A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design.

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.

Lymphatic Embolization for the Management of Post-operative Chyle Leaks Following Solid Tumor Resection in Pediatric Patients.

BACKGROUND: Chyle leaks are a common post-operative complication following solid-tumor resection in pediatric patients. Current treatments for persistent chyle leaks are limited, leading many patients to experience prolonged hospitalization, nutritional deficits and/or delays in cancer therapies. Lymphatic embolization is an emerging treatment option for chyle leaks, however, limited reports exist of its use in pediatric populations. METHODS: We conducted a retrospective review of pediatric patients (<18) who underwent lymphangiogram with intent for lymphatic embolization for the management of chyle leaks following solid-tumor resection between 2017 and 2022. RESULTS: Seven patients underwent a total of 11 attempted lymphatic embolization procedures after current standard of care treatments failed to resolve the leak. Lymphangiograms identified a chyle leak in 6 of 7 patients and embolization had a technical success rate of 73%. The complication rate was 9% and complications were limited to one episode of inadvertent gastric wall perforation that did not result in a gastric leak. Lymphatic embolization was ultimately associated with chyle leak resolution in 100% of patients within a median of 24 days, however, repeat embolization was required in 5 of 7 patients (83%). CONCLUSION: Lymphatic embolization appears to be a safe and effective treatment for persistent chyle leaks in pediatric patients, leads to a direction reduction in chyle output, and has high rates of technical and clinical success. Complete resolution of the chyle leak may require multiple embolization procedures. Further work is needed to determine whether earlier intervention may offer benefit for the management of pediatric chyle leaks. LEVEL OF EVIDENCE: IV.

Classification of lower extremity venous malformations and risk of knee involvement: A retrospective cohort study.

BACKGROUND: Venous malformation (VM) is the most common vascular anomaly in the lower extremity. VMs can be classified as focal, multifocal, or diffuse types. Intraarticular VM (IA-VM) of the knee portends morbidity. Association of the lower extremity VM type with IA-VM is not well defined. OBJECTIVE: To classify a large cohort of lower extremity, nonsyndromic VMs by type and determine associations with IA-VM. METHODS: Retrospective cohort study. RESULTS: We assessed 156 patients with nonsyndromic, lower extremity VM; 71 (46%) were focal and 85 (54%) were diffuse type VM, and 97 (62%) were IA-VM. Of diffuse VMs, 26 (31%) were Bockenheimer and 59 (69%) were localized subtypes. Pure VM had a significantly elevated risk of IA-VM (relative risk [RR], 2.34; 95% confidence interval [CI], 1.42-3.89). IA-VM was more common in diffuse (73%) versus focal (49%) types. Risk of IA-VM in diffuse type VM was significantly elevated (RR, 1.48; 95% CI, 1.13-1.94). One hundred percent of diffuse Bockenheimer type VM had IA-VM, and this subtype had the highest risk (RR, 1.83; 95% CI, 1.56-2.14) of IA-VM. LIMITATIONS: Retrospective, single-institution study. CONCLUSIONS: Intraarticular involvement of the knee should be considered in all lower extremity VMs. Pure VM and the Bockenheimer diffuse VM subtype had the highest risk of IA-VM.

Contemporary Management of Vascular Anomalies of the Head and Neck-Part 1: Vascular Malformations: A Review.

