Bladder-Sparing Treatment With Radical Dose Radiotherapy Is an Effective Alternative to Radical Cystectomy in Patients With Clinically Node-Positive Nonmetastatic Bladder Cancer.

PURPOSE: Bladder-sparing trimodal therapy (TMT) is an alternative to radical cystectomy (RC) according to international guidelines. However, there are limited data to guide management of nonmetastatic clinically node-positive bladder cancer (cN+ M0 BCa). We performed a multicenter retrospective analysis of survival outcomes in node-positive patients to inform practice. METHODS: Data from patients diagnosed with cN+ M0 BCa were collected from participating UK Oncology centers offering both TMT and RC. Overall survival (OS) and progression-free survival (PFS) outcomes were collected with details of treatment and clinical factors. RESULTS: A total of 287 patients with cN+ M0 BCa were included in the survival analysis. Median OS across all patients was 1.55 years (95% CI, 1.35 to 1.82 years). Receiving radical treatments was associated with improved OS (hazard ratio [HR], 0.32; 95% CI, 0.23 to 0.44; P < .001) compared with receiving palliative treatment. Radically treated patients (n = 163) received RC (n = 76) or radical dose radiotherapy (RT, n = 87); choice of radical treatment showed no association with OS (HR, 0.94; 95% CI, 0.63 to 1.41; P = .76) or PFS (HR, 0.74; 95% CI, 0.50 to 1.08; P = .12) on multivariable analysis. CONCLUSION: Patient cohorts with cN+ M0 BCa had equivalent survival outcomes whether treated with surgery or radical RT. Given the known morbidities of RC-in a patient group with poor survival-this study confirms that bladder-sparing TMT treatment should be a treatment option available to all patients with cN+ M0 BCa.

Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1.

Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this resistance and improve response rates but reported clinical trial results have thus far been disappointing. Novel approaches are required to overcome this resistance and reprogram the immunosuppressive tumor microenvironment (TME) and address this major unmet clinical need. Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten-/-/trp53-/-) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. The addition of anti-CD40mAb to RT resulted in an increase in IFN-y signaling, activation of Th-1 pathways with an increased infiltration of CD8+ T-cells and regulatory T-cells with associated activation of the CTLA-4 signaling pathway in the TME. Anti-CTLA-4mAb in combination with RT further reprogrammed the immunosuppressive TME, resulting in durable, long-term tumor control. Our data provide novel insights into the underlying mechanisms of the immunosuppressive TME that result in resistance to RT and anti-PD-1 inhibitors and inform therapeutic approaches to reprogramming the immune contexture in the TME to potentially improve tumor responses and clinical outcomes.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.

INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

Toll-Like Receptor Agonists and Radiation Therapy Combinations: An Untapped Opportunity to Induce Anticancer Immunity and Improve Tumor control.

The premise that therapies targeting immune checkpoints can enhance radiation therapy (RT)-induced antitumor immunity is being explored rigorously in the preclinical setting, and early clinical trials testing this hypothesis are beginning to report. Although such approaches might prove efficacious in certain settings, it is likely that many tumor types, particularly those that have a deeply immune-suppressed microenvironment with little or no T cell infiltration, will require alternative approaches. Thus, there is now considerable drive to develop novel immune modulatory therapies that target other areas of the cancer immunity cycle. Toll-like receptors (TLRs) are expressed on sentinel immune cells and play a key role in the host defense against invading pathogens. Innate sensing via TLR-mediated detection of pathogen-derived molecular patterns can lead to maturation of antigen-presenting cells and downstream activation of adaptive immunity. After demonstrating promising efficacy in preclinical studies, drugs that stimulate TLR have been approved for use clinically, albeit to a limited extent. There is a growing body of preclinical evidence that novel agonists targeting TLR3, TLR7/8, or TLR9 in combination with RT might lead to enhanced antitumor immunity. Mechanistic studies have revealed that TLR agonists enhance dendritic cell-mediated T cell priming after RT, in some cases leading to the generation of systemic antitumor immunity and immune memory. In this report, we describe results from preclinical studies that advocate the strategy of combining RT with TLR agonists, discuss reported mechanisms of action, and explore the exciting opportunities of how this approach may be successfully translated into clinical practice.

