Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
LBA5500 Background: Optimal timing of cytoreduction in non-frail patients (pts) with seemingly resectable stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma (OC) remains controversial. Methods: TRUST is an international randomized multicenter phase III trial in pts with stage IIIB-IVB OC and good performance status (ECOG 0/1) comparing primary cytoreductive surgery (PCS) followed by 6 cycles of intravenous (iv) chemotherapy to 3 cycles of neoadjuvant iv chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) and 3 further iv cycles. Maintenance treatment with bevacizumab and/or PARP inhibitors was allowed if selection criteria was similar for both arms. Pts were eligible for the study if preoperative clinical and radiologic assessment identified them as potential candidates for PCS. To ensure surgical quality, participating centers complied with an onsite surgery quality assurance audit, had adequate infrastructure, surgical proficiency (complete resection rates ≥50% in PCS) and sufficient volume (≥36 PCS/year). The intent to treat analysis population included all eligible pts with confirmed stage IIIB-IVB disease. The primary endpoint was overall survival (OS). Superiority was tested using a two-sided stratified log-rank test with significance level 0.05. Secondary endpoints were progression-free survival (PFS) and surgical complications. Results: A total of 688 eligible pts (median age: 63y; range: 32-83) underwent randomization: 345 were assigned to PCS and 343 to NACT/ICS. 91% had high-grade serous histology. Complete resection was achieved in 61.7%/62.9% of all randomized/all operated pts in the PCS group and 72%/76.6% in the ICS group. Median PFS was 22.2 months in the PCS group, and 19.7 months in the ICS group (HR 0.80 95%CI: 0.66-0.96; p=0.02). Median OS was 54.3 months in the PCS group and 48.3 months in the ICS group (HR 0.89 95%CI: 0.74-1.08; p=0.24). Pts with complete cytoreduction after PCS had the most favorable outcome, with a median PFS and OS of 27.9 and 67.0 months, respectively. A long-term benefit from PCS was seen in all analyzed subgroups. The benefit of PCS was most prominent in stage III pts (n=468): median PFS for PCS vs ICS, 26.3 vs 21.4 mos; median OS for PCS vs ICS, 63.7 vs 53.2 months. Major postoperative complication rates were acceptable, with a 30-day postoperative mortality rate of < 1% in both groups. Conclusions: In expert centers with proven surgical quality, PCS followed by iv chemotherapy resulted in a significantly longer median PFS and a numerically longer OS compared to NACT/ICS in non-frail OC pts. Although statistical significance in the primary endpoint was not reached, this is the first randomized trial to show a benefit of PCS over ICS. This benefit is likely to be associated with the high complete resection rate, reinforcing PCS as a standard of care in non-frail pts with seemingly resectable advanced OC. Clinical trial information: NCT02828618 .
Macropinocytosis and lysosomal degradation of extracellular protein constitute a nutrient acquisition pathway in Ras-driven cancers. By catabolizing albumin, the most abundant plasma protein, Ras-transformed cells sustain growth in environments where free amino acids are scarce. Under physiological conditions, however, albumin is normally protected from lysosomal degradation by the neonatal Fc receptor (FcRn), which recycles albumin back to the extracellular space. Here, by investigating how cancer cells overcome FcRn-mediated albumin recycling, we identify the Ras-Erk MAPK signaling pathway as a critical regulator of FcRn. Expression of constitutively active Ras variants or stimulation with growth factors represses FcRn transcription through activation of the MAPK pathway, leading to decreased FcRn protein abundance. Conversely, pharmacological inhibition of Ras-MAPK signaling de-represses FcRn expression. Restoring FcRn levels in Ras-transformed cells limits lysosomal albumin degradation and impairs the proliferation of cells that depend on albumin as an essential amino acid source. Thus, oncogenic Ras signaling promotes the nutritional utilization of albumin by suppressing FcRn, thereby supporting cancer cell adaptation to nutrient-poor environments.
To evaluate the safety, feasibility and imaging outcomes of percutaneous image-guided cryoablation as a minimally invasive treatment for umbilical endometriosis (UE). Between March 2017 and December 2024, 17 women (median age: 38 years; [IQR, 32–38]) underwent percutaneous cryoablation of UE at a single institution. Procedures were performed under ultrasound (US) alone or combined US/CT-scan guidance. Pain severity was assessed using the visual analog scale (VAS), imaging (US and MRI) and cosmetic outcomes were compared before and after treatment. Adverse events were reported according to the Society of Interventional Radiology classification (SIR). Median lesion volume was 2.42 cm3 [IQR, 0.82–4.70] on US and 2.98 cm3 [IQR, 1.14–5.49] on MRI. 12/17 procedures (70
PURPOSE:Incidentally found brain metastases often lead to emergency room referrals even in asymptomatic patients-a pathway of care that could be unnecessary. We sought to compare time and financial toxicity, and treatment outcomes between a multidisciplinary outpatient (MP) and acute care pathways (AP). METHODS:Patients referred for de novo asymptomatic brain metastases at an NCI-designated Cancer Center with a Multidisciplinary Brain Metastasis Program were identified via retrospective review. Scans, encounters, time to local interventions, and survival data were collected and compared. RESULTS:Seventy-eight patients were identified, 47 referred to MP and 31 AP. Both groups had similar disease-specific prognostic scores and received similar treatments. Patients managed via AP had larger dominant lesions (2.9 cm vs. 2.0 cm, p < 0.002) and shorter time to therapy (13.7 days vs. 9.2 days; p = 0.047). AP patients also had more medical-encounter (7.1 vs. 2.5; p < 0.001) and admitted days (5.9 vs. 1.1; p < 0.001), with increased median gross charge amount ($185,961 vs. $126,831; p = 0.003) despite similar 6-month survival (83% MP vs. 81% AP, p > 0.999) and local tumor control (95% MP vs. 96% AP, p = 0.849). CONCLUSION:Patients with asymptomatic brain metastases managed through an outpatient pathway attained similar disease outcomes with lower time and financial toxicity compared to patients managed through inpatient pathways. Characteristics of such patients that qualify them for outpatient pathway should be confirmed prospectively.
