Background. The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencingbased genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,1543. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p 5 .24). The most common actionable alterations were in PIK3CA (n 5 9,
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.
Fistulas of the lower urinary tract are uncommon conditions that may occur spontaneously or after therapy in patients with various pelvic abnormalities. When present, these fistulas are associated with urine leakage, which is often socially distressing and disabling. Unfortunately, factors that lead to the formation of genitourinary fistulas often increase their complexity or preclude surgical repair. A high failure rate is associated with surgical repair, and many patients are not optimal surgical candidates. For such patients, a percutaneous treatment approach is highly desirable. Percutaneous ureteral occlusion combined with insertion of a functioning nephrostomy tube allows complete diversion of urine in those patients in whom nephrostomy alone does not provide adequate relief. Many approaches to percutaneous ureteral occlusion have been used with variable success, including coils and gelatin sponge, isobutyl-2-cyanoacrylate, detachable balloons, radiofrequency electrocautery, ureteral clipping, and solid and soft polymer agents. Furthermore, percutaneous or retrograde ureteral stents may be used to preserve antegrade urine flow, and surgical options are also available. It is essential that the interventional radiologist involved in the care of these patients be familiar with these different techniques as well as with the limitations, pitfalls, and possible complications of their use.
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