Handheld vital microscopy for the identification of microcirculatory alterations in cervical intraepithelial neoplasia and cervical cancer.

BACKGROUND: Ninety percent of cervical cancer (CC) diagnoses and deaths occur in low and middle-income countries (LMICs). Especially in these countries, where human and material resources are limited, there is a need for real-time screening methods that enable immediate treatment decisions (i.e., 'see and treat'). OBJECTIVE: To evaluate whether handheld vital microscopy (HVM) enables real-time detection of microvascular alterations associated with cervical intraepithelial neoplasia (CIN) and CC. METHODS: A cross-sectional study was conducted in an oncologic hospital and outpatient clinic, and included ten healthy controls, ten women with CIN, and ten women with CC. The microvasculature was assessed in four quadrants of the uterine cervix using HVM. The primary outcome was the presence of abnormal angioarchitecture (AA). Secondary outcomes included capillary loop density (CD), total vessel density (TVD), functional capillary density (FCD), and the proportion of perfused vessels (PPV). RESULTS: 198 image sequences of the cervical microvasculature were recorded. Compared to healthy controls, significantly more abnormal image sequences were observed in women with high-grade CIN (11 % vs. 44 %, P < 0.001) and women with CC (11 % vs. 69 %, P < 0.001). TVD, FCD, and PPV were lower in women with CIN and CC. CONCLUSIONS: HVM enables easy, real-time, non-invasive assessment of cervical lesions through the detection of microvascular alterations. Thereby, HVM potentially provides an opportunity for point-of-care screening, which may enable immediate treatment decisions (see and treat) and reduce the number of unnecessary surgical interventions.

Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement. METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment. RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.

Lung metastases in low-risk gestational trophoblastic neoplasia: a retrospective cohort study.

OBJECTIVE: Presence of lung metastases in low-risk gestational trophoblastic neoplasia (GTN) is generally considered not to influence prognosis. However, in a recent study in the Netherlands, GTN patients with lung metastases had a higher recurrence rate and more disease-specific deaths compared with patients without metastases. The aim of the present study was to validate these findings in a different country. DESIGN: Historical cohort study. SETTING: Charing Cross Hospital, United Kingdom. POPULATION: A total of 1040 low-risk GTN patients treated with methotrexate (MTX) between 2002 and 2016 were identified: 65 with lung metastases (group 1) and 975 without metastases (group 2). METHODS: Baseline characteristics, MTX resistance, survival and recurrence rates were recorded and compared between both groups. MAIN OUTCOME MEASURES: MTX resistance, recurrence rate and survival. RESULTS: The occurrence of MTX resistance and median number of MTX courses to achieve remission was significantly higher in patients with lung metastases than patients without metastases (60% versus 38.9%, P = 0.001; and nine versus six courses, P < 0.001). All choriocarcinoma patients (n = 4) with lung metastases developed MTX resistance. The recurrence rate was also higher in group I (9.2% versus 2.7%; P = 0.012). Disease-specific survival was 100% in both groups. CONCLUSIONS: The presence of lung metastases at the start of MTX therapy is associated with increased incidence of MTX resistance and recurrence in low-risk GTN without affecting overall survival, which remains 100%. However, individuals with low-risk choriocarcinoma with lung metastases are likely to become resistant to MTX and primary multi-agent chemotherapy should be considered. TWEETABLE ABSTRACT: The presence of lung metastases appears to increase the risk of recurrence in low-risk GTN, but does not affect overall cure rates and survival.

Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database.

OBJECTIVE: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT. METHODS: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS). RESULTS: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively). CONCLUSIONS: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN.

[Trophoblastic diseases]. / Trofoblastziekten.

Hydatidiform mole is the most frequently-occurring gestational trophoblastic disease (GTD). Patients with GTD have elevated human chorionic gonadotrophin (HCG) produced by the trophoblast. After evacuation of the mole, weekly serum HCG determinations can be used to assess whether the trophoblast is persisting or regressing based on the standardised normal Nijmegen serum HCG regression curve. The serum HCG pattern is used to establish the diagnosis 'persistent trophoblastic disease'. Treatment with monochemotherapy in the form of methotrexate is the treatment of choice. For about 80% of women with a persistent trophoblastic disease following a molar pregnancy this treatment will lead to a complete remission of the disorder. If resistance to methotrexate occurs then a combined therapy is indicated. A recently developed, and as yet unvalidated, normogram for the serum HCG level during methotrexate treatment might in the near future be able to identify patients with methotrexate resistance at an early stage. Hysterectomy or curettage may be indicated as part of therapy in selected patients. The incidence of choriocarcinoma after a live birth is estimated at 1 in every 40,000 full-term pregnancies. These patients have a high risk for resistance to methotrexate (75%). Treatment of these patients with primary combination therapy at a specialised medical centre is then indicated.

Early identification of persistent trophoblastic disease with serum hCG concentration ratios.

