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BackgroundFms-like tyrosine kinase 3 ligand (FLT3L) is a potent hematopoietic growth factor that mobilizes stem cells and increases the number of circulating dendritic cells (DCs) in blood and organs. In a murine lung adenocarcinoma model, FLT3L had modest activity as monotherapy but demonstrated synergy when combined with high-dose radiotherapy.1 Clinical trials have demonstrated that FLT3L is safe but has minimal activity in cancer patients. We performed a prospective trial for patients with advanced non-small cell lung cancer (NSCLC) to evaluate the immune correlates of combining FLT3L with stereotactic body radiotherapy (SBRT).MethodsTwenty-nine subjects were enrolled between October 2016 and January 2020 in a Phase II clinical, and all subjects failed at least one previous round of treatment (median 3 lines, range 1 to 5). Subcutaneous CDX-301 (75 µg/kg) was administered daily for five days with concomitant treatment of SBRT (figure 1). To identify immune cell signatures of response, we developed two high dimensional flow cytometry panels measuring 31 unique subsets found in peripheral blood mononuclear cells (PBMCs) and performed multiplex proteomic analysis measuring 92 different proteins at baseline, 2 weeks, 4 weeks, and 8 weeks post treatment.ResultsIn our trial, 55% of patients achieved progression free survival four months (PSF4) after treatment with 31% of the patients achieving abscopal responses. SBRT and CDX-301 induced significant increases in the myeloid compartment, including subsets of monocytes, myeloid-derived suppressor cells (MDSCs) and DCs (figure 2). Within the DC compartment, we found heterogeneity, with FceR1-expressing DC2 and DC3 being the most responsive to treatment. Despite the strong responses from DCs and MDSCs to SBRT and CDX-301, cellular responses returned to baseline 8 weeks post treatment. Notably, the treatment induced greater co-expression of HLADR and Ki67 on CD4 T cells than CD8 T cells. In abscopal responders, CD4 T cell phenotype continued to evolve over a longer time period with concomitant increases of Th1-like CD4 T cells, IL21, and DC1 over 4 weeks (figure 3).ConclusionsCDX-301 and SBRT emerge as a compelling approach to reactivate the immune system that has facilitated the progression of NSCLC. Patients with abscopal responses exhibit distinct cellular responses to FLT3L and SBRT that align with the emerging significance of DC1 and CD4 T cells. This sustained Type 1 response over 4 weeks in abscopal responders independent of high grade adverse events, indicating a unique therapeutic axis to harness systemic immunity against metastatic lesions in NSCLC.AcknowledgementsThe authors would like to thank patients and families who enrolled into the study. Furthermore, the authors thank the Wherry and Guha labs for valuable scientific discussions.ReferenceChakravarty PC. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res.1999;59;6028–32.Ethics ApprovalThis study (2015–5267) was approved by the Albert Einstein College of Medicine IRB on 9/30/2015. All participants provided informed consentAbstract 1522 Figure 1Trial schemeAbstract 1522 Figure 2Patient level PCA using aggregated flow cytometry data representing 31 unique immune populations. Each point is colored by timepoint with the green arrow representing the mean of PC1 and PC2 at each timepoint. Variable contributions for the PC1 axis (right) and PC2 axis (bottom) are ranked by magnitude and direction of contribution and colored by parent populationAbstract 1522 Figure 3Spearman rank correlations of the fold change from T4 to T0 (baseline) in DC1, preDC, pDC, CD14-DC3, CD14+DC3, CD5+DC2, CDS- DC2, Th1-like CD4 T cells (CXCR5+), exhausted CD8 T cells (PD1+CD39+), activated CD4 T cells (HLADR+Ki67+), activated CD8 T cells (HLADR+Ki67+), and the top 10 cytokines from that are changing the most with time. Nodes are colored by associated group (cytokine, T cells, and DCs). Green edges represent positive correlations and red edges represent negative correlations. Correlations >0.7 for inclusion in correlation network

Financial toxicity (FT) describes patients’ burden from out-of-pocket medical treatment costs. We studied associations between patient-reported pretreatment FT, socioeconomic status and clinical outcomes for locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Patients received chemoradiotherapy for locally advanced non-small-cell lung cancer and completed the European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) quality of life assessment before treatment. One question asks whether patients experience ‘financial difficulties’. We tested FT and socioeconomic status (SES) as predictors of progression-free survival (PFS) and overall survival (OS). A total of 43 patients were included. Median follow-up for surviving patients was 15 months. A total of 19 patients (44%) experienced disease progression and 17 patients (40%) died. Increasing FT was associated with shorter PFS (p = 0.011). FT did not predict overall survival (p = 0.67). Higher pretreatment FT is associated with shorter PFS.

