A novel Frizzled 7 antibody disrupts the Wnt pathway and inhibits Wilms tumor growth

Frizzled 7 (FZD7), a Wnt receptor that activates canonical Wnt/β-catenin signaling, has been implicated in multiple cancers, including Wilms tumor (WT), the most common pediatric kidney malignancy. We previously identified FZD7 as a marker of the WT cancer stem cell population and a potential therapeutic target. To evaluate this, we generated a panel of monoclonal anti-FZD7 antibodies using epitope mapping of the receptor and assessed their functional activity in primary WT cells and xenograft models. Among the panel, clone 288.1 induced significant cell death in primary Wilms tumor cells and inhibited cell proliferation and migration. This effect correlated with canonical Wnt signaling inhibition, a reduction in activated β-catenin and downregulation of Wnt/β-catenin target genes concomitant with diminished Wilms tumor cancer stem cell (CSC) markers. In vivo, treatment with anti-FZD7-288.1 significantly inhibited WT xenograft growth, resulting in reduced tumor volume. These findings demonstrate that FZD7 is a critical driver of Wilms tumor progression and support antibody-mediated FZD7 blockade as a promising therapeutic strategy

Pancreatic cancer outcome—local treatment with radiation using MRI-LINAC

IntroductionStereotactic MR-guided on-table adaptive radiotherapy (SMART) allows the precise delivery of high-dose radiation to tumors in great proximity to radiation-sensitive organs. The aim of this study is to evaluate the toxicity and clinical outcome in locally advanced or recurrent pancreatic tumors, with or without prior irradiation, treated with SMART.MethodsPatients were treated for pancreatic cancer (PC) using SMART technology to a prescribed dose of 50 Gy (BED10, 100 Gy) in five fractions, with daily on-table adaptation of treatment plan. Endpoints were acute and late toxicities, local control, local disease-free period, and overall survival.ResultsA total of 54 PC patients were treated between August 2019 and September 2022, with a median follow-up of 8.9 months from SMART. The median age was 70.4 (45.2–86.9) years. A total of 40 patients had upfront inoperable PC (55% were locally advanced and 45% metastatic), and 14 had local recurrence following prior pancreatectomy (six patients also had prior adjuvant RT). Of the patients, 87% received at least one chemotherapy regimen (Oxaliplatin based, 72.2%), and 25.9% received ≥2 regimens. Except from lower CA 19-9 serum level at the time of diagnosis and 6 weeks prior to SMART in previously operated patients, there were no significant differences in baseline parameters between prior pancreatectomy and the inoperable group. On-table adaptive replanning was performed for 100% of the fractions. No patient reported grade ≥2 acute GI toxicity. All previously irradiated patients reported only low-grade toxicities during RT. A total of 48 patients (88.9%) were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for a median of 9 months (2.8–28.8); three had later local progression. Eight patients had regional or marginal recurrence. Six- and 12-month OS were 75.0% and 52.1%, respectively. Apart from mild diarrhea 1–3 months after SMART and general fatigue, there were no significant differences in toxicity and outcomes between post-pancreatectomy and inoperable groups.ConclusionSMART allows safe delivery of an ablative dose of radiotherapy, with minimal treatment-related toxicity, even in previously resected or irradiated patients. In this real-world cohort, local control with complete response was achieved by 20% of the patients. Further studies are needed to evaluate long-term outcome and late toxicity

Dynamic Cross Talk between S1P and CXCL12 Regulates Hematopoietic Stem Cells Migration, Development and Bone Remodeling

Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly in the BM, and S1P, mainly in the blood, dynamically regulates HSC recruitment to the circulation versus their retention in the BM. During alarm situations, stress-signals induce a decrease in CXCL12 levels in the BM, while S1P levels are rapidly and transiently increased in the circulation, thus favoring mobilization of stem cells as part of host defense and repair mechanisms. Myeloid cytokines, including G-CSF, up-regulate S1P signaling in the BM via the PI3K pathway. Induced CXCL12 secretion from stromal cells via reactive oxygen species (ROS) generation and increased S1P1 expression and ROS signaling in HSCs, all facilitate mobilization. Bone turnover is also modulated by both CXCL12 and S1P, regulating the dynamic BM stromal microenvironment, osteoclasts and stem cell niches which all functionally express CXCL12 and S1P receptors. Overall, CXCL12 and S1P levels in the BM and circulation are synchronized to mutually control HSC motility, leukocyte production and osteoclast/osteoblast bone turnover during homeostasis and stress situations

Do All Women with Abnormal Sonographic Axillary Lymph Nodes Need a Biopsy?

Purpose With the increased use of breast ultrasound for different indications, sonographically abnormal axillary lymph nodes are not a rare finding. We examined clinical and imaging characteristics in correlation with pathological reports of the sonographic guided biopsies to assess the yield of needle biopsy of these nodes. Methods Clinical, imaging and pathology data were collected for 171 consecutive patients who underwent sonographic guided needle biopsy of an abnormal lymph node between 2008 and 2013. Malignancy rates were examined for different clinical settings: palpable axillary mass, previous history of breast cancer, findings suggestive of a systemic disease, and those with a breast finding of low suspicion or an incidental abnormal axillary lymph node. Patients with newly diagnosed breast cancer were excluded. Results Twelve patients (7%) were found to have a malignancy on their axillary lymph node biopsy. Malignancy rates increased with age, and varied with clinical presentation: Axillary mass (8, 26%); history of breast cancer (2, 11%); systemic disease (0%) and breast finding of low suspicion or incidental abnormal lymph node on screening (1, 1%). Low rates of malignancy were found when the cortex was &lt;6 mm (1, 0.8%). The most important imaging finding associated with malignancy was lack of a preserved hilum, in which case almost a third (10, 29%) of the biopsies were malignant. Only 1 of 89 women with a breast finding of low suspicion or an incidental abnormal axillary lymph node was found to have malignancy. In this case the lymph node had no hilum. Conclusions In women without breast cancer, a highly suspicious breast mass or an axillary mass, more stringent criteria should be used when evaluating an abnormal axillary lymph node on sonography, as the malignancy rates are very low (1%). </jats:sec