Ten-Year Outcomes of Moderately Hypofractionated Salvage Postprostatectomy Radiation Therapy and External Validation of a Contemporary Multivariable Nomogram for Biochemical Failure.

PURPOSE: Although high-level evidence supports moderately hypofractionated radiation therapy for definitive prostate treatment, there is less evidence for its use in the postprostatectomy setting. We externally validated a contemporary nomogram predicting biochemical failure (BF) after salvage radiation therapy (SRT) and report long-term disease control outcomes for hypofractionated SRT to the prostate bed. METHODS AND MATERIALS: A retrospective review was performed for 112 patients treated with hypofractionated SRT (52.5 Gy in 20 fractions using 3-dimensional conformal radiation therapy) for pT2-4R0-1N0/XM0 prostate adenocarcinoma, with postoperative prostate-specific antigen (PSA) greater than 0.1 ng/mL or rising. Freedom from BF (FFBF), distant metastasis, cancer-specific mortality, and overall survival were analyzed from commencement of radiation therapy. Cox regression was performed on FFBF to account for covariates. BF was defined as a PSA ≥0.4 ng/mL and rising after SRT. Early SRT was defined as SRT commencing at a pre-SRT PSA of ≤0.2 ng/mL. RESULTS: Median follow-up was 10.0 years (interquartile range, 9.3-10.7 years), median pre-SRT PSA was 0.4 ng/mL, and androgen deprivation therapy was used in 14% of patients. The 5/10-year FFBF, distant metastasis, cancer-specific mortality, and overall survival were 68%/51%, 7%/16%, 5%/11%, and 90%/75%, respectively. FFBF for early SRT compared with late SRT was 81% versus 66% at 5 years and 68% versus 49% at 10 years. On multivariable analysis, pre-SRT PSA, International Society of Urologic Pathology grade group, seminal vesicle invasion, and androgen deprivation therapy use were associated with FFBF. The nomogram c-index was 0.67, and it overestimated FFBF by 10% and 15% at 5 and 10 years, respectively, with confidence intervals overlapping the line of unity. CONCLUSIONS: Hypofractionated SRT provides long-term disease control outcomes comparable to conventionally fractionated radiation therapy. Early SRT provides improved disease control, with two-thirds of patients with pre-SRT PSA of ≤0.2 ng/mL free of BF at 10 years. We performed the first external validation of the Tendulkar salvage nomogram, which showed a robust model performance.

High-speed imaging of ice nucleation in water proves the existence of active sites.

Understanding how surfaces direct nucleation is a complex problem that limits our ability to predict and control crystal formation. We here address this challenge using high-speed imaging to identify and quantify the sites at which ice nucleates in water droplets on the two natural cleavage faces of macroscopic feldspar substrates. Our data show that ice nucleation only occurs at a few locations, all of which are associated with micron-size surface pits. Similar behavior is observed on α-quartz substrates that lack cleavage planes. These results demonstrate that substrate heterogeneities are the salient factor in promoting nucleation and therefore prove the existence of active sites. We also provide strong evidence that the activity of these sites derives from a combination of surface chemistry and nanoscale topography. Our results have implications for the nucleation of many materials and suggest new strategies for promoting or inhibiting nucleation across a wide range of applications.

The anti-PD-1 era - an opportunity to enhance radiotherapy for patients with bladder cancer.

An urgent need exists to improve the outcomes of patients with muscle-invasive bladder cancer (MIBC), and especially of those with metastatic disease. Treatments that enhance antitumour immune responses - such as immune-checkpoint inhibition - provide an opportunity to do this. Despite initial success, durable response rates in patients with advanced-stage MIBC treated with novel inhibitory antibodies targeting programmed cell death protein 1 (PD-1) or its endogenous ligand programmed cell death 1 ligand 1 (PD-L1) remain low. Radiotherapy is part of the management of bladder cancer in many patients. Evidence that radiotherapy has immunogenic properties is now available, but radiotherapy-induced immune responses are often negated by immunosuppression within the tumour microenvironment. Anti-PD-1 or anti-PD-L1 antibodies might enhance radiotherapy-induced antitumour immunity. This effect has been demonstrated in preclinical models of bladder cancer, and clinical trials involving this approach are currently recruiting. Combination treatment strategies provide an exciting opportunity for urological oncologists to not only improve the chances of cure in patients undergoing radical treatment for MIBC, but also to increase long-term response rates in those with metastatic disease.

