The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced ...in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow‐up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at‐risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25–75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at‐risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.
In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline
mutation; however, in most cases the cause remains unknown. ...Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes
,
or
.
We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a
germline mutation for germline variants affecting
,
and
using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.
Predicted deleterious germline variants were not encountered in
, but recurrently observed in
(n=2) and
(n=3) in our cohort of patients with GC. In contrast to deleterious variants in
, deleterious variants in
also occur frequently in the general population.
Based on our results
should no longer be considered a GC predisposition gene, whereas deleterious
variants are confirmed as an infrequent cause of GC susceptibility. Biallelic
germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
OBJECTIVEOptimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We ...analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODSWe selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTSOf 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% 95% CI: 1.4%-5.8%) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% 95% CI: 0.1%-4.5%) had a contralateral groin recurrence. CONCLUSIONThe risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.
To investigate the effects of PFR after LAR compared to usual care without PFR.
Functional complaints, including fecal incontinence, often occur after LAR for rectal cancer. Controversy exists about ...the effectiveness of PFR in improving such postoperative functional outcomes.
This was a multicenter, randomized controlled trial involving 17 Dutch centers. Patients after LAR for rectal cancer were randomly assigned (1:1) to usual care or PFR and stratified by sex and administration of neoadjuvant therapy. Selection was not based on severity of complaints at baseline. Baseline measurements were taken 3 months after surgery without temporary stoma construction or 6 weeks after stoma closure. The primary outcome measure was the change in Wexner incontinence scores 3 months after randomization. Secondary outcomes were fecal incontinence-related quality of life, colorectal-specific quality of life, and the LARS scores.
Between October 2017 and March 2020, 128 patients were enrolled and 106 randomly assigned (PFR n = 51, control n = 55); 95 patients (PFR n = 44, control n = 51) were assessable for final analysis. PFR did not lead to larger changes in Wexner incontinence scores in nonselected patients after LAR compared to usual care PFR: -2.3, 95% confidence interval (CI) -3.3 to -1.4, control: -1.3, 95% CI -2.2 to -0.4, P = 0.13. However, PFR was associated with less urgency at follow-up (odds ratio 0.22, 95% CI 0.06-0.86). Patients without near-complete incontinence reported larger Wexner score improvements after PFR (PFR: -2.1, 95% CI -3.1 to -1.1, control: -0.7, 95% CI -1.6 to 0.2, P = 0.045). For patients with at least moderate incontinence PFR resulted in relevant improvements in all fecal incontinence-related quality of life domains, while the control group deteriorated. These improvements were even larger when patients with near-complete incontinence were excluded. No serious adverse PFR-related events occurred.
No benefit was found of PFR in all patients but several subgroups were identified that did benefit from PFR, such as patients with urgency or with at least moderate incontinence and no near-complete incontinence. A selective referral policy (65%-85% of all patients) is suggested to improve postoperative functional outcomes for patients after LAR for rectal cancer.
Netherlands Trial Registration, NTR5469, registered on 3 September 2015.
Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2-7 % and has ...hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy.
The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m(2)/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response.
The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer.
Trial open for accrual: 3 April 2013 The Netherlands National Trial Register - NTR3709 (8 November 2012) EU Clinical Trials Register - 2012-003181-40 (11 December 2012).
FoCal: A highly granular digital calorimeter van der Kolk, N.
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2020, Letnik:
958
Journal Article
Recenzirano
This contribution discusses the recent progress in the development of a highly granular digital electromagnetic calorimeter proposed as an upgrade to the ALICE detector. This forward electromagnetic ...calorimeter (FoCal) must be able to discriminate decay photons from direct photons at very high energy, which requires extremely high granularity and a small Molière radius. A dedicated R&D program is ongoing to develop the technology needed for such a high-granularity device. Within this program we have constructed a prototype of a digital electromagnetic calorimeter based on CMOS monolithic active pixel sensors (MAPS). This prototype has demonstrated the unique capabilities of such a highly granular digital calorimeter, providing unprecedented shower profile measurements and good linearity and energy resolution. The prototype was based on the MIMOSA chip, which is however not fast enough for application in a full detector at the LHC. As a next step, the ALPIDE chip developed for the ALICE Inner Tracker Upgrade is being investigated for performance with high occupancy. This contribution presents results from the current prototype, the performance of the ALPIDE and plans for the next prototype.
Several studies have attempted to characterize intracranial atherosclerotic plaques by using MR imaging sequences. However, dedicated validation of these sequences with histology has not yet been ...performed. The current study assessed the ability of ultra-high-resolution 7T MR imaging sequences with different image contrast weightings to image plaque components, by using histology as criterion standard.
