Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is ...normally protected from these noxious blood‐borne chemicals by the blood–brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P‐glycoprotein (P‐gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P‐gp gene. We hypothesized that PD patients have reduced P‐gp function in the blood–brain barrier. We used positron emission tomography to measure brain uptake of 11C‐verapamil, which is normally extruded from the brain by P‐gp. Here, we show significantly elevated uptake of 11C‐verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood–brain barrier as a causative mechanism in PD. Ann Neurol 2005;57:176–179
Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal ...breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.
We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.
Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.
Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.
Aims
Treatment with anti‐HER2 therapy could be beneficial for patients with HER2‐positive endometrial and ovarian clear cell carcinoma (CCC). We studied HER2 overexpression by immunohistochemistry ...(IHC) using three different antibodies, including concordance with amplification by in‐situ hybridisation (ISH).
Methods and results
IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC, 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC. IHC was performed using SP3, 4B5 and HercepTest antibodies, and was scored by two independent observers. ISH was performed using dual‐colour silver ISH. Using IHC, agreement was poor between SP3/4B5 (61.4%), poor between SP3/HercepTest (68.3%) and reasonable between 4B5/HercepTest (75.2%). Interobserver agreement was substantial to almost perfect for all antibodies (SP3: linear weighted κ = 0.89, 4B5: κ = 0.90, HercepTest: κ = 0.76). HER2‐positivity by ISH was 17.8% (endometrial pure CCC: 24.1%, endometrial mixed: 0%, ovarian pure CCC: 16.7%). IHC/ISH concordance was poor, with a high false‐negative rate of all three IHC antibodies: sensitivity (38.9–50.0%) and positive predictive value (PPV) (37.5–58.3%) were poor; specificity (81.9–94.0%) and negative predictive value (NPV) (87.1–88.3%) were reasonable. When excluding 2+ cases, sensitivity declined (26.7–43.8%) but PPV (80.0–87.5%) and specificity (98.6–98.7%) improved.
Conclusions
In ovarian and endometrial CCC, there is considerable difference in HER2 overexpression by different IHC antibodies and marked discordance with ISH. As such, no single antibody can be considered conclusive for determining HER2 status in CCC. Based on these results, the lack of predictive value of different HER2 testing methods, as used in other studies, could be explained.
To study the impact of the COVID-19 pandemic and consequent lockdown on the number of diagnoses of gynaecological malignancies in the Netherlands.
We performed a retrospective cohort study using data ...from the Netherlands Cancer Registry (NCR) on women of 18 years and older diagnosed with invasive endometrial, ovarian, cervical or vulvar cancer in the period 2017–2021. Analyses were stratified for age, socioeconomical status (SES) and region.
The incidence rate of gynaecological cancer was 67/100.000 (n = 4832) before (2017–2019) and 68/100.000 (n = 4833) during (2020) the COVID-19 pandemic. Comparing the number of diagnoses of the two periods for the four types of cancer separately showed no significant difference. During the first wave of COVID-19 (March-June 2020), a clear decrease in number of gynaecological cancer diagnoses was visible (20–34 %). Subsequently, large increases in number of diagnoses were visible (11–29 %). No significant differences in incidence were found between different age groups, SES and regions. In 2021 an increase of 5.9 % in number of diagnoses was seen.
In the Netherlands, a clear drop in number of diagnoses was visible for all four types of gynaecological cancers during the first wave, with a subsequent increase in number of diagnoses in the second part of 2020 and in 2021. No differences between SES groups were found. This illustrates good organisation of and access to health care in the Netherlands.
•The decrease in incidence was mainly visible during the first wave of COVID-19.•Differences in COVID-19 burden across the country did not impact the incidence.•No differences in incidence were found for SES and age before and during COVID-19.
Abstract Objective To determine the prevalence, localisation and type of occult (non)invasive cancer in risk-reducing salpingo-oophorectomy (RRSO) specimens in BRCA -mutation carriers and high-risk ...women from BRCA -negative families. Methods A consecutive series of RRSO specimens of asymptomatic, screen-negative high-risk women were prospectively collected in our tertiary multidisciplinary cancer clinic from January 2000 until March 2012. All high-risk women in this study underwent genetic testing on BRCA -mutations. The surgico-pathological protocol comprised complete resection of ovaries and fallopian tubes, transverse sectioning at 2–3 mm (sectioning and extensively examining the fimbrial end SEE-FIM protocol from 2006) and double independent pathology review of morphologically deviant sections. Results Three hundred and sixty RRSOs were performed in 188 BRCA1- carriers, 115 BRCA2 -carriers and 57 BRCA -negative women at a median age of 44.0 years. Four occult invasive cancers were detected in BRCA -carriers (1.3%, 95%-confidence interval (CI) 0.03–2.61), all in BRCA1 -carriers >40 years of age. All cancers, of which two tubal and two ovarian cancers, were FIGO-stage I/II. Three non-invasive serous intraepithelial carcinomas (STICs) were detected in BRCA -carriers (1.0%, 95%-CI 0.00–2.10). In BRCA -negative women one STIC was found (1.8%, 95%-CI 0.00–5.16), however she carried an unclassified variant in BRCA2 . Total follow-up after RRSO was 1691 woman-years, in which one BRCA1 -carrier developed peritoneal cancer (0.3%, 95%-CI 0.00–0.82). Conclusions A low prevalence of occult invasive cancer (1.1%) was found in young asymptomatic, screen-negative women at increased ovarian cancer risk undergoing RRSO. This study adds to the advice to perform RRSO in BRCA1 -carriers before the age of 40. Our findings support the hypothesis of the fallopian tube as the primary site of origin of pelvic high-grade serous cancer.
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