Comparing Clinical Outcomes for Radium-223: Do Older Patients Do Worse?

PURPOSE: To examine the clinical benefits and toxicities of 223Ra in 2 different age groups of patients with castrate-resistant prostate cancer. METHODS AND MATERIALS: This was a retrospective study of patients treated with 223Ra in 2 tertiary centers. Patients were divided into 2 different groups based on their age (≥72 years old and <72 years old). Treatment toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. Comparison of characteristics and outcome was carried out with the Mann-Whitney test and analysis of overall survival with the log-rank test. RESULTS: In all, 129 patients were treated during the study period. Clinical benefit was similar in both groups. However, a statistically significant higher proportion of patients in the younger group had previously been treated with docetaxel. There was a higher rate of grade 3 anemia in younger patients. CONCLUSIONS: In line with other studies, 223Ra was well tolerated with minimum toxicities. The significantly higher rate of grade 3 anemia in younger patients may be due to more cautious patient selection in the elderly population.

Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy?

Radiotherapy (RT) is effective at cytoreducing tumours and until relatively recently the focus in radiobiology has been on the direct effects of RT on the tumour. Increasingly, however, the effect of RT on the tumour vasculature, tumour stroma and immune system are recognized as important to the overall outcome. RT is known to lead to the induction of immunogenic cell death (ICD), which can generate tumour-specific immunity. However, systemic immunity leading to "abscopal effects" resulting in tumour shrinkage outside of the RT treatment field is rare, which is thought to be caused by the immunosuppressive nature of the tumour microenvironment. Recent advances in understanding the nature of this immunosuppression and therapeutics targeting immune checkpoints such as programmed death 1 has led to durable clinical responses in a range of cancer types including malignant melanoma and non-small-cell lung cancer. The effects of RT dose and fraction on the generation of ICD and systemic immunity are largely unknown and are currently under investigation. Stereotactic ablative radiotherapy (SABR) provides an opportunity to deliver single or hypofractionated large doses of RT and potentially increase the amount of ICD and the generation of systemic immunity. Here, we review the interplay of RT and the tumour microenvironment and the rationale for combining SABR with immunomodulatory agents to generate systemic immunity and improve outcomes.

The Crystal Hotel: A Microfluidic Approach to Biomimetic Crystallization.

A "crystal hotel" microfluidic device that allows crystal growth in confined volumes to be studied in situ is used to produce large calcite single crystals with predefined crystallographic orientation, microstructure, and shape by control of the detailed physical environment, flow, and surface chemistry. This general approach can be extended to form technologically important, nanopatterned single crystals.

Histomorphometric analysis and regional variations of full thickness skin grafts in dogs.

OBJECTIVE: To (1) compare thickness of the epidermis and dermis of anatomically different donor sites in dogs, and (2) evaluate hair follicle damage during full thickness skin grafts (FTSG) preparation from anatomically different donor sites. Another objective was to compare the extent of agreement between gross and histologic quality of graft preparation. STUDY DESIGN: Ex vivo study. ANIMALS: Healthy Beagle dogs (n = 12). METHODS: Skin samples were harvested from fresh cadavers free of gross dermatopathology and FTSG prepared. Regional, epidermal and dermal thickness, and hair follicle density in intact skin and FTSG specimens from different regions were determined by histomorphometric analysis. Hair follicle density in intact skin and FTSG specimens, and skin thickness measurements were compared among regions. RESULTS: Mean epidermis and dermis thickness of the dorsal lumbar and lateral neck regions were significantly greater when compared with other sites. Total hair follicle (superficial and deep dermis) densities were significantly less in prepared FTSG versus intact skin specimens. The dorsal lumbar region had the highest hair follicle density. CONCLUSIONS: Thickness of the epidermis and dermis is dependent on body region. Hair follicle density in the FTSG specimens was decreased compared with intact skin specimens, which may affect hair regrowth in FTSG.

