Technical feasibility and clinical success of direct "free hand" EUS-guided gastroenterostomy in patients with gastric outlet obstruction.

Background and study aims Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) with lumen-apposing metal stents (LAMS) appears to be a promising intervention in management of gastroduodenal out obstruction (GOO), particularly for patients for whom surgery is high risk or in a palliative setting. This study aimed to evaluate the technical feasibility, procedure-associated adverse events (AEs), and clinical outcome of direct "free hand" EUS-GE. Patients and methods This retrospective two-center study included patients who underwent direct "free hand" EUS-GE (April 2017 to March 2021) investigating technical success (correctly placed LAMS), clinical outcome (successful oral nutrition), and management of procedure-associated AEs. "Free hand" was defined as the use of the electrocautery enhanced stent delivery system alone without additional guidewire-assistance for EUS-GE creation. Results Forty-five patients (58 % women/42 % men; mean age 65 years) with malignant (n = 39), benign (n = 4) or unclear (n = 2) GOO underwent direct "free hand" EUS-GE. The technical success rate was 98 % (44/45). Of the patients, 95% (42/44) had less vomiting and increased ability to tolerate oral food intake after the intervention. In one patient, a second EUS-GE was necessary to achieve sufficient clinical improvement. Procedure-associated AEs were observed in 24 % (11/45) of cases including stent misplacement (n = 7), leakage (n = 1), development of a gastrojejunocolic fistula (n = 1), and bleeding (n = 2), which could be all managed endoscopically. Conclusions Direct EUS-GE has a favorable risk-benefit profile for patients with GOO, showing high technical success rates, manageable AEs, and rapid symptom relief.

Integration of PET-imaging into radiotherapy treatment planning for low-grade meningiomas improves outcome.

PURPOSE: Meningiomas have an excellent survival prognosis, and radiotherapy (RT) is a central component of interdisciplinary treatment. During treatment planning, the definition of the target volume remains challenging using MR and CT imaging alone. This is the first study to analyze the impact of additional PET-imaging on local control (LC) and overall survival (OS) after high-precision RT. METHODS: We analyzed 339 meningiomas treated between 2000 and 2018. For analyses, we divided the patients in low-grade (n = 276) and high-grade (n = 63) cases. We performed RT in an adjuvant setting due to subtotal resection or later due to recurrent tumor growth. The target volumes were delineated based on diagnostic CT and MRI and, if available, additional PET-imaging (low-grade: n = 164, 59.4%; high-grade: n = 39, 61.9%) with either 68Ga-Dotanoc/Dotatoc, 18F-fluoroethyltyrosine or 11C-methionine tracer. Patients were treated with fractionated stereotactic RT with a median total dose and dose per fraction of 54 Gy and 1.8 Gy, respectively. RESULTS: Median follow-up was 5.6 years. For low-grade meningiomas, mean OS was 15.6 years and mean LC was 16.9 years; for high-grade cases mean OS was 11.6 years, and mean LC was 11.1 years. In univariate analyses, PET-imaging had a significant impact on OS (p = 0.035) and LC (p = 0.041) for low-grade meningiomas and remained significant (p = 0.015) for LC in the multivariate analysis. For high-grade cases, PET did not influence both OS and LC. Further prognostic factors could be identified. CONCLUSIONS: For low-grade meningiomas, we showed that the addition of PET-imaging for target volume definition led to a significantly enhanced LC. Thus, PET improves the detection of tumor cells and helps distinguish between healthy tissue and meningioma tissue, especially during the treatment planning process.

Mobile App Delivery of the EORTC QLQ-C30 Questionnaire to Assess Health-Related Quality of Life in Oncological Patients: Usability Study.

BACKGROUND: Mobile apps are evolving in the medical field. However, ongoing discussions have questioned whether such apps are really valuable and whether patients will accept their use in day-to-day clinical life. Therefore, we initiated a usability study in our department. OBJECTIVE: We present our results of the first app prototype and patient testing of health-related quality of life (HRQoL) assessment in oncological patients. METHODS: We developed an app prototype for the iOS operating system within eight months in three phases: conception, initial development, and pilot testing. For the HRQoL assessment, we chose to implement only the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30; German version 3). Usability testing was conducted for three months. Participation was voluntary and pseudonymized. After completion of the QLQ-C30 questionnaire using iPads provided by our department, we performed a short survey with 10 questions. This survey inquired about patients' opinions regarding general aspects, including technical advances in medicine, mobile and app assistance during cancer treatment, and the app-specific functions (eg, interface and navigation). RESULTS: After logging into the app, the user can choose between starting a questionnaire, reviewing answers (administrators only), and logging out. The questionnaire is displayed with the same information, questions, and answers as on the original QLQ-C30 sheet. No alterations in wording were made. Usability was tested with 81 patients; median age was 55 years. The median time for completing the HRQoL questionnaire on the iPad was 4.0 minutes. Of all participants, 84% (68/81) owned a mobile device. Similarly, 84% (68/81) of participants would prefer a mobile version of the HRQoL questionnaire instead of a paper-based version. Using the app in daily life during and after cancer treatment would be supported by 83% (67/81) of participants. In the prototype version of the app, data were stored on the device; in the future, 79% (64/81) of the patients would agree to transfer data via the Internet. CONCLUSIONS: Our usability test showed good results regarding attractiveness, operability, and understandability. Moreover, our results demonstrate a high overall acceptance of mobile apps and telemedicine in oncology. The HRQoL assessment via the app was accepted thoroughly by patients, and individuals are keen to use it in clinical routines, while data privacy and security must be ensured.

