The epithelial Na⁺ channels (ENaCs) are present in kidney and contribute to Na⁺ and water homeostasis. All three ENaC subunits (α, β, and γ) were demonstrated in the cardiovascular regulatory centers ...of the rat brain, including the magnocellular neurons (MNCs) in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). However, the functional significance of ENaCs in vasopressin (VP) and oxytocin (OT) synthesizing MNCs is completely unknown. In this study, we show with immunocytochemical double-labeling that the α-ENaC is colocalized with either VP or OT in MNCs in the SON and PVN. In addition, parvocellular neurons in the dorsal, ventrolateral, and posterior subregions of the PVN (not immunoreactive to VP or OT) are also immunoreactive for α-ENaC. In contrast, immunoreactivity to β- and γ-ENaC is colocalized with VP alone within the MNCs. Furthermore, immunoreactivity for a known target for ENaC expression, the mineralcorticoid receptor (MR), is colocalized with both VP and OT in MNCs. Using single-cell RT-PCR, we detected mRNA for all three ENaC subunits and MR in cDNA libraries derived from single MNCs. In whole cell voltage clamp recordings, application of the ENaC blocker benzamil reversibly reduced a steady-state inward current and decreased cell membrane conductance approximately twofold. Finally, benzamil caused membrane hyperpolarization in a majority of VP and about one-half of OT neurons in both spontaneously firing and quiet cells. These results strongly suggest the presence of functional ENaCs that may affect the firing patterns of MNCs, which ultimately control the secretion of VP and OT.
•SRS for multiple BrMs from EGFR and ALK driven NSCLC demonstrates favorable outcomes.•Excellent OS and LC in patients with EGFR and ALK NSCLC treated with SRS to ≥4 BrMs.•SRS and TKIs in patients ...with oncogene-driven NSCLC BrMs represent promising treatment options.
Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited.
Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT).
Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4–26) and median for all treatments was 9 (range 4–47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %.
This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.
Nasopharyngeal carcinoma (NPC) is a rare cancer of the nasopharyngeal mucosa with a specific geographic predisposition. NPC is often associated with Epstein-Barr Virus (EBV) infection and as a result ...contains many characteristic biomarkers. Treatment of locally-contained NPC is generally achieved through use of radiotherapy (RT), as part of a multimodality treatment regimen. Induction chemotherapy followed by concurrent RT and platinum-based chemotherapy regimen has emerged as the definitive treatment of choice for locoregionally-advanced NPC. Recently, immunotherapy is finding a role in the treatment of recurrent or metastatic NPC. Immune checkpoint blockade therapies targeted against the programmed death-1 (PD-1) receptor have demonstrated efficacy in early phase clinical trials, with ongoing phase III trials in effect. Biomarkers for treatment efficacy remain an ongoing area of investigation, with important prognostic implications on the horizon.
The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not ...been established.
We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy).
Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups.
In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.
A 59-year-old man presented with an unresectable bulky giant basal cell carcinoma on his upper back. A trial of chemotherapy did not help relieve his symptoms or reduce the tumor. He was referred for ...and received definitive radiation therapy via IMRT with dramatic regression. The patient had been unable to lie on his back for many years but currently can sleep comfortably on his back without pain, which has dramatically improved his quality of life.
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Background: Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with high unmet need. Trabectedin (T) is an FDA-approved chemotherapy that blocks cell cycling and DNA repair ...pathways. Combination T and conventional radiation (XRT) in STS nonrandomized phase 1/2 trials demonstrated objective response rates (ORR) of 36-72% in localized and low burden metastatic disease, while pre-treated metastatic STS treated with T alone has an ORR of 10-14%. We hypothesize that the combination of T and hypofractionated radiation (hXRT) will exhibit a tolerable safety profile and improve ORR relative to historical outcomes with T or hXRT alone. Here we report our experience in the treatment of oligometastatic STS with combined T and hXRT. Methods: We reviewed our institutional experience to identify patients treated with T and XRT. We included patients with high risk localized or metastatic STS (majority of patients had metastatic disease at time of treatment). All patients received at least 1 cycle of T and concurrent XRT to at least 1 lesion. ORR and local control rate (LCR) were determined for irradiated lesions by RECIST 1.1. Results: Between 2020 – 2021, 9 STS patients with 21 tumors were treated at the University of Colorado with XRT and concurrent T. The median age was 39.2 (range 26.0 – 64.6) years. 8 patients had metastatic disease at the time of treatment. Treated tumor sites included 1 lung,1 extremity, 2 liver, 2 retroperitoneal, 5 bone, and 10 peritoneal. The following histologic subtypes were included: myxoid liposarcoma (3), uterine leiomyosarcoma (2), non-uterine leiomyosarcoma (1), dedifferentiated liposarcoma (1), undifferentiated pleomorphic sarcoma (1), and synovial sarcoma (1). All metastatic patients were pre-treated with a median of 3 lines of systemic therapy. The median number of T cycles delivered was 5 (range 1 – 20). The median XRT prescription dose was 3000cGy (range 2000cGy – 5000cGy), with 8 patients having received hXRT (5 -10 fractions) and 1 having received conventionally fractionated XRT. 8 patients underwent 1 course of XRT, while 1 received 3 courses in combination with T. All patients had a Karnofsky performance status equal to or greater than 60. After a median follow-up 5.4 months, the LCR of treated lesions was 90.5%. The ORR (CR or PR) was 57.1% and median decrease in tumor diameter at time of maximum response was 52.0%. The median time until maximum response was 3.7 months. 2 patients experienced grade 3 toxicity (LFT elevation) attributable to T, and 2 patients experienced grade 3 toxicity due to XRT. There were no grade 4 or 5 toxicities. Conclusions: T in combination with hXRT appears to be safe and feasible in this patient population. Based on these data, a phase 1/2 prospective clinical trial is being planned in oligometastatic and high risk localized STS. Table: see text
Background
In radiation therapy (RT), accelerated partial breast irradiation (APBI) has emerged as an increasingly preferred treatment modality over conventional whole breast irradiation due to its ...targeted dose delivery and shorter course of treatment. APBI can be delivered through various modalities including Cobalt‐60‐based systems and linear accelerators with C‐arm, O‐ring, or robotic arm design. Each modality possesses distinct features, such as beam energy or the degrees of freedom in treatment planning, which influence their respective dose distributions. These modality‐specific considerations emphasize the need for a quantitative approach in determining the optimal dose delivery modality on a patient‐specific basis. However, manually generating treatment plans for each modality across every patient is time‐consuming and clinically impractical.
