Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.

INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. METHODS: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. RESULTS: Of the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro. CONCLUSION: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.

Who benefits from guided internet-based interventions? A systematic review of predictors and moderators of treatment outcome.

To our knowledge, no systematic review has been conducted on predictors or moderators of treatment outcome across diagnoses in guided internet-based interventions (IBIs) for adults. To identify who benefits from this specific format and therein inform future research on improving patient-treatment fit, we aimed to aggregate results of relevant studies. 2100 articles, identified by searching the databases PsycInfo, Ovid Medline, and Pubmed and through snowballing, were screened in April/May 2021 and October 2022. Risk of bias and intra- and interrater reliability were assessed. Variables were grouped by predictor category, then synthesized using vote counting based on direction of effect. N = 60 articles were included in the review. Grouping resulted in 88 predictors/moderators, of which adherence, baseline symptoms, education, age, and gender were most frequently assessed. Better adherence, treatment credibility, and working alliance emerged as conclusive predictors/moderators for better outcome, whereas higher baseline scores predicted more reliable change but higher post-treatment symptoms. Results of all other predictors/moderators were inconclusive or lacked data. Our review highlights that it is currently difficult to predict, across diagnoses, who will benefit from guided IBIs. Further rigorous research is needed to identify predictors and moderators based on a sufficient number of studies. PROSPERO registration: CRD42021242305.

Differential diagnoses of right lower quadrant pain in late pregnancy.

We present two patients with right lower quadrant pain during the 36th week of pregnancy. In both cases, the challenges in diagnosing acute appendicitis in late pregnancy is underlined by misleading imaging results, revealing fluid in the lower abdomen, suggesting an appendicitis. Surgery was performed. Pre- and intraoperative gynecological examinations showed no signs of fetal distress. In patient 1, surgery revealed a torsion and necrosis of the right ovary and a 7-cm cyst of the fallopian tube. Open ovariectomy and appendectomy were performed. In patient 2, we saw a perforated appendicitis and cloudy ascites. Histology after appendectomy showed spots of endometriosis and serositis infiltrating into the appendix with signs of perforation at the tip. Patient 1 recovered after a short period of bowel paralysis. Patient 2 needed Caesarean section due to severe deceleration in the cardiotocograph and irregular uterine contractions. The newborn was kept in the neonatal ICU for 10 days.

Continuously sutured versus linear-stapled anastomosis in robot-assisted hybrid Ivor Lewis esophageal surgery following neoadjuvant chemoradiotherapy: a single-center cohort study.

BACKGROUND: Esophageal cancer surgery is technically highly demanding. During the past decade robot-assisted surgery has successfully been introduced in esophageal cancer treatment. Various techniques are being evaluated in different centers. In particular, advantages and disadvantages of continuously sutured (COSU) or linear-stapled (LIST) gastroesophageal anastomoses are debated. Here, we comparatively analyzed perioperative morbidities and short-term outcomes in patients undergoing hybrid robot-assisted esophageal surgery following neoadjuvant chemoradiotherapy (nCRT), with COSU or LIST anastomoses in a single center. METHODS: Following standardized, effective, nCRT, 53 patients underwent a hybrid Ivor Lewis robot-assisted esophagectomy with COSU (n = 32) or LIST (n = 21) gastroesophageal anastomoses. Study endpoints were intra- and postoperative complications, in-hospital morbidity and mortality. Duration of operation, intensive care unit (ICU) and overall hospital stay were also evaluated. Furthermore, rates of rehospitalization, endoscopies, anastomotic stenosis and recurrence were assessed in a 90-day follow-up. RESULTS: Demographics, ASA scores and tumor characteristics were comparable in the two groups. Median duration of operation was similar in patients with COSU and LIST anastomosis (467 vs. 453 min, IQR 420-521 vs. 416-469, p = 0.0611). Major complications were observed in 4/32 (12.5%) and 4/21 (19%) patients with COSU or LIST anastomosis, respectively (p = 0.697). Anastomotic leakage was observed in 3/32 (9.3%) and 2/21 (9.5%) (p = 1.0) patients with COSU or LIST anastomosis, respectively. Pleural empyema occurred in 1/32 (3.1%) and 2/21 (9.5%) (p = 0.555) patients, respectively. Mortality was similar in the two groups (1/32, 3.1% and 1/21, 4.7%, p = 1.0). Median ICU stay did not differ in patients with COSU or LIST anastomosis (p = 0.255), whereas a slightly, but significantly (p = 0.0393) shorter overall hospital stay was observed for COSU, as compared to LIST cohort (median: 20 vs. 21 days, IQR 17-22 vs. 18-28). CONCLUSIONS: COSU is not inferior to LIST in the performance of gastroesophageal anastomosis in hybrid Ivor Lewis operations following nCRT.

[Adrenal tumors]. / Nebennierentumore.

Adrenal tumors Abstract. The term 'adrenal tumor' describes benign and malignant mass lesions of the adrenal gland, including primary adrenal tumors and metastases from extra-adrenal origin. With the widespread use of imaging technique, adrenal tumors have become increasingly detected as 'incidentalomas'. The detection of an adrenal tumor raises two questions: Is the mass malignant? Is the mass hormonally active? Whereas the evaluation for malignancy is based on specific imaging characteristics (imaging phenotype), a targeted clinical examination and specific biochemical tests are required to assess for hormonal secretion. An adrenal mass < 4 cm with clear benign features on imaging and with a normal hormonal workup does not require treatment. If malignancy is suspected further diagnostic procedures and / or adrenalectomy are indicated. For hormonally active tumors surgery is generally considered the treatment of choice; however, the decision for surgery has to be individualized for aldosterone-secreting tumors and for cortisol-secreting tumors with only mild cushing's syndrome. Also in patients with large tumors (> 4 cm), and in cases with non-conclusive evaluation for malignancy or hormonal activity, the decision for further management has to be made on an individual basis. A minimally invasive surgical approach may be considered in adrenal tumors < 6 cm and without local infiltration of adjacent structures. Both laparoscopic (transabdominal) and retroperitoneoscopic techniques are possible. The surgical outcome depends on the surgeon's experience. A close interdisciplinary collaboration is mandatory in the evaluation and treatment of adrenal tumors.

A Multi-Institution Collaboration to Define Core Content and Design Flexible Curricular Components for a Foundational Medical School Course: Implications for National Curriculum Reform.

Medical educators have not reached widespread agreement on core content for a U.S. medical school curriculum. As a first step toward addressing this, five U.S. medical schools formed the Robert Wood Johnson Foundation Reimagining Medical Education collaborative to define, create, implement, and freely share core content for a foundational medical school course on microbiology and immunology. This proof-of-concept project involved delivery of core content to preclinical medical students through online videos and class-time interactions between students and facilitators. A flexible, modular design allowed four of the medical schools to successfully implement the content modules in diverse curricular settings. Compared with the prior year, student satisfaction ratings after implementation were comparable or showed a statistically significant improvement. Students who took this course at a time point in their training similar to when the USMLE Step 1 reference group took Step 1 earned equivalent scores on National Board of Medical Examiners-Customized Assessment Services microbiology exam items. Exam scores for three schools ranged from 0.82 to 0.84, compared with 0.81 for the national reference group; exam scores were 0.70 at the fourth school, where students took the exam in their first quarter, two years earlier than the reference group. This project demonstrates that core content for a foundational medical school course can be defined, created, and used by multiple medical schools without compromising student satisfaction or knowledge. This project offers one approach to collaboratively defining core content and designing curricular resources for preclinical medical school education that can be shared.