High-precision radiotherapy for meningiomas : Long-term results and patient-reported outcome (PRO).

OBJECTIVE: To evaluate long-term outcome after high-precision radiotherapy (RT) of meningioma patients in terms of survival and side effects. METHODS: We analyzed 275 meningioma cases: 147 low-grade and 43 high-grade meningiomas (WHO II: n = 40, III: n = 3). In all, 85 patients had no pathologically confirmed histology but were determined as low-grade based on multimodal imaging. Surgery was performed in 183 cases. RT was delivered as either radiosurgery (RS, n = 16), fractionated stereotactic radiotherapy (FSRT, n = 241), or intensity-modulated radiation therapy (IMRT, n = 18). Of 218 patients contacted for patient-reported-outcome (PRO), 207 responded (95%). RESULTS: Median follow-up was 7.2 years. For low-grade meningioma the survival rate (OS) was 97% at 3 years, 85% at 10 years, and 64% at 15 years, for atypical meningioma 91% at 3 years, 62% at 10 years, and 50% at 15 years. Local control rate (PFS) for low-grade meningioma was 91% at 3 years, 87% at 5 years, and 86% at 10 years, for atypical cases 67% at 3 years and 55% at 5 years. Of all, 3.0% of patients reported worsened or new symptoms grade ≥3 during RT and the first 6 months thereafter; 17.5% reported a deterioration after more than 2 years. We found the prognostic factors tumor volume and age significantly influencing OS and PFS. CONCLUSION: Complemented by PRO, we found long-term low toxicity rates in addition to excellent local control. Thus, due to the beneficial risk-benefit profile of benign and high-risk meningiomas, RT should be performed as adjuvant treatment and should not be postponed until tumor progression.

Fractionated vs. single-fraction stereotactic radiotherapy in patients with vestibular schwannoma : Hearing preservation and patients' self-reported outcome based on an established questionnaire.

BACKGROUND: Stereotactic radiotherapy (RT) has been established as a valid treatment alternative in patients with vestibular schwannoma (VS). There is ongoing controversy regarding the optimal fractionation. Hearing preservation may be the primary goal for patients with VS, followed by maintenance of quality of life (QoL). METHODS: From 2002 to 2015, 184 patients with VS were treated with radiosurgery (RS) or fractionated stereotactic radiotherapy (FSRT). A survey on current symptoms and QoL was conducted between February and June 2016. RESULTS: Median follow-up after RT was 7.5 years (range 0-14.4 years). Mean overall survival (OS) after RT was 31.1 years, with 94 and 87% survival at 5 and 10 years, respectively [corrected]. Mean progression-free survival (PFS) was 13.3 years, with 5­ and 10-year PFS of 92%. Hearing could be preserved in RS patients for a median of 36.3 months (range 2.3-13.7 years). Hearing worsened in 17 (30%) cases. Median hearing preservation for FSRT was 48.7 months (range 0.0-13.8 years); 29 (23%) showed hearing deterioration. The difference in hearing preservation was not significant between RS and FSRT (p = 0.3). A total of 123/162 patients participated in the patient survey (return rate 76%). The results correlate well with the information documented in the patient files for tinnitus and facial and trigeminal nerve toxicity. Significant differences appeared regarding hearing impairment, gait uncertainty, and imbalance. CONCLUSION: These data confirm that RS and FSRT are comparable in terms of local control for VS. RS should be reserved for smaller lesions, while FSRT can be offered independently of tumor size. Patient self-reported outcome during follow-up is of high value. The established questionnaire could be validated in the independent cohort.

Gossypol toxicity and detoxification in Helicoverpa armigera and Heliothis virescens.

Gossypol is a polyphenolic secondary metabolite produced by cotton plants, which is toxic to many organisms. Gossypol's aldehyde groups are especially reactive, forming Schiff bases with amino acids of proteins and cross-linking them, inhibiting enzyme activities and contributing to toxicity. Very little is known about gossypol's mode of action and its detoxification in cotton-feeding insects that can tolerate certain concentrations of this compound. Here, we tested the toxicity of gossypol and a gossypol derivative lacking free aldehyde groups (SB-gossypol) toward Helicoverpa armigera and Heliothis virescens, two important pests on cotton plants. Larval feeding studies with these two species on artificial diet supplemented with gossypol or SB-gossypol revealed no detectable toxicity of gossypol, when the aldehyde groups were absent. A cytochrome P450 enzyme, CYP6AE14, is upregulated in H. armigera feeding on gossypol, and has been claimed to directly detoxify gossypol. However, using in vitro assays with heterologously expressed CYP6AE14, no metabolites of gossypol were detected, and further studies suggest that gossypol is not a direct substrate of CYP6AE14. Furthermore, larvae feeding on many other plant toxins also upregulate CYP6AE14. Our data demonstrate that the aldehyde groups are critical for the toxicity of gossypol when ingested by H. armigera and H. virescens larvae, and suggest that CYP6AE14 is not directly involved in gossypol metabolism, but may play a role in the general stress response of H. armigera larvae toward plant toxins.