The objective of the present study was to assess the diagnostic potential of serum human chorionic gonadotropin (hCG) ratios obtained at different intervals after evacuation of hydatidiform mole to diagnose persistent trophoblastic disease (PTD) and to compare its diagnostic accuracy with the current FIGO 2000 criteria as a gold standard. We calculated hCG ratios from serum hCG concentrations of 204 patients (86 with and 118 without PTD) registered with the Dutch Central Registry for Hydatidiform Moles between 1977-2004. The hCG ratios obtained in week 1, 3, and 5 after evacuation identified, respectively, 20%, 52%, and 79% of patients with PTD (median: 3.0 weeks) at the 95% specificity level, while FIGO 2000 criteria identified, respectively, 0%, 16%, and 66% (median: 4.7 weeks). It is concluded that a serum hCG ratio identifies patients with PTD approximately 2 weeks earlier than the internationally accepted FIGO 2000 criteria and identifies more than 75% of patients who develop PTD by the fifth week after evacuation.

Clinical utility of hyperglycosylated hCG in serum taken before hydatidiform mole evacuation to predict persistent trophoblastic disease.

OBJECTIVE: Human chorionic gonadotropin (hCG) is widely used in the management of hydatidiform mole and persistent trophoblastic disease (PTD). Studies on hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen, ITA) in PTD are limited. In serum samples taken before evacuation of molar pregnancies we measured the concentrations of free hCG beta-subunit (free hCGbeta), "total" hCG (hCG+hCGbeta) and ITA, and determined whether ITA, the two other hCG analytes, or the calculated ratios of hCGbeta/hCG+hCGbeta, hCGbeta/ITA and hCG+hCGbeta/ITA could predict the later development of PTD. DESIGN: A retrospective study based on blood specimens collected in the Dutch Central Registry for Hydatidiform Moles. The study group comprised 97 patients with hydatidiform moles who did not develop PTD after mole evacuation and 33 patients who did develop PTD. METHODS: Serum samples from 130 patients with hydatidiform mole with or without PTD were assayed using specific (radio)immunoassays for free hCGbeta, total hCG, and ITA. From these analytes we also calculated the ratios hCGbeta/hCG+hCGbeta, hCGbeta/ITA, and hCG+hCGbeta/ITA. To predict the development of PTD from these analytes and parameters we performed receiver-operating characteristic (ROC) curve analysis, resulting in areas under the curve (AUCs) that represented the diagnostic accuracy which was rated in a range from excellent (AUC >0.9 or <0.1) to poor (AUC 0.4-0.6). RESULTS: The diagnostic accuracy of ITA was moderate (0.618) and not different from that of free hCGbeta (0.610) and hCG+hCGbeta (0.622). CONCLUSIONS: ITA as well as the other analytes and parameters in serum taken prior to evacuation from patients with molar pregnancies cannot be used to predict the subsequent development of persistent trophoblastic disease.

Patient compliance with a rehabilitation program after flexor tendon repair in zone II of the hand.

The use of early mobilization during rehabilitation of a finger after flexor tendon repair in zone II has achieved worldwide acceptance. Different exercise instructions are given to patients in different clinics, however. When using Kleinert dynamic splinting, some hand therapists instruct patients to exercise 10 times an hour, while others tell their patients to exercise as many times as possible. How often a patient should exercise to achieve optimal results has never, to the authors' knowledge, been investigated. To identify a relationship between exercise behavior and range of motion achieved at 6 months postoperatively, the authors started a pilot study of the compliance of 15 patients with a rehabilitation program following flexor tendon repair in zone II. A portable rehabilitation device was used to deliver an isotonic tensile force and to record when (during the day) a patient exercises and how many exercises the patient performs. Patients were instructed to perform at least ten exercises per hour. The average count per hour was 69 exercises (range, 14-213). In this small group study, no strong correlation was found between exercise count and the total active or total passive motion achieved.

A portable device for finger tendon rehabilitation that provides an isotonic training force and records exercise behaviour after finger tendon surgery.

For most hand surgeons, flexor tendon repairs in zone 2 of the hand still present a clinical problem. The surgeon is placed in a dilemma: on the one hand, if repair is achieved and the finger is kept immobile during the healing phase, dense adhesions may bind the tendons within the sheath and limit motion. On the other hand, uncontrolled early flexion may disrupt the tendon repair. Early 'controlled motion' increases tensile strength, reduces the formation of adhesions and improves clinical results. To investigate the relationship between the patient's compliance concerning the post-operative motion regimen and the final range of motion, a device has been developed which records when and how often the patient exercises. The device is attached to a modified Kleinert splint. This configuration enables comparison of the outcome of the rehabilitation of patients who exercise according to the rehabilitation programme with patients who exercise less often. The device measures for up to one week. It is possible to download the available measurement samples (exercise count per quarter of an hour) for inspecting the training course or for further analysis/statistics.