Importance: Vascular anomalies of the head and neck are relatively rare lesions. Management is challenging because of the high likelihood of involvement of functionally critical structures. Multiple modalities of treatment exist for vascular anomalies of the head and neck, including medical therapies, sclerotherapy and embolization procedures, and surgery. This review focuses on the accurate diagnosis and the relative roles of the various therapeutic options. Observations: Vascular anomalies are classified by the International Society for the Study of Vascular Anomalies into 2 major groups: vascular tumors and vascular malformations. Vascular tumors encompass proliferative lesions ranging from infantile and congenital hemangiomas to kaposiform hemangioendothelioma. Alternatively, vascular malformations are embryologic errors in vasculogenesis. This article focuses on the management of vascular malformations. The 3 primary vascular malformation subclassifications are lymphatic, venous, and arteriovenous. The burden of disease, diagnosis, and current management options are discussed in detail for each subtype. Conclusions and Relevance: Most vascular malformations of the head and neck require a multidisciplinary approach. Available medical, interventional radiologic, and surgical interventions are constantly evolving. Optimization of function and cosmesis must be balanced with minimization of treatment-associated morbidity. Otolaryngologists-head and neck surgeons must remain up to date regarding options for diagnosis and management of these lesions.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Endovascular Treatment of Congenital Arterioportal Fistulas.

PURPOSE: To characterize anatomy of congenital arterioportal fistulas (CAPF) and correlate this with technique and outcomes of transcatheter embolization (TCE). MATERIALS AND METHODS: Retrospective review was conducted of children with CAPF that underwent TCE in a 10-year period. Medical records, imaging and procedure details were reviewed. TCE was performed via transarterial (n = 5), portal (n = 5) or patent ductus venosus (n = 1) approach. Embolic agents used were coils (n = 10), Onyx (n = 1) and Amplatzer septal occluder (n = 1). RESULTS: A total of 7 patients were included (4 female). Median age at treatment was 4 months (2 month-3 year). Most common symptoms were GI bleeding (n = 4), anemia (n = 4) and ascites (n = 3). Hepatopetal flow was seen in all on pre-procedure sonography. On angiography, a simple lesion, with direct fistulous connections, from hepatic arterial (HA) branches to portal venous (PV) system was seen in 3. A complex lesion with multiple connections was identified in 4. In simple lesions, cessation of shunting was achieved in 1 procedure, with embolization of afferent vessels. In complex lesions, multiple procedures were required in 3 of 4 patients. All 4 with complex connections required embolization of the aneurysmal PV segment. There were no major complications. Two minor complications were noted: localized biliary leak in 1 and femoral pseudoaneurysm in 1. There was resolution of symptoms in 6. CONCLUSIONS: TCE is effective as primary treatment of CAPF. Patients with simple arteriovenous connections can be treated with embolization of afferent vessels, but children with multiple complex connections usually require embolization of the dilated PV segment.

Combined glue embolization and excision for the treatment of venous malformations.

BACKGROUND: The purpose of this study was to evaluate safety, technical success, and clinical outcomes of treatment for venous malformations using n-BCA glue embolization immediately prior to excision. Sixty three patients (22 male, 41 female; mean age 12 years (range 1-25)) who underwent 70 procedures for extremity and trunk venous malformations were reviewed. Indications for treatment included pain (100%), swelling (22%), and diminished range of motion (16%). Thirty seven patients (59%) had undergone prior stand-alone interventional or surgical treatment but were persistently symptomatic. Safety, technical and clinical success were retrospectively assessed. RESULTS: Embolization was technically successful in 100% of patients. Mean lesion size was 3.0 × 2.9 × 5.7 cm. Three patients (5%) underwent planned, second stage procedures for lesions intentionally not treated at the first procedure. Four patients (6%) underwent an unplanned, second stage procedure for residual disease after the primary operation. Mean and median follow-up duration were 18 and 17 months, respectively (range 3 to 35 months). Symptomatic improvement was achieved in 58 patients (92%), of whom 41 (65%) reported complete elimination of pain. There were no recognized instances of nontarget embolization or other complications of the interventional procedure. One patient required additional surgery for wound dehiscence and one patient developed an abscess requiring incision and drainage. Minor surgical complications included surgical site skin infections (n = 5) and numbness (n = 1). Mean and median surgical blood loss volumes were 131 mL and 10 mL, respectively. One patient required perioperative blood transfusion. CONCLUSIONS: Extremity and truncal venous malformations can be safely and effectively treated in a single-stage fashion using glue embolization immediately preceding excision.