Multifaceted biological insights from a draft genome sequence of the tobacco hornworm moth, Manduca sexta.

Manduca sexta, known as the tobacco hornworm or Carolina sphinx moth, is a lepidopteran insect that is used extensively as a model system for research in insect biochemistry, physiology, neurobiology, development, and immunity. One important benefit of this species as an experimental model is its extremely large size, reaching more than 10 g in the larval stage. M. sexta larvae feed on solanaceous plants and thus must tolerate a substantial challenge from plant allelochemicals, including nicotine. We report the sequence and annotation of the M. sexta genome, and a survey of gene expression in various tissues and developmental stages. The Msex_1.0 genome assembly resulted in a total genome size of 419.4 Mbp. Repetitive sequences accounted for 25.8% of the assembled genome. The official gene set is comprised of 15,451 protein-coding genes, of which 2498 were manually curated. Extensive RNA-seq data from many tissues and developmental stages were used to improve gene models and for insights into gene expression patterns. Genome wide synteny analysis indicated a high level of macrosynteny in the Lepidoptera. Annotation and analyses were carried out for gene families involved in a wide spectrum of biological processes, including apoptosis, vacuole sorting, growth and development, structures of exoskeleton, egg shells, and muscle, vision, chemosensation, ion channels, signal transduction, neuropeptide signaling, neurotransmitter synthesis and transport, nicotine tolerance, lipid metabolism, and immunity. This genome sequence, annotation, and analysis provide an important new resource from a well-studied model insect species and will facilitate further biochemical and mechanistic experimental studies of many biological systems in insects.

Potential detoxification of gossypol by UDP-glycosyltransferases in the two Heliothine moth species Helicoverpa armigera and Heliothis virescens.

The cotton bollworm Helicoverpa armigera and the tobacco budworm Heliothis virescens are closely related generalist insect herbivores and serious pest species on a number of economically important crop plants including cotton. Even though cotton is well defended by its major defensive compound gossypol, a toxic sesquiterpene dimer, larvae of both species are capable of developing on cotton plants. In spite of severe damage larvae cause on cotton plants, little is known about gossypol detoxification mechanisms in cotton-feeding insects. Here, we detected three monoglycosylated and up to five diglycosylated gossypol isomers in the feces of H. armigera and H. virescens larvae fed on gossypol-supplemented diet. Candidate UDP-glycosyltransferase (UGT) genes of H. armigera were selected by microarray studies and in silico analyses and were functionally expressed in insect cells. In enzymatic assays, we show that UGT41B3 and UGT40D1 are capable of glycosylating gossypol mainly to the diglycosylated gossypol isomer 5 that is characteristic for H. armigera and is absent in H. virescens feces. In conclusion, our results demonstrate that gossypol is partially metabolized by UGTs via glycosylation, which might be a crucial step in gossypol detoxification in generalist herbivores utilizing cotton as host plant.

Phylogenetic relatedness and host plant growth form influence gene expression of the polyphagous comma butterfly (Polygonia c-album).

BACKGROUND: The mechanisms that shape the host plant range of herbivorous insect are to date not well understood but knowledge of these mechanisms and the selective forces that influence them can expand our understanding of the larger ecological interaction. Nevertheless, it is well established that chemical defenses of plants influence the host range of herbivorous insects. While host plant chemistry is influenced by phylogeny, also the growth forms of plants appear to influence the plant defense strategies as first postulated by Feeny (the "plant apparency" hypothesis). In the present study we aim to investigate the molecular basis of the diverse host plant range of the comma butterfly (Polygonia c-album) by testing differential gene expression in the caterpillars on three host plants that are either closely related or share the same growth form. RESULTS: In total 120 genes were identified to be differentially expressed in P. c-album after feeding on different host plants, 55 of them in the midgut and 65 in the restbody of the caterpillars. Expression patterns could be confirmed with an independent method for 14 of 27 tested genes. Pairwise similarities in upregulation in the midgut of the caterpillars were higher between plants that shared either growth form or were phylogenetically related. No known detoxifying enzymes were found to be differently regulated in the midgut after feeding on different host plants. CONCLUSION: Our data suggest a complex picture of gene expression in response to host plant feeding. While each plant requires a unique gene regulation in the caterpillar, both phylogenetic relatedness and host plant growth form appear to influence the expression profile of the polyphagous comma butterfly, in agreement with phylogenetic studies of host plant utilization in butterflies.