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The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0–2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60–70 Gy in ten fractions or 52·5–67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2–24·6), median progression-free survival was 22·7 months (95% CI 10·4–not reached; 1-year progression-free survival 64% [95% CI 48–85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.

BackgroundIntratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy.MethodsIntratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution.ResultsVariations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal).ConclusionsInjection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.

The geometry and quality of a weld seam are critical factors in laser beam welding, influencing mechanical performance and structural integrity. Dynamically modulated laser beams provide a precise means of tailoring energy input in high-power laser welding processes. This study investigates the influence of beam shape and modulated frequency on weld seam geometry, penetration depth, and capillary behaviour using a coherent beam combining (CBC) laser system from Civan Lasers. Three beam intensity distributions—single point, line–point–line (LPL), and boomerang—were applied across a modulation frequency range of 1, 10, and 100 kHz during the welding of duplex and austenitic stainless steels. High-speed imaging captured real-time capillary dynamics, and the data were analysed to assess capillary stability, measure capillary diameter, and determine the capillary front angle as a function of frequency and beam shape. Transverse cross-sections of the welds were prepared to evaluate seam geometry and microstructure. The results show that beam shape significantly affects energy distribution and weld profile, while modulation frequency critically influences capillary behaviour and penetration characteristics. These findings highlight the critical role of dynamic beam shaping and frequency modulation in optimizing laser welding processes for material-specific performance, offering a versatile platform for advancing precision manufacturing using CBC technology.

In this study, the evolution of volume fractions during laser beam welding (LBW) of stainless steel, with a specific focus on incorporating the low transformation temperature (LTT) effect using the dilatometer, has been proposed. The LTT effect refers to the phase transformations that occur at lower temperatures and lead to the formation of a martensitic microstructure, which will significantly influence the residual stresses and distortion of the welded joints. In this research, the LTT conditions are achieved by varying the Cr and Ni content in the weld seam by varying the weld parameter, including laser power, welding speed and filler wire speed. The dilatometer analysis technique is employed to simulate the thermal conditions encountered during LBW. By subjecting the stainless steel samples to controlled heating and cooling cycles, the kinetics of the volume fractions can be measured using the lever rule and empirical method (KOP and Lee). The phase transformation simulation model is computed by integrating the thermal and metallurgical effects to predict the volume fractions in LBW joints and has been validated using dilatometer results. This provides valuable insight into the relationship between welding parameters and phase transformations in stainless steel with the LTT effect during laser beam welding. Using this relationship, the weld quality can be improved by reducing the residual stresses and distortion.

Purpose To evaluate the use of a self-expanding tract sealant device (BioSentry™) on the rates of pneumothorax and chest tube insertion after percutaneous lung biopsy. Materials and Methods In this retrospective study, we compared 318 patients who received BioSentry™ during percutaneous lung biopsy (treated group) with 1956 patients who did not (control group). Patient-, lesion-, and procedure-specific variables, and pneumothorax and chest tube insertion rates were recorded. To adjust for potential selection bias, patients in the treated group were matched 1:1 to patients in the control group using propensity score matching based on the above-mentioned variables. Patients were considered a match if the absolute difference in their propensity scores was ≤equal to 0.02. Results Before matching, the pneumothorax and chest tube rates were 24.5 and 13.1% in the control group, and 21.1 and 8.5% in the treated group, respectively. Using propensity scores, a match was found for 317 patients in the treatment group. Chi-square contingency matched pair analysis showed the treated group had significantly lower pneumothorax (20.8 vs. 32.8%; p  = 0.001) and chest tube (8.2 vs. 20.8%; p  < 0.0001) rates compared to the control group. Sub-analysis including only faculty who had >30 cases of both treatment and control cases demonstrated similar findings: the treated group had significantly lower pneumothorax (17.6 vs. 30.2%; p  = 0.002) and chest tube (7.2 vs. 18%; p  = 0.001) rates. Conclusions The self-expanding tract sealant device significantly reduced the pneumothorax rate, and more importantly, the chest tube placement rate after percutaneous lung biopsy.

