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BackgroundThe role of the vulvar microbiome in the development of (pre)malignant vulvar disease is scarcely investigated. The aim of this exploratory study was to analyze vulvar microbiome composition in lichen sclerosus (LS) and vulvar high-grade squamous intraepithelial lesions (HSIL) compared to healthy controls.MethodsWomen with vulvar lichen sclerosus (n = 10), HSIL (n = 5) and healthy controls (n = 10) were included. Swabs were collected from the vulva, vagina and anal region for microbiome characterization by metagenomic shotgun sequencing. Both lesional and non-lesional sites were examined. Biophysical assessments included trans-epidermal water loss for evaluation of the vulvar skin barrier function and vulvar and vaginal pH measurements.ResultsHealthy vulvar skin resembled vaginal, anal and skin-like microbiome composition, including the genera Prevotella, Lactobacillus, Gardnerella, Staphylococcus, Cutibacterium, and Corynebacterium. Significant differences were observed in diversity between vulvar skin of healthy controls and LS patients. Compared to the healthy vulvar skin, vulvar microbiome composition of both LS and vulvar HSIL patients was characterized by significantly higher proportions of, respectively, Papillomaviridae (p = 0.045) and Alphapapillomavirus (p = 0.002). In contrast, the Prevotella genus (p = 0.031) and Bacteroidales orders (p = 0.038) were significantly less abundant in LS, as was the Actinobacteria class (p = 0.040) in vulvar HSIL. While bacteria and viruses were most abundant, fungal and archaeal taxa were scarcely observed. Trans-epidermal water loss was higher in vulvar HSIL compared to healthy vulvar skin (p = 0.043).ConclusionThis study is the first to examine the vulvar microbiome through metagenomic shotgun sequencing in LS and HSIL patients. Diseased vulvar skin presents a distinct signature compared to healthy vulvar skin with respect to bacterial and viral fractions of the microbiome. Key findings include the presence of papillomaviruses in LS as well as in vulvar HSIL, although LS is generally considered an HPV-independent risk factor for vulvar dysplasia. This exploratory study provides clues to the etiology of vulvar premalignancies and may act as a steppingstone for expanding the knowledge on potential drivers of disease progression.

Introduction Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson’s disease (PD) via the gut–brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy.Methods and analysis We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor–recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months.Ethics and dissemination This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences.Trial registration number International Clinical Trial Registry Platform: NL9438.

Abstract Background The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion Transplanting fecal microbiota to restore the patients’ perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. Trial registration ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08–02-2022).

Abstract Functionality of the gastrointestinal tract is essential for growth and development of newborns. Preterm infants have an immature gastrointestinal tract, which is a major challenge in neonatal care. This study aims to improve the understanding of gastrointestinal functionality and maturation during the early life of preterm infants by means of gastrointestinal enzyme activity assays and metaproteomics. In this single-center, observational study, preterm infants born between 24 and 33 weeks (n = 40) and term infants born between 37 and 42 weeks (n = 3), who were admitted to Isala (Zwolle, the Netherlands), were studied. Enzyme activity analyses identified active proteases in gastric aspirates of preterm infants. Metaproteomics revealed human milk, digestive and immunological proteins in gastric aspirates of preterm infants and feces of preterm and term infants. The fecal proteome of preterm infants was deprived of gastrointestinal barrier-related proteins during the first six postnatal weeks compared to term infants. In preterm infants, bacterial oxidative stress proteins were increased compared to term infants and higher birth weight correlated to higher relative abundance of bifidobacterial proteins in postnatal week 3 to 6. Our findings indicate that gastrointestinal and beneficial microbial proteins involved in gastrointestinal maturity are associated with gestational and postnatal age.

Pseudobankesia keersmaekersi sp. n. (Lepidoptera, Psychidae, Taleporiinae) is described from Greece and compared with its likely close relatives Pseudobankesia arahova Stengel, 1990 and Pseudobankesia darwinii Stengel, 1990. The new species is well characterized by its remarkably coloured forewings and wing-pattern and the unusually large larval cases.

The nutritional requirements of preterm infants are unique and challenging to meet in neonatal care, yet crucial for their growth, development and health. Normally, the gut microbiota has distinct metabolic capacities, making their role in metabolism of dietary components indispensable. In preterm infants, variation in microbiota composition is introduced while facing a unique set of environmental conditions. However, the effect of such variation on the microbiota's metabolic capacity and on the preterm infant's growth and development remains unresolved. In this review, we will provide a holistic overview on the development of the preterm gut microbiota and the unique environmental conditions contributing to this, in addition to maturation of the gastrointestinal tract and immune system in preterm infants. The role of prematurity, as well as the role of human milk, in the developmental processes is emphasized. Current research stresses the early life gut microbiota as cornerstone for simultaneous development of the gastrointestinal tract and immune system. Besides that, literature provides clues that prematurity affects growth and development. As such, this review is concluded with our hypothesis that prematurity of the gut microbiota may be an inconspicuous clinical challenge in achieving optimal feeding besides traditional challenges, such as preterm breast milk composition, high nutritional requirements and immaturity of the gastrointestinal tract and immune system. A better understanding of the metabolic capacity of the gut microbiota and its impact on gut and immune maturation in preterm infants could complement current feeding regimens in future neonatal care and thereby facilitate growth, development and health in preterm infants.

Morphological variation in three rarely collected European species of the genus Lasiochernes Beier, 1932 is thoroughly examined in the present study. Detailed descriptions of previously ignored morphological characters of L. cretonatus Henderickx, 1998, L. jonicus (Beier, 1929) and L. pilosus (Ellingsen, 1910) are presented. The female of L. cretonatus and the nymphs of L. pilosus are described for the first time. Multivariate morphometric techniques (principal coordinate analysis and discriminant analyses) were employed to confirm morphological differentiation of the three Lasiochernes species and to identify the most reliable characters for their separation. The usefulness of particular body parts for species identification was evaluated. An identification key for the females of the Lasiochernes species studied is provided. Geographic distribution and habitat preferences of the three species are summarized.