This study assessed the modeled probability of tumor control and organ at risk toxicities in locally advanced cervical cancer in patients treated by external beam radiation plus brachytherapy using intracavitary combined with interstitial brachytherapy (IC/IS) vs. intracavitary brachytherapy (IC) alone. Twenty cervical cancer patients with a mean HR-CTV volume of 47.4 cm and a mean width of 54 mm were planned with both IC/IS and IC brachytherapy alone. A probit model was utilized to model 3-year (3-yr) local control rate (LC), 3-yr cancer specific survival rate (CSS), and the adverse effect (AE) of the organ at risk by using a modeled data set from multiple institutions. Modeling results were used to estimate the LC, CSS, and AE of the treatments in this study. Using the IC/IS technique, an EQD increase of 12.3 Gy to D (from 76.1 Gy to 88.3 Gy) of HR-CTV is expected to increase 3-yr LC and 3-yr CSS by 12.5%, and 11.0%, respectively. Comparing IC/IS to IC alone, the expected G2 AE were 7.7% vs. 7.9% for the bladder, and 5.9% vs. 6.8% for the rectum. The IC/IS technique improved dose coverage to the HR-CTV without significantly increasing dose to 2 cm of the organ at risk (OAR) surrounding it. With different regimens of EBRT combined with BT, IC/IS can be used to increase the probability of LC and CSS, or decrease the risk of AE.

Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001). Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect.

Background and Purpose: To assess the dosimetric flexibility of a dual balloon brachytherapy applicator developed for the treatment of anorectal lesions. Materials and Methods: Different amounts of water were infused into the inner and outer balloon separately to study the asymmetrical distribution of the catheter, the radial distance of the active source channel to the inner surface of the global target volume , the space between the active source channels, and their dosimetric impact to target tissues and uninvolved rectum. Results: Increasing inner balloon volume directly increased both the space between the active source channels and the radial distance of the active source channel to the inner surface of the global target volume. The space between the active source channels and the percentage of global target volume received 150% or more of the prescribed dose to target had a strong inverse correlation (−0.881/P = .007, −0.976/P = .001, respectively) with the radial distance of the active source channel to the inner surface of the global target volume. Conformity index, dose to 2 cm3 of rectum, and total reference air kerma were strongly correlated with the radial distance of the active source channel to the inner surface of the global target volume, with values of 0.952 (P = .001), 0.833 (P = .015), and 0.922 (P = .002), respectively. Percentage of global target volume received 150% or more of the prescribed dose was significantly correlated with the space between the active source channels (0.81/P = .022), and conformity index was strongly inversely correlated with the space between the active source channels (−0.833/P = .015). Conclusion: The dual balloon-constructed Anorectal Applicator offers a flexible way to adjust the distances of the active source positions to the target in relation to uninvolved rectal wall. This flexibility simplifies planning which results in a highly conformal dose distribution to the target lesion while minimizing dose to normal rectal tissue.

To evaluate the variations of multi-lumen balloon (MLB)-based brachytherapy from simulation day to treatment day and their dosimetric impacts during accelerated partial breast irradiation (APBI). A total of 42 CT images scanned from seven patients were evaluated with regards to daily variation due to of: 1) internal uncertainty: size and shape of balloon, seroma volume; 2) geometrical uncertainty-random: length of each catheter was measured for each fraction (total 70); 3) geometrical uncertainty-systematic: virtual systematic errors were tested by offsetting dwell positions. The original plans (as group A) had a mean value of 96.8% on V95 of the PTV_Eval. Plans were rerun (as group B) such that the mean value of the V95 was relaxed to 90.4%. By applying the reference plan to each daily CT image, variations of target coverage under different sources of error were evaluated. Shape and size of the balloon had means of < 1 mm decreased in diameter and < 0.4 cm(3) decreased in volume; the mean seroma volume increased by 0.2 cm(3). This internal variation has a mean of < 1% difference for both V90 and V95. The geometrical uncertainty made a mean deviation of 2.7 mm per root of sum of square. It caused the degradations of V90 and V95 by mean values of 1.0% and 1.2%, respectively. A systematic error of 3 mm and 4 mm would degrade both of V90 and V95 by 4% and 6%, respectively. The degradations on target coverage of the plans in group A were statistically the same as those in group B. Overall, APBI treatments with MLB based brachytherapy are precise from day to day. However, minor variation due to daily treatment uncertainties can still degrade tumor bed coverage to an unacceptable coverage when V95 of the original plan is close to 90%.