Vascularized ulnar bone grafts for limb-sparing surgery for the treatment of distal radial osteosarcoma.

The objective of this retrospective study was to compare vascularized free or roll-in ulnar bone grafts for limb-sparing surgery in dogs with radial osteosarcoma with the cortical allograft, metal endoprosthesis, or distraction osteogenesis techniques. Overall, the ulnar graft techniques used in this study demonstrated excellent healing properties. Complications included recurrence of the tumor in 25% (2/8) of the dogs, metastasis in 50% (4/8) of the dogs, implant loosening in 37.5% (3/8) of the dogs, implant failure in 12.5% (1/8) of the dogs, and infection in 62.5% (5/8) of the dogs. Mean survival time was 29.3 mo (range, 9 to 61 mo). The mean metastasis-free interval was 33.67 mo (range, 8 to 54 mo). Tumors recurred locally in two dogs at 10 mo and 20 mo postoperatively. This study yielded similar long-term complications as other limb-sparing options (such as cortical allografts and metal endoprostheses) and allowed dogs to bear weight on the operated limb with acceptable limb function. More research is needed regarding specific healing times for ulnar vascularized grafts, time until implant removal, and the extent of radial bone that could ultimately be replaced by the ulna.

Hilar liver resection in dogs.

OBJECTIVE: To describe hepatic vasculobiliary anatomy important to hilar liver lobe resection in the dog. STUDY DESIGN: Experimental study. ANIMALS: Canine cadavers (n=7). METHODS: The vasculobiliary system of 7 fresh canine livers was injected with a polymer. The parenchyma was dissected at the level of the hilus to determine the vascular and biliary supply to each liver lobe, and then macerated with a corrosion preparation. The information gathered was used to describe a surgical approach for hilar liver lobe resection. RESULTS: Each liver lobe had a single hepatic artery and biliary duct. The location of these structures was consistent, although minor variations existed (dorsal versus ventral to the lobar portal vein) in the left lateral lobe and papillary process in 2 specimens. Most liver lobes (34/49) were supplied by 1 lobar portal vein and drained by 1 lobar hepatic vein (39/49). The location of the portal and hepatic veins was consistent among specimens. CONCLUSIONS: The left division is the most mobile of the liver lobes and each lobe can be removed separately or en bloc. Because of the location of the hepatic veins, the central division is best removed as a single unit. The right lateral lobe can be removed individually or together with the caudate process. The papillary process is removed by itself. CLINICAL RELEVANCE: A hilar liver lobectomy technique can provide an alternative approach to conventional procedures for tumors that encroach upon the hilus of the liver.

Postenucleation orbital sialocele in a dog associated with prior parotid duct transposition.

An orbital sialocele developed in a dog following enucleation for protracted glaucoma. This eye had historically been treated for keratoconjunctivitis sicca by parotid duct transposition approximately 5 years previously, and the duct was ligated distally at the time of enucleation. One month following enucleation, the dog presented with a fluctuant conical-shaped swelling ventrolateral to the orbital socket. Surgical exploration revealed a dilated, fibrotic distal portion of the previously transposed parotid duct, and saliva, within the enucleated orbit. The distal portion of the duct and saliva-containing tissues from within the orbit were excised. The remaining proximal normal portion of the parotid duct was re-routed into the oral cavity. Clinicopathologic and histologic examination of the excised orbital contents and dilated portion of duct revealed a sterile sample of saliva and moderate chronic periductal fibrosis. At a 6-month re-evaluation there was no evidence of recurrence of the sialocele, and the parotid duct was functional.

Chronic vaginitis associated with vaginal foreign bodies in a cat.

A 2-year-old, spayed female, domestic shorthaired cat was presented for evaluation of a chronic, purulent vulvar discharge. Survey radiographs of the abdomen and pelvis revealed bone fragments in the pelvic canal. A vaginoscopy was performed, and five bony foreign bodies were removed from the vaginal lumen. Using anatomical landmarks, the bones were identified as remnants of a fetal kitten.