Objective: To evaluate the oncological outcome at 5-year follow-up after laparoscopic cryoablation (LCA) for small renal masses (SRMs), as there is an increasing interest in ablative therapy for cT1a renal tumours due to the rising incidence of SRMs, the trend towards minimally invasive nephron-sparing treatments, and the ageing population. Patients and methods: Between 2004 and 2015, 233 consecutive LCA were performed in 219 patients for SRMs at two referral centres. We only included those patients with ≥5 years of follow-up (n = 165) in a prospectively maintained database. A descriptive analysis was conducted for pre-, peri- and postoperative characteristics. A Kaplan–Meier analysis assessed overall (OS), disease-specific (DSS), and recurrence-free survival (RFS). Results: The median (interquartile range [IQR]) age of our patient cohort was 68 (60.5–76) years. The median (IQR) body mass index was 26.2 (23.8–29) kg/m2, and the median (IQR) Charlson Comorbidity Index score corrected for age was 4 (2.5–6). The median (IQR) tumour diameter was 28 (21–33) mm. In all, 15% developed a complication in the first 30 days after LCA, of which 1% had a major complication (Clavien–Dindo Grade ≥III). The median (IQR) preoperative estimated glomerular filtration rate (eGFR) was 82.5 (65–93.75) mL/min/1.73 m2. The median eGFR decreased by 16.4% and 15.2% at the 3-month and 5-year follow-up, respectively. Persistence was found in 1%, local recurrence in 2%, and systemic progression in 4%. The OS, DSS, and RFS were 74%, 96.9% and 95.4%, respectively. Conclusion: LCA is a safe and effective treatment for SRMs in selected cases and shows good oncological outcomes after 5 years of follow-up, with only 1% developing a major complication. [ABSTRACT FROM AUTHOR]

Summary Introduction Renal papillary necrosis is not commonly seen in daily practice, but can have severe consequences when it is not diagnosed in time. It is known to be associated with sickle cell hemoglobinopathies; however a wide range of etiologies are possible, and it is therefore not the first diagnosis clinicians consider in patients with sickle cell disease who present with hematuria. Methods A literature search was performed to summarize the current knowledge about renal papillary necrosis associated with sickle cell disease. These findings are illustrated with a case of a 9-year old girl with sickle cell disease who was referred with painless gross hematuria. Results Typical radiologic signs for renal papillary necrosis are necrotic cavities that fill with contrast, small collections of contrast peripheral to the calyces in the papillary region (ball-on-tee sign), calcification of the papillary defect, filling defects, hydronephrosis, blunted papillary tip, clefts in the renal medulla filled with contrast, hyperattenuated medullary calcifications, non-enhanced lesions surrounded by rings of excreted contrast, and clubbed calyces. Discussion This study focuses on the pathophysiology of renal papillary necrosis associated with sickle cell disease, the possible symptoms, as well as the diagnostic steps, with a special interest in particular presentation on old (retrograde pyelography) and new (computed tomography) gold standard in radiologic imaging, and the management for this pathology. Conclusion This study aims to remind clinicians of this “forgotten” diagnosis and what signs to look for in pediatric patients with sickle cell disease who present with hematuria. In pediatric cases radiation protection is important, therefore knowing what radiologic signs can be found on retrograde pyelography can lead to early identification of this pathology without having to proceed to computed tomography. [ABSTRACT FROM AUTHOR]

Introduction: Dose-escalation radiotherapy for rectal tumours is increasingly considered as a non-operative approach, with online-adaptive radiotherapy (oART) supporting this approach by correcting inter-fraction tumour position errors. However, using cone-beam computed tomography (CBCT)-guided oART requires daily target volume delineation by different operators, leading to inter-operator delineation variability and potential dosimetric issues. This study aims to compare and quantify the inter-operator and inter-professional delineation variability of the rectal boost volume on CBCT, including volumes by an automatically delineated oART treatment planning system., Materials and Methods: A rectal boost volume, defined as the primary tumour extended to the entire adjacent rectal wall, was delineated on 10 CBCTs from 5 patients by 15 operators: 4 expert radiation oncologists (ROs), 4 radiation therapists (RTTs) and 7 non-expert ROs. These contours were compared between the different professional groups. A comparison to the average volume of the group (ROs, RTTs, or non-expert ROs) with the lowest delineation variability was also performed for each individual volume including the volume automatically generated by an oART treatment planning system., Results: Delineation variability was the highest in the superior (range: 2.3-6.0 mm), and inferior (2.3-12.4 mm) directions, compared to the left (0.2-4.4 mm), right (0.3-2.0 mm), anterior (0.1-2.9 mm), and posterior (0.5-4.0 mm) directions. Non-expert ROs, RTTs, and automatic oART volume showed similar ranges of delineation errors when compared to the expert ROs' volume, which was chosen as reference volume since this professional group showed the lowest variability., Discussion: Expert ROs showed consistent results. Other professional groups exhibit similar variability, comparable to the automatic oART volume. Therefore, RTTs could safely perform the rectal boost delineation without non-expert ROs supervision in the absence of expert ROs during CBCT-based oART. Moreover, these findings provide quantitative data to compute accurate margins for the rectal boost planning target volume in a CBCT-guided oART workflow., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background and Purpose: Deep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations., Materials and Methods: We conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility., Results: Differences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V 5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V 20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V 30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart's inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar., Conclusion: Mechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)