Outcomes of Locoregional Tumor Therapy for Patients with Hepatocellular Carcinoma and Transjugular Intrahepatic Portosystemic Shunts.

PURPOSE: Locoregional therapy for hepatocellular carcinoma (HCC) can be challenging in patients with a transjugular intrahepatic portosystemic shunt (TIPS). This study compares safety and imaging response of ablation, chemoembolization, radioembolization, and supportive care in patients with both TIPS and HCC. METHODS: This retrospective study included 48 patients who had both a TIPS and a diagnosis of HCC. Twenty-nine of 48 (60%) underwent treatment for HCC, and 19/48 (40%) received best supportive care (i.e., symptomatic management only). While etiology of cirrhosis and indication for TIPS were similar between the two groups, treated patients had better baseline liver function (34 vs. 67% Child-Pugh class C). Tumor characteristics were similar between the two groups. A total of 39 ablations, 17 chemoembolizations, and 10 yttrium-90 radioembolizations were performed on 29 patients. RESULTS: Ablation procedures resulted in low rates of hepatotoxicity and clinical toxicity. Post-embolization/ablation syndrome occurred more frequently in patients undergoing chemoembolization than ablation (47 vs. 15%). Significant hepatic dysfunction occurred more frequently in the chemoembolization group than the ablation group. Follow-up imaging response showed objective response in 100% of ablation procedures, 67% of radioembolization procedures, and 50% of chemoembolization procedures (p = 0.001). When censored for OLT, patients undergoing treatment survived longer than patients receiving supportive care (2273 v. 439 days, p = 0.001). CONCLUSIONS: Ablation appears to be safe and efficacious for HCC in patients with TIPS. Catheter-based approaches are associated with potential increased toxicity in this patient population. Chemoembolization appears to be associated with increased toxicity compared to radioembolization.

Postembolization syndrome after hepatic transarterial chemoembolization: effect of prophylactic steroids on postprocedure medication requirements.

PURPOSE: To evaluate the impact of prophylactic use of dexamethasone and scopolamine on analgesic and antiemetic agent requirements after transarterial chemoembolization. MATERIALS AND METHODS: A total of 148 patients underwent 316 rounds of chemoembolization for hepatocellular carcinoma at a single institution over a 17-month period. Patient charts were retrospectively reviewed for demographic data, procedural technique, and use of analgesic and antiemetic medications. Patients were grouped into three categories: group A received steroid prophylaxis before and after the procedure, group B received steroid prophylaxis before the procedure only, and group C received no steroid prophylaxis. RESULTS: Analysis was performed on 125 patients undergoing 252 procedures. Demographics were similar among groups. Overall, 86 (68.8%) were male, and mean age was 62 years (range, 39-82 y). Ninety-one patients (75%) had Child-Pugh class A cirrhosis and 25% had Child-Pugh class B cirrhosis. Dexamethasone was not significantly associated with decreased analgesic agent use (P = .6). Group A patients used significantly fewer antiemetic agents (Δ = 0.89; P = .007) compared with group C. A transdermal scopolamine patch was not associated with reduced use of antiemetic agents (P = .3). Age was inversely associated with analgesic (P <.001) and antiemetic agent use (P = .004). Men received significantly fewer antiemetic agents than women (P = .002), whereas there was no significant difference in analgesic agent use (P = .7). CONCLUSIONS: The use of steroids did not affect analgesic agent use and had a minor effect on antiemetic requirements. The use of a scopolamine patch was not associated with reduced antiemetic agent use.

Gadolinium-based contrast media and the development of nephrogenic systemic fibrosis in patients with renal insufficiency.

Gadolinium-based contrast media are important tools in diagnostic and interventional radiology that are particularly useful in patients with renal insufficiency. Recent reports in which exposure to gadolinium compounds has been linked to the development of nephrogenic systemic fibrosis in this patient population, however, are quite concerning. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, <60 mL/min/1.73 m(2)) to severe (glomerular filtration rate, <15 mL/min/1.73 m(2)) renal disease.

