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.

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.

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.

[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.