ were 8/11 versus 70.2% (73/104). Ratio of risk factor score 0-6 were 11/11 versus 84.6% (88/104), risk factor score >6 were 0 versus 15.4% (16/104). There were no significant statistical differences between two groups in age, clinical stage or risk factor score (all P>0.05). (2) Treatment: the total chemotherapy courses between prophylactic chemotherapy group and non-prophylactic chemotherapy group (median 7 versus 5) were significantly different (Z=3.071,P=0.002). There were no significant statistical differences between two groups in the chemotherapy courses until negative conversion of ß-hCG, consolidation chemotherapy courses, total therapeutic chemotherapy courses or ratio of hysterectomy (all P>0.05). (3) Outcomes and relapse: between the prophylactic chemotherapy group and the non-prophylactic chemotherapy group, the complete remission rate were 11/11 versus 98.1%(102/104), the relapse rate were 0 versus 1.0%(1/102). There were no significant difference between the two groups in outcomes or relapse rate (P>0.05). Conclusions: Prophylactic chemotherapy does not substantially benefit the IM patients older than 40 years. Prophylactic chemotherapy may not significantly improve patients' prognosis, in which increased sample size is required in further study.

Placental site trophoblastic tumor: A review of 108 cases and their implications for prognosis and treatment.

OBJECTIVE: To identify important prognostic factors and optimized treatment strategies through the analysis of the clinical and pathological characteristics of placental site trophoblastic tumor. METHODS: 108 patients with PSTT registered in two GTD centers or in six tertiary hospitals in China were analyzed retrospectively between the years 1998 and 2013. The computerized database of clinical and pathological reports was reviewed on this patient group. The data were subsequently analyzed retrospectively using SPSS software. RESULTS: Among 3581 patients with GTNs treated in GTD centers or in the tertiary hospitals between 1998 and 2013, 108 cases were histologically confirmed PSTT (3%). Only seven deaths and eleven relapse cases were observed. All seven of the deaths were disease related, due to chemotherapy-resistant or relapsed. 23 patients who received fertility preservation treatment did not experience poor outcome or high risk of relapse. In 71 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I disease, the use of adjuvant chemotherapy following surgery (n=49) or not (n=22) made no significant difference in relapse rate (P=0.303) or survival (P=0.782). Univariate analysis revealed the interval between antecedent pregnancy and onset of PSTT, stage, prognosis score, and necrosis as significant predictors of poor survival but only stage remained significant on multivariate analysis. CONCLUSIONS: Patients with FIGO stage IV disease demonstrate the most critical risk indicator of PSTT in the current study. Preservation of fertility is considered in highly-selected patients with localized tumor; and surgery without chemotherapy is recommended as first line treatment for patients with stage I who are at low-risk.

[Clinical analysis of hypersensitivity reaction of platinum in ovarian cancer and cervical cancer patients].

Objective: To investigate the incidence, risk factors, management and prognosis of hypersensitivity reaction (HSR) of platinum-based chemotherapy in patients of ovarian cancer and cervical cancer. Methods: Cases from Peking Union Medical College Hospital from Jan. 2013 to Jan. 2016 were checked for patients' data of epithelial ovarian cancer treated with carboplatin/paclitaxel (every 3 weeks) and patients of cervical cancer treated with concurrent radiochemotherapy using cisplatin (every week). General characters, pathological features, treatment and prognosis of patients were analyzed to determine the severity, symptoms, outcomes and risk factors of HSR. Results: (1) Prevalence of HSR: there were 860 cases of ovarian cancer and 580 cases of cervical cancer, among which HSR occurred in 8.8% (76/860) and 5.9% (34/580) patients, respectively. (2) Grading for HSR: most HSR were grade 1 or 2, with 78.9%(60/76) in ovarian cancer and 82.4%(28/34) in cervical cancer patients. In ovarian cancer patients, there were 7 cases of grade 1 HSR and 53 cases of grade 2 HSR, and in cervical cancer patients, there were 11 cases of grade 1 HSR and 17 cases of grade 2 HSR. (3) Symptoms of HSR: most of HSR happened during intravenous infusion of platinum agents, with 98.7% (75/76) in ovarian cancer and 97.1% (33/34) in cervical cancer patients. In ovarian and cervical cancer patients, most common symptom were tight chest and dyspnea, which happened in 92.1% (70/76) and 97.1% (33/34) patients, respectively. Secondary common symptom were skin reactions, which happened in 53.9% (41/76) and 88.2% (30/34) patients respectively. (4) Treatment after HSR: of 76 ovarian cancer cases with HSR, there were no significant difference in the ratio of HSR recurrence among patients of different treatment after HSR (χ2=0.517, P=0.915): 1 of 4 patients applying prior chemotherapy, 4 of 13 cases receiving desensitization, 3 of 11 cases separating medicine, 2 of 11 patients switching to cisplatin. In 34 cervical cancer cases of HSR, there were also no significant difference in the ratio of HSR recurrence among patients of different treatment after HSR (χ2=0.079, P=1.000): 2 of 9 patients applying prior chemotherapy, 3 of 17 cases receiving desensitization. (5) Risk factors of HSR and patients prognosis: in ovarian cancer patients of HSR, risk factors included relapse (P=0.010), courses of chemotherapy reaching seven or nine for patients of primary treatment or reaching six or seven for recurrent patients (all P<0.05). There were no significant risk factors for cervical cancer patients of HSR (all P>0.05). HSR had no impact on the progression- free survival for ovarian cancer (P=0.144) or cervical cancer (P=0.782). Conclusions: In ovarian cancer patients treated with carboplatin and cervical cancer patients treated with concurrent radiochemotherapy using cisplatin, most HSR of platinum are mild and favorable outcomes. Relapse and longer chemotherapy courses are risk factors for HSR of carboplatin for epithelial ovarian cancer.