To perform a dosimetric comparison between a pre-planned technique and a pre-plan based intraoperative technique in prostate cancer patients treated with I-125 permanent seed implantation. Thirty patients were treated with I-125 permanent seed implantation using TRUS guidance. The first 15 of these patients (Arm A) were treated with a pre-planned technique using ultrasound images acquired prior to seed implantation. To evaluate the reproducibility of the prostate volume, ultrasound images were also acquired during the procedure in the operating room (OR). A surface registration was applied to determine the 6D offset between different image sets in arm A. The remaining 15 patients (Arm B) were planned by putting the pre-plan on the intraoperative ultrasound image and then re-optimizing the seed locations with minimal changes to the pre-plan needle locations. Post implant dosimetric analyses included comparisons of V(100)(prostate), D(90)(prostate) and V(100)(rectum). In Arm A, the 6D offsets between the two image sets were θ(x)=-1.4±4.3; θ(y)=-1.7±2.6; θ(z)=-0.5±2.6; X=0.5±1.8 mm; Y=-1.3±-3.5 mm; Z=-1.6±2.2 mm. These differences alone degraded V(100) by 6.4% and D(90) by 9.3% in the pre-plan, respectively. Comparing Arm A with Arm B, the pre-plan based intraoperative optimization of seed locations used in the plans for patients in Arm B improved the V(100) and D(90) in their post-implant studies by 4.0% and 5.7%, respectively. This was achieved without significantly increasing the rectal dose (V(100)(rectum)). We have progressively moved prostate seed implantation from a pre-planned technique to a pre-plan based intraoperative technique. In addition to reserving the advantage of cost-effective seed ordering and efficient OR implantation, our intraoperative technique demonstrates increased accuracy and precision compared to the pre-planned technique.

Surface mixed‐layer dynamics play a crucial role in modulating the climate as it is the oceanic layer that directly communicates with the atmosphere. The resolution of global ocean models is, however, often restricted to O(1/4°) $\\mathcal{O}(1/4{}^{\\circ})$; this is too coarse to adequately resolve mixed‐layer processes, and we depend on parametrizations. One of such parametrizations is the mixed‐layer eddy (MLE) parametrization. Here, we compare the performance of two MLE parametrizations [Fox‐Kemper et al. (2011, hereon BFF11) and Bodner et al. (2023, hereon BOD23)], and document their impact in three global ocean simulations. Upon tuning, and diagnosing submesoscale‐permitting truth simulations, the MLE efficiency coefficient in BOD23 ranges between the values of 0.003–0.038, while 0.06 to 0.07 for BFF11. We find that the spatial distribution of mixed‐layer depth and ventilation of the abyssal ocean, using the ideal‐age tracer and Atlantic Meridional Overturning Circulation as its proxy, are sensitive to the interaction between MLE parametrizations and ocean surface boundary‐layer mixing schemes.

This article introduces an ensemble clustering tool developed at the Weather Prediction Center (WPC) to assist forecasters in the preparation of medium-range (3–7 day) forecasts. Effectively incorporating ensemble data into an operational forecasting process, like that used at WPC, can be challenging given time constraints and data infrastructure limitations. Often forecasters do not have time to view the large number of constituent members of an ensemble forecast, so they settle for viewing the ensemble’s mean and spread. This ignores the useful information about forecast uncertainty and the range of possible forecast outcomes that an ensemble forecast can provide. Ensemble clustering could be a solution to this problem as it can reduce a large ensemble forecast down to the most prevalent forecast scenarios. Forecasters can then quickly view these ensemble clusters to better understand and communicate forecast uncertainty and the range of possible forecast outcomes. The ensemble clustering tool developed at WPC is a variation of fuzzy clustering where operationally available ensemble members with similar 500-hPa geopotential height forecasts are grouped into four clusters. A representative case from 15 February 2021 is presented to demonstrate the clustering methodology and the overall utility of this new ensemble clustering tool. Cumulative verification statistics show that one of the four forecast scenarios identified by this ensemble clustering tool routinely outperforms all the available ensemble mean and deterministic forecasts.

Physical therapists are uniquely positioned in health care to initiate or support smoking cessation (SC). Little is known, however, about their knowledge and views of SC as part of their practices. Objective The purpose of this study was to assess Canadian physical therapists' knowledge about the health effects of smoking, their views about addressing SC in practice, and their self-efficacy in enabling patients to quit smoking. Design This study was a cross-sectional survey. Licensed physical therapists in Canada were surveyed with postal methods. A total of 738 survey questionnaires were returned. The mean age and years of clinical experience of the respondents were 41.9 (SD=10.8) years and 17.4 (SD=11.0), respectively. Most respondents (78.6%) were women. Canadian physical therapists are largely informed about the negative effects of smoking on health. Although 76.9% of the physical therapists agreed or strongly agreed that the profession should be more involved in helping people who smoke quit, only 56.8% of the physical therapists agreed or strongly agreed that they should receive training on SC. More than 70% of the physical therapists reported that they were not prepared to provide counseling and, overall, the level of self-efficacy regarding counseling about SC was low. Lack of resources and time were reported to be key barriers to counseling patients to quit smoking. Limitations The findings of this study are limited to Canadian physical therapists. Response bias and social desirability bias also are potential limiters in this study. Overall, the majority of physical therapists expressed the view that advising people who smoke to quit is a clinical responsibility and endorsed greater involvement of the profession in helping people who smoke quit. Discordance existed, however, between these views and the physical therapists' interest in receiving training on counseling about SC. This is a benchmark study that has practical implications for targeting training consistent with the profession's mission to improve health by increasing physical therapists' preparedness and self-efficacy regarding counseling about SC.