Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy.

Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible.

[Three patients with differing manifestations of uterine sarcoma]. / Drie patiënten met verschillende manifestaties van uterussarcoom.

A 70-year-old woman with postmenopausal blood loss proved to have a stage-IV high-grade endometrial stromal sarcoma; 9 months after resection the patient was well. In a 53-year-old woman with symptoms of neurological deficit and weight loss accompanying an increase in abdominal girth and postmenopausal vaginal blood loss a high-grade leiomyosarcoma at stage IV was diagnosed. Despite treatment the neurological symptoms worsened and the patient died within 2 months of diagnosis. Another woman, aged 53, with abdominal pain but no blood loss proved to have a high-grade leiomyosarcoma at stage 1. Nine months after resection and radiotherapy the patient was well. The incidence of carcinomas of the uterus in The Netherlands is on average 113 women per year. They manifest themselves in different ways which can sometimes be misleading. The most common symptom is vaginal bleeding, in combination with abdominal pain or a pelvic mass. The only curative therapy is surgical excision. The 5-year survival rate is 50% in tumours confined to the uterus as opposed to 20% in those that spread further.

[Invasive prenatal diagnosis in the Netherlands, 1991-2000: number of procedures, indications and abnormal results detected]. / Invasieve prenatale diagnostiek in Nederland, 1991-2000: aantallen ingrepen, indicaties, en gevonden afwijkingen.

OBJECTIVE: To provide an overview of invasive prenatal diagnosis in the Netherlands during the period 1991-2000 and to analyse potential trends. DESIGN: Retrospective. METHOD: The annual results from all 13 Dutch centres for invasive prenatal diagnosis over the period 1991-2000 were combined and described, with particular emphasis on indications, number and type of invasive procedures, and number and type of abnormal results. RESULTS: The percentage of pregnancies in which invasive prenatal diagnostics were carried out increased from 5% in 1991 to 6% in 1996 and remained at the same level until 2000. 'Maternal age' was the main reason for prenatal testing (69.2-73.3% of procedures). However, the number of pregnant women aged 36 or over increased by 69.9%. An abnormal result was found in an average of 4.7% of procedures, rising from 3.6% in 1991 to 5.4% in 2000. In 70.8% of cases with abnormal results, the pregnancy was terminated. Important trends were the relative decrease of cordocentesis (-82%) and chorionic villi biopsy (-18%) in favour of amniocentesis (+48%), and a strong decrease in the number of amniocentesis procedures on indication of increased risk of neural tube defect. CONCLUSION: The total number of invasive prenatal diagnostic procedures remained stable. However, there was an important decrease in the percentage of pregnant women aged 36 or over who underwent invasive prenatal diagnosis without previous prenatal screening.

Outcome of children with prenatally diagnosed central nervous system malformations.

OBJECTIVE: To study the outcome of pregnancies with a prenatally diagnosed central nervous system (CNS) malformation. METHODS: Leiden University Medical Centre is a tertiary referral center for fetal ultrasound and invasive prenatal diagnosis. Maternal and neonatal records of prenatally diagnosed CNS malformations were retrospectively reviewed over a 6-year period (1993-1998). Information on current development of surviving children was obtained by contacting the care-giving pediatric neurologist. RESULTS: During the study period 124 fetuses were diagnosed with a CNS malformation. Data on pregnancy and delivery were available for 118 pregnancies. Additional malformations were present in 47% of fetuses (55/118). A total of 46% of pregnancies (54/118) were terminated, and 15% (18/118) ended in spontaneous intrauterine death. A total of 39% of pregnancies (46/118) resulted in live birth, and 29 of the infants were still alive at the age of 3 months. One child was lost to follow-up, one infant died at the age of 4 months, and two children died at the age of 3 years. Psychomotor development of the remaining 25 children was normal for five, slightly disabled for seven, moderately disabled for five and severely disabled for eight. CONCLUSION: Due to the high rate of termination of pregnancy and to the frequent association with other anomalies, the survival rate of pregnancies in which a CNS defect had been diagnosed prenatally was only 25%. More than 50% of surviving children were moderately or severely disabled.