The development of inoperable biliary obstruction in patients with liver, biliary, and pancreatic neoplasia is commonplace particularly in the advanced stages of these diseases. Under these circumstances, restoring bile flow to the gut is paramount in reestablishing homeostasis. Hitherto, this has been achieved by utilizing passive, gravity-dependent bilioenteric conduits with the use of perforated plastic catheters or metallic stents inserted either in a percutaneous transhepatic fashion or via endoscopic techniques. A frequent untoward event of biliary decompression utilizing percutaneous transhepatic catheters (PTC) is the development of pain, cholangitis, hyperbilirubinemia, or pericatheter bile leak due to the suboptimal normalization of bile flow. In some instances, the etiology of PTC malfunction can be correctly ascribed to catheter malposition and/or catheter lumen obstruction; however, in the majority, it remains radiographically occult on transcatheter cholangiography—the “gold standard.” Regardless of findings, the management remains fluoroscopic repositioning or exchanges for larger diameter catheters to attempt to seal the pericatheter potential space and prevent bile seepage. Unfortunately, these maneuvers are met with limited and unpredictable levels of success. We present the successful management of an instance of recalcitrant external pericatheter bile leak mitigated by employing a hybrid closed loop biliary catheter-pump system by employing an assortment of FDA approved off-the-shelf medical devices.

Abstract Allergic fungal sinusitis (AFS), a noninvasive form of fungal sinusitis, is rarely seen in immunocompetent patients. Involvement of sphenoid sinus can result in proptosis and loss of vision. We report AFS masquerading as posterior cavernous sinus syndrome. A 59-year-old African-American man presented with right complete ptosis with ophthalmoplegia. After an initial work-up and imaging studies, patient underwent endonasal sphenoid surgery, which revealed characteristic ‘allergic fungal mucin’. Cavernous sinus syndrome is a rare presenting clinical feature of allergic fungal sinusitis. Ophthalmologists should be aware of this rare presentation of relatively common otorhinological disease for timely referral and appropriate management.

Objective. To prospectively evaluate the effect of intravitreal bevacizumab on aqueous levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in patients with exudative age-related macular degeneration (AMD) and correlate clinical outcomes with cytokine levels. Methods. 30 eyes of 30 patients with exudative AMD underwent intravitreal injection of bevacizumab three times at monthly intervals. The aqueous samples prior to the 1st injection (baseline) and 3rd injection were analyzed for VEGF and IL-6 levels. Subjects were subgrouped based upon change in the central subfield (CSF) macular thickness on SD-OCT at 8 weeks. Group 1 included patients ( n = 14 ) with a decrease in CSF thickness greater than 10% from the baseline (improved group). Group 2 included patients ( n = 16 ) who had a decrease in CSF thickness 10% or less (treatment-resistant). Results. In subgroup analysis, in both groups 1 and 2 patients, compared to aqueous VEGF, aqueous IL-6 levels showed a better correlation with CSF thickness on SD-OCT ( r = 0.72 and 0.71, resp.). Conclusions. Aqueous IL-6 may be an important marker of treatment response or resistance in wet macular degeneration. Future therapeutic strategies may include targeted treatment against both VEGF and IL-6, in patients who do not respond to anti-VEGF treatment alone.

BackgroundDecreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab.MethodsA total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors.ResultsA decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies.ConclusionPatients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies.Trial registration number NCT02721732

Aqueous levels of vascular endothelial growth factor (VEGF) can be a surrogate marker of intraocular VEGF activity and a measure of efficacy of anti-VEGF treatment in a variety of vasoproliferative retinal disorders, including diabetic retinopathy, age-related macular degeneration, and central retinal vein occlusion. Measurement of the VEGF level may be adversely affected by premeasurement variables, such as freezing and delay, in sample analysis. We aim to evaluate the effect of storage and delayed measurement of human aqueous VEGF levels in these conditions. Aqueous samples collected from patients receiving intravitreal injection of bevacizumab for various retinal diseases were divided into two groups. In Group 1, the VEGF levels were analyzed on the same day; in Group 2, the VEGF levels were analyzed after 21 days of freezer storage (-80°C) using immunobead assay. Statistical comparison using a paired t-test was performed between the two groups. Thirty-one aqueous humor samples were collected, and the VEGF concentration for fresh samples was 7.8 ± 5.9 pg/mL (mean ± SD) compared to 6.5 ± 6.0 pg/mL in frozen samples, resulting in a statistically significant difference (P = 0.03). Accurate measurement of the VEGF level is a vital component of clinical decision-making. Delayed analysis of VEGF levels in aqueous samples may result in significant sample degradation and lower levels of measured VEGF.