The prognostic analysis of 123 postpartum choriocarcinoma cases.

A retrospective analysis of 123 postpartum choriocarcinoma cases treated at the Peking Union Medical College Hospital between December 1985 and December 2006 was performed. All the patients with postpartum choriocarcinoma received chemotherapy, combined with comprehensive therapy. The total number of chemotherapy cycles was 1041 (8.5 for every patient on average). The complete remission (CR) was achieved in 108 patients (87.8%), whereas five patients had partial remission and ten died. Of the 26 patients who became resistant to 5-fluorouracil combined chemotherapy, 18 achieved CR. Of the four cases who had recurrence, three achieved CR. The patients were divided into high- and low-risk groups, based on the new FIGO 2000 risk factor scoring system. Seventy-five patients were in high-risk group, with a score of 7 or more. Among them, 62 achieved CR (82.7%). The remaining 48 patients were in the low-risk group, with a score of 6 or less, among whom 46 patients achieved CR (95.8%). There is a significant difference in CR rate between the two groups. Based on the FIGO staging and scoring system, 24 patients were diagnosed as FIGO stage I, 9 stage II, 66 stage III, and 24 stage IV. The rate of CR was 100%, 100%, 91%, and 62.5%, respectively. Our experience shows that prognosis of postpartum choriocarcinoma is good when multiagent systemic chemotherapy is applied. Shortened time interval between the antecedent pregnancy and the treatment will lead to better prognosis.

Emergency craniotomy in patients with intracranial metastatic gestational trophoblastic tumor.

OBJECTIVE: To study the diagnosis, management and prognosis of intracranial metastases of gestational trophoblastic tumor (GTT) patients who had emergency craniotomy. METHODS: Sixty three intracranial metastases of GTT patients were hospitalized in Peking Union Medical College Hospital from 1985 to 2004. Thirteen of them had craniotomy that were retrospectively analyzed and all of them had a feature of raised intracranial pressure followed by intracranial hemorrhagic mass. RESULTS: Of the thirteen patients who had undergone surgery combined with multiagent chemotherapy, seven got complete remission (CR), five got partial remission (PR), and one died of progress of the disease (PD). There were three patients who died (23.1%) during or after therapy. CONCLUSIONS: Emergency craniotomy has a small but important role to play in selected patients with brain metastases who display rapidly deteriorating signs. An undetermined intracranial hemorrhage in young female patients of a reproductive age group should raise the suspicion of cerebral metastatic GTT.

Diagnosis and management of uterine arteriovenous fistulas with massive vaginal bleeding.

OBJECTIVE: To study the clinical manifestations, diagnosis, management, and prognosis of uterine arteriovenous fistulas with massive vaginal bleeding. METHODS: The clinical records of 15 patients who satisfied the diagnostic criteria were retrospectively analyzed. RESULTS: All patients had massive vaginal bleeding and a history of cesarean section, curettage, or gynecologic carcinoma. The disease was diagnosed by angiography or color Doppler ultrasonography. Vaginal bleeding can be aggravated by dilation and curettage. No complications occurred in the 14 patients who were treated with uterine artery embolization. Of the 11 patients who underwent successful embolizations, all returned to a normal menstrual cycle and 5 later became pregnant. CONCLUSION: Uterine arteriovenous fistula is a rare and potentially life-threatening condition. Uterine artery embolization is a safe and effective choice of treatment for this condition, and it can preserve both uterus and ovary function.

Molecular genetic analyses of choriocarcinoma.

BACKGROUND: Choriocarcinoma is a highly malignant trophoblastic neoplasm. Most of them are gestational in origin, while non-gestational ones are exceedingly rare. The genetic origin, immunogenicity, sensitivity to chemotherapy and prognosis of these two kinds of conditions are quite different, so identification of these two kinds of choriocarcinoma is of great importance. The objective of this study is to distinguish choriocarcinoma as gestational or non-gestational and identify the causative pregnancy of gestational choriocarcinoma through molecular genetic analysis. METHODS: Twelve patients with choriocarcinoma, who had experienced surgery prior to chemotherapy, were enrolled in this study. DNA was prepared from blood samples from the patient and her partner using standard techniques. In order to prepare DNA from choriocarcinoma tissue, areas of choriocarcinoma were firstly microdissected from haematoxylin and eosin-stained sections. PCR amplification and fluorescent microsatellite genotyping were performed using DNA from the couples and captured tissue. The genetic contributions to the choriocarcinoma were determined by comparing the genotypes of the choriocarcinoma and that of the couples. RESULTS: Four of twelve cases had only a maternal contribution, indicating a non-gestational origin. The remaining eight cases were all gestational in origin and the causative pregnancies were identified as AnCHM (androgenetic complete hydatidiform mole) in six and normal pregnancies in two respectively. CONCLUSION: Microsatellite polymorphism analysis is a molecular approach for distinguishing the non-gestational choriocarcinoma from the gestational one, and can also be used to identify the causative pregnancy of gestational choriocarcinoma. Antecedent pregnancy prior to choriocarcinoma is not always its causative pregnancy. Therefore, it is reasonable to identify the causative pregnancy by its genetic origin, instead of clinical impression.