Purpose
We aim to develop an efficient and personalized approach for determining the optimal RT modality for APBI by training predictive models using two different deep learning‐based convolutional neural networks. The baseline network performs a single‐task (ST), predicting dose for a single modality. Our proposed multi‐task (MT) network, which is capable of leveraging shared information among different tasks, can concurrently predict dose distributions for various RT modalities. Utilizing patient‐specific input data, such as a patient's computed tomography (CT) scan and treatment protocol dosimetric goals, the MT model predicts patient‐specific dose distributions across all trained modalities. These dose distributions provide patients and clinicians quantitative insights, facilitating informed and personalized modality comparison prior to treatment planning.
Methods
The dataset, comprising 28 APBI patients and their 92 treatment plans, was partitioned into training, validation, and test subsets. Eight patients were dedicated to the test subset, leaving 68 treatment plans across 20 patients to divide between the training and validation subsets. ST models were trained for each modality, and one MT model was trained to predict doses for all modalities simultaneously. Model performance was evaluated across the test dataset in terms of Mean Absolute Percent Error (MAPE). We conducted statistical analysis of model performance using the two‐tailed Wilcoxon signed‐rank test.
Results
Training times for five ST models ranged from 255 to 430 min per modality, totaling 1925 min, while the MT model required 2384 min. MT model prediction required an average of 1.82 s per patient, compared to ST model predictions at 0.93 s per modality. The MT model yielded MAPE of 1.1033 ± 0.3627% as opposed to the collective MAPE of 1.2386 ± 0.3872% from ST models, and the differences were statistically significant (p = 0.0003, 95% confidence interval = –0.0865, –0.0712).
Conclusion
Our study highlights the potential benefits of a MT learning framework in predicting RT dose distributions across various modalities without notable compromises. This MT architecture approach offers several advantages, such as flexibility, scalability, and streamlined model management, making it an appealing solution for clinical deployment. With such a MT model, patients can make more informed treatment decisions, physicians gain more quantitative insight for pre‐treatment decision‐making, and clinics can better optimize resource allocation. With our proposed goal array and MT framework, we aim to expand this work to a site‐agnostic dose prediction model, enhancing its generalizability and applicability.
The second messenger cyclic AMP (cAMP) promotes apoptosis in many cell types, including certain lymphoid cells, by poorly understood mechanisms. Murine S49 T‐lymphoma cells are a model system to ...study cAMP‐mediated apoptosis and have a distinct advantage for such studies: a clonal variant (kin‐) that lacks protein kinase A (PKA) activity and cAMP‐induced apoptosis, thereby facilitating analysis of PKA‐regulated apoptotic components. We have compared protein levels and subcellular localization of pro‐ and anti‐apoptotic Bcl family proteins in wild‐type (WT) and kin‐ S49 cells treated with the cell‐permeable analog CPT‐cAMP (CPT). We found that WT, but not kin‐, cells treated with CPT time‐dependently increase their level of the S, L and EL isoforms of the pro‐apoptotic protein Bim. We also examined PKA‐promoted phosphorylation of Bad, which is anti‐apoptotic when phosphorylated. We detected no phosphorylation of Bad at Ser155 (a PKA target site) in kin‐ cells during 72 hr treatment with CPT. Unexpectedly, WT cells showed strong Ser155 phosphorylation of Bad (and an increased ratio of p‐Ser155 Bad/total Bad) in response to 24‐72 h CPT treatment. Thus, cAMP acts via PKA to enhance both pro‐ and anti‐apoptotic proteins. We speculate that the late increase in pBAD in WT S49 cells may be an attempt by the cells to reverse their ultimate apoptotic response to cAMP/PKA activation.
Grant Funding Source: Supported by: ASPET 2013 Summer Undergraduate Research Fellowship
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