Surgical approaches to recipient vessels of the fore- and hindlimbs for microvascular free tissue transfer in dogs.

OBJECTIVE: To develop and evaluate surgical approaches to the arteries and veins of the fore- and hindlimbs for use as potential recipient vessels for free tissue transfer. STUDY DESIGN: Experimental anatomic study. SAMPLE POPULATION: Canine cadavers (11): 2 preserved and 9 fresh cadavers. METHODS: Fore- and hindlimbs from 1 preserved cadaver injected with a pigmented silicone/barium mixture, through the common carotid artery and external jugular vein, were cut in 1 cm cross-sections. Tissue sections were used to identify the location of vessels >1 mm that could be used as recipient vessels for free tissue transfer. The other preserved cadaver was used to develop surgical approaches to these vessels. Three surgeons evaluated the written descriptions and illustrations for these approaches using fresh cadavers. Modifications to the surgical approaches were made based on recommendations from these surgeons. RESULTS: Six approaches were developed to isolate forelimb recipient vessels: palmar access, distal medial antebrachial, mid-antebrachial, proximal antebrachial, distal humeral, and mid-humeral vascular access. Twelve approaches were developed to isolate recipient vessels of the hindlimb: plantar access, dorsal tarsal, cranial distal tibial, craniomedial distal tibial, lateral distal tibial, medial distal tibial, medial femorotibial, lateral distal femoral, medial femoral, proximal medial femoral, groin, and proximal lateral femoral vascular access. CONCLUSIONS: Six forelimb and 12 hindlimb sites were identified for surgical access to recipient vessels (>1 mm diameter) suitable for use in free tissue transfer for wound reconstruction. CLINICAL RELEVANCE: For reconstruction of complex wounds of the extremities of dogs, surgeons should consider use of readily accessible recipient vessels that would allow for free tissue transfer to the fore- and hindlimbs.

Evaluation of the effects of nephrotomy on renal function in clinically normal cats.

OBJECTIVE: To evaluate the effects of nephrotomy on renal function in clinically normal cats. ANIMALS: 20 specific-pathogen-free, 9- to 11-month-old female mixed-breed cats. PROCEDURE: Serum chemistry analyses, CBC determinations, urinalyses, microbiologic urine cultures, renal ultrasonography, abdominal radiography, and single-kidney and total glomerular filtration rate (GFR) determinations by use of renal scintigraphy and measurements of plasma disappearance of technetium 99m-diethylenetriaminepentaacetic acid were performed before surgery and at 3, 12, 26, 52, and 78 weeks after surgery in 10 cats that underwent unilateral nephrotomy and in 10 control cats that underwent a sham surgical procedure. RESULTS: Two cats (1 from each group) did not complete the study, and their data were eliminated from analyses. Unilateral nephrotomy resulted in a 10% to 20% reduction in mean single-kidney GFR, compared with that of nephrotomy contralateral control kidneys. However, mean total GFR in nephrotomy-group cats was not significantly different from that of sham-group cats. Over the 78 weeks of study, mean total GFR declined 34% and 40% in nephrotomy- and sham-group cats, respectively. Adverse events associated with nephrotomy included persistent microscopic hematuria, renal pelvis hyperechogenicity with distant shadowing on ultrasonographic evaluation, dilatation of renal pelves, and hydronephrosis. CONCLUSIONS AND CLINICAL RELEVANCE: Nephrotomy in normal functioning feline kidneys results in a modest relative reduction in renal function, compared with contralateral kidney controls, but has minimal effect on total GFR when compared with sham-operated control cats. However, any detrimental effects of nephrotomy may be magnified in cats with diseased kidneys, which may have little or no capacity for repair or compensation.

Primary splenic mesenchymal chondrosarcoma in a dog.

A large splenic mass was found during exploratory celiotomy in a 12-year-old Labrador retriever. Histologic examination of the mass revealed a mesenchymal chondrosarcoma. The dog was euthanatized 7 wk postoperatively, due to suspected tumor recurrence. Extraskeletal mesenchymal chondrosarcomas are rare in dogs and are associated with a guarded prognosis.