Five specimens of the circle of Wills were imaged at 7T with 0.11 × 0.11 mm in-plane-resolution proton attenuation-, T1-, T2-, and T2*-weighted sequences (through-plane resolution, 0.11-1 mm). Tissue samples from 13 fiducial-marked locations (per specimen) on MR imaging underwent histologic processing and atherosclerotic plaque classification. Reconstructed MR images were matched with histologic sections at corresponding locations.
Forty-four samples were available for subsequent evaluation of agreement or disagreement between plaque components and image contrast differences. Of samples, 52.3% (n = 23) showed no image contrast heterogeneity; this group comprised solely no lesions or early lesions. Of samples, 25.0% (n = 11, mostly advanced lesions) showed good correlation between the spatial organization of MR imaging heterogeneities and plaque components. Areas of foamy macrophages were generally seen as proton attenuation-, T2-, and T2*- hypointense areas, while areas of increased collagen content showed more ambiguous signal intensities. Five samples showed image-contrast heterogeneity without corresponding plaque components on histology; 5 other samples showed contrast heterogeneity based on intima-media artifacts.
MR imaging at 7T has the image contrast capable of identifying both focal intracranial vessel wall thickening and distinguishing areas of different signal intensities spatially corresponding to plaque components within more advanced atherosclerotic plaques.
Summary
Background
Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be ...a potential novel treatment for cutaneous warts.
Objectives
To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT.
Methods
Treatment with ICVT was assessed for efficacy, safety and tolerability in a single‐ centre, randomized, double‐blind, placebo‐controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed‐model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643.
Results
Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (−3·0 mm, 95% confidence interval −4·9 to −1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (−94%, 95% confidence interval −100 to −19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts.
Conclusions
This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.
What's already known about this topic?
Cutaneous warts are caused by the human papillomavirus (HPV).
Ionic contraviral therapy (ICVT) might be a potential treatment for cutaneous warts.
A previous phase I/II open‐label study demonstrated the safety and efficacy of ICVT.
What does this study add?
Proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.
Topical ICVT demonstrates a favourable safety profile, with the effects most pronounced when it is combined in a formulation for common warts.
Wart size reduction was related to HPV load reduction measured by quantitative polymerase chain reaction (qPCR) in swabs.
qPCR is a valuable disease biomarker for drug development in cutaneous warts.
Plain language summary available online
Respond to this article
Following the identification in a proband of a germline
BRCA1
/
BRCA2
mutation in hereditary breast-ovarian cancer (HBOC) or a DNA mismatch repair gene mutation in Lynch syndrome (LS) he or she will ...be asked to inform at-risk family members about the option for presymptomatic DNA testing. However, in clinical practice multiple factors may complicate the process of information sharing. We critically evaluated studies on the uptake of presymptomatic genetic testing in both syndromes. A search of relevant MeSH terms and key words in PubMed, Embase and PsycINFO yielded 795 articles published between 2001 and 2017. Thirty of these publications included outcome measures relevant for the current study. Based on information provided by the proband (15 studies) the uptake of presymptomatic genetic testing ranged from 15 to 57% in HBOC, while one study in LS kindreds reported an uptake of 70%. Based on information provided by genetics centres (the remaining 15 studies) the uptake ranged from 21 to 44% in HBOC and from 41 to 94% in LS. However, when genetics centres contacted relatives directly a substantial number of additional family members could be tested. Proband-mediated provision of information to at-risk relatives is a standard procedure in hereditary breast-ovarian cancer and Lynch syndrome. However, the resulting uptake of presymptomatic testing is disappointing—an issue that is now urgent due to the increased use of genetic testing in clinical oncology. We propose that additional strategies should be introduced including the geneticist directly contacting relatives. The outcomes of these strategies should be carefully monitored and evaluated.
A prototype of a new type of calorimeter has been designed and constructed, based on a silicon–tungsten sampling design using pixel sensors with digital readout. It makes use of the ALPIDE sensor ...developed for the ALICE Inner Tracking System (ITS) upgrade. A binary readout is possible due to the pixel size of ≈30×30μm2. This prototype has been successfully tested with cosmic muons and with test beams at DESY and the CERN SPS. We report on performance results obtained at DESY, showing good energy resolution and linearity, and compare to detailed MC simulations. Also shown are preliminary results of the high-energy performance as measured at the SPS. The two-shower separation capabilities are discussed.
•First fully digital electromagnetic calorimeter with high-speed readout built.•ALPIDE pixel sensors work well in high particle-density environment.•Basic calorimetric performance of pixel calorimeter on par with state of the art.•Has unique capabilities in terms of position resolution and two-shower separation.
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