DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women

Background:

Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed.

Methods:

Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT.

Results:

In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001).

Conclusions:

DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.     

Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia

BackgroundCisplatin-based chemotherapy (etoposide 100 mg/m² days 1–5, methotrexate 300 mg/m² day 1, cyclophosphamide 600 mg/m² day 1, actinomycin D 0.6 mg/m² day 2 and cisplatin 60 mg/m² day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m² days 1–2, methotrexate 300 mg/m² day 1 and actinomycin D 0.5 mg i.v. bolus day 1 and 0.5 mg/m² day 2, alternating with cyclophosphamide 600 mg/m² day 8 and vincristine 1 mg/m² day 8) for the treatment of high-risk gestational trophoblastic neoplasia (GTN).Patients and methodsIn the Netherlands, 83 patients were treated with EMACP and 103 patients with EMA/CO. Outcome measures were remission rate, median number of courses to achieve normal human chorionic gonadotrophin (hCG) concentrations, toxicity, recurrent disease rate and disease specific survival.ResultsRemission rates were similar (EMACP 91.6%, EMA/CO 85.4%). The median number of courses of EMA/CO to reach hCG normalisation for single-agent resistant disease and primary high-risk disease was three and five courses, respectively, compared to 1.5 (p = 0.001) and three (p < 0.001) courses of EMACP. Patients treated with EMACP more often developed fever, renal toxicity, nausea and diarrhoea compared to patients treated with EMA/CO. Patients treated with EMA/CO more often had anaemia, neuropathy and hepatotoxicity.ConclusionEMACP combination chemotherapy is an effective treatment for high-risk GTN, with a remission rate comparable to EMA/CO. However, the difference in duration of treatment is only slightly shorter with EMACP. Cisplatin-based chemotherapy in the form of EMACP in this study was not proven more effective than EMA/CO.     

Immunohistochemical expression of CD10 antigen in uterine adenosarcoma

Uterine adenosarcoma (UAS) is microscopically characterized by a biphasic growth pattern. By definition, the epithelial component is benign, whereas the stromal component typically has the appearance of a low-grade sarcoma, usually an endometrial stromal sarcoma. CD10 acts by reducing cellular response to peptide hormones and is currently regarded as a specific marker for endometrial stromal tumors. In this international multicenter study, we further explored CD10 immunoreactivity in 30 UASs. We encountered CD10 positivity of the sarcomatous component in 18/20 (90%) of UASs, in five of eight (63%) of UASs with sarcomatous overgrowth as well as in both cases of recurrent UAS. The epithelial component stained negative in all cases. These findings suggest that CD10 can be used to differentiate UAS from cellular leiomyoma, or in case endometrial stromal cells exhibit muscle differentiation. Furthermore, CD10 positivity in recurrent UAS might guide the pathologist toward an endometrial stromal origin.     

Rheumatoid arthritis: explanatory power of specific radiographic findings for patient clinical status

Radiographs of the hands and wrists of 201 patients with rheumatoid arthritis (RA) were scored for erosion, joint space narrowing, and malalignment. The explanatory power of these findings for measures of clinical status was studied with stepwise multiple linear regression analyses. Radiographic scores explained 59.2% of variation in physical joint count deformity scores, 58.5% of variation in limited motion scores, 22.5% of variation in grip strength scores, 20.5% of variation in button test scores, and 13.5% of variation for the American Rheumatism Association (ARA) Functional Class. Malalignment scores best explained variation in physical deformity, limited motion, and button test scores; joint-space-narrowing scores best explained variation in grip strength; erosion scores best explained variation in ARA Functional Class. When age, duration of disease, erythrocyte sedimentation rate, and rheumatoid factor titer were included in the regression analyses, results were similar to those without these variables. Therefore quantitative scores of specific radiographic findings are in themselves explanatory for measures of clinical status.     

CUTANEOUS VASOCONSTRICTION WITH ALERTING STIMULI IN RABBITS REFLECTS A PATTERNED REDISTRIBUTION OF CARDIAC OUTPUT

1. In conscious rabbits, when alerting stimuli elicit vasoconstriction in the ear vascular bed, there is little or no associated change in cardiac output (CO), as measured by chronically implanted Doppler ultrasonic probes. 2. Local anaesthetic injected around the base of the ear substantially diminished the degree of the vasoconstriction elicited during responses. 3. Our results emphasize that selective cutaneous vasoconstriction, an integral part of the response to alerting stimuli in conscious animals, is part of a patterned redistribution of the CO, organized by the brain.     

Leiomyomatosis peritonealis disseminata: does malignant transformation occur? A literature review.

Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumor. In the literature more than 100 cases have been described. LPD is characterized by multiple small nodules on the peritoneal surface, mimicking a malignant process with metastases, but generally demonstrates benign histologic features. Exposure to estrogen seems to play an etiologic role. Many patients have uterine leiomyomas as well. The diagnosis of LPD is easily made on biopsy. Reduction of estrogen exposure is generally sufficient to cause regression of LPD. Surgical castration or gonadotrophin releasing hormone agonists seem good alternatives in the case of progression or recurrence of LPD. In six patients a malignant leiomyosarcoma has been described shortly after the diagnosis of LPD was made. Five of these patients did not have uterine leiomyomas or exposure to exogenous or increased endogenous estrogen. The relationship with pregnancy in the sixth patient may be coincidental. Whether malignant transformation of LPD occurs remains uncertain. Characteristics of these patients differ from those of LPD patients and may indicate a high malignant potential, necessitating a different approach.     

Is pre-operative risk-assessment in laparoscopic treatment of presumed low-risk endometrial cancer effective?

In endometrial (pre)malignancy the pre-operative work-up is primarily based on the histopathological specimen obtained. Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy (TLH + BSO) in presumed low-risk clinical stage I endometrioid endometrial carcinoma (EEC) or atypical hyperplasia (AH), is nowadays considered preferred and sufficient treatment in the Netherlands. To test the effectiveness of this pre-operative work-up, a retrospective cohort analysis was performed. Revised pre- and post-operative histopathology was compared and intra- and post-operative complications registered. In 116 consecutive patients with a pre-operative diagnosis of AH or presumed stage I, grade I or II EEC planned for TLH + BSO. In 24.1 % (28/116) revised endometrial histopathology was upgraded on the definitive hysterectomy specimen. In 3.5 % (4/116) upgrading to high-risk grade III endometrial cancer (EC) was observed. In 9.9 % (8/81) of EC cases a post-operative FIGO stage IG3, II, or III was diagnosed. The major and minor short-term complication rates of TLH + BSO were 12.1 and 7.8 %. In 13.8 % (16/116) of cases conversion to laparotomy was necessary, with a significant higher percentage of obese (68.8 %) patients in the conversion versus the successful TLH + BSO group (42 %). Clinical relevant inconsistency between pre- and post-operative histopathology or FIGO stage was observed in 9.9 % of EC cases. More extensive pre-operative risk analysis of presumed low-risk EEC may be indicated, especially for the morbid obese, harboring a substantial risk for conversion to laparotomy and complications.