Programmed cell death in flight muscle histolysis of the house cricket.

We have characterized the process of flight muscle histolysis in the female house cricket, Acheta domesticus, through analysis of alterations of tissue wet weight, total protein content, and percent shortening of the dorsal longitudinal flight muscles (DLMs). Our objectives were to (1) define the normal course of histolysis in the cricket, (2) analyze the effects of juvenile hormone (JH) removal and replacement, (3) determine the effects of cycloheximide treatment, and (4) examine patterns of protein expression during histolysis. Our results suggest that flight muscle histolysis in the house cricket is an example of an active, developmentally regulated cell death program induced by an endocrine signal. Initial declines of total protein in DLMs indicated the JH signal that induced histolysis occurred by Day 2 and that histolysis was essentially complete by Day 3. Significant reductions in tissue weight and percent muscle shortening were observed in DLMs from Day 3 crickets. Cervical ligation of Day 1 crickets prevented histolysis but this inhibition could be reversed by continual topical treatments with methoprene (an active JH analog) although ligation of Day 2 crickets did not prevent histolysis. A requirement for active protein expression was demonstrated by analysis of synthesis block by cycloheximide and short-term incorporation of (35)S-methionine. Treatment with cycloheximide prevented histolysis. Autofluorographic imaging of DLM proteins separated by electrophoresis revealed apparent coordinated regulation of protein expression.

Epidermal growth factor receptor inhibition by tyrphostin 51 induces apoptosis in luteinized granulosa cells.

Growth factors may be involved in the control of ovarian cell fate and could contribute to regulation of ovarian cell apoptosis. Our objective is to test the hypothesis that, in human luteinized granulosa cells, epidermal growth factor (EGF) works through the MAPK signaling pathway and inhibition of EGF receptor by a specific tyrosine kinase inhibitor, tyrphostin 51, will inhibit the activation of MAPK and induce apoptosis. Luteinized granulosa cells from human in vitro fertilization aspirates were treated as follows: 1) vehicle (dimethylsulfoxide:ethanol), 2) EGF, 3) tyrphostin 51, and 4) tyrphostin 51 plus EGF. Blockage of EGF receptor by tyrphostin 51 reduced the MAPK activity and inhibited phosphorylation and nuclear translocation of activated MAPK. Blockage of EGF receptor also induced apoptosis as demonstrated by the activation of caspase-3, an executioner protease of the apoptotic pathway, and by an increased percentage of subdiploid apoptotic nuclei. These results support the hypothesis that in human luteinized granulosa cells, EGF works through the MAPK signaling pathway and that its inhibition by tyrphostin 51 inhibits MAPK phosphorylation and induces apoptotic nuclear changes. Our data thus provide additional information regarding regulation of apoptosis in luteinized granulosa cells.

A randomized trial of minidose warfarin for the prevention of late malfunction in tunneled, cuffed hemodialysis catheters.

BACKGROUND: Minidose warfarin (1 mg/day) has been associated with a 74% reduction in the thrombosis rate of central venous catheters used in oncology patients. To determine the efficacy of minidose warfarin on late malfunction caused by thrombosis or fibrin sheath formation in tunneled, cuffed catheters (TCC) used for hemodialysis (HD), we performed a randomized, placebo-controlled trial. METHODS: One hundred five chronic HD patients with TCCs were initially randomized. Of these, 85 (warfarin 41 and placebo 44) completed the first two weeks of the protocol and were followed for the first year of TCC life or until TCC removal. RESULTS: Sixteen TCCs failed with late TCC malfunction, eight in each group. In a multivariate analysis, there was no significant effect of warfarin on thrombosis-free TCC survival or time to the first urokinase (UK) instillation for incipient thrombosis. The presence of a low hemoglobin (Hgb; <10.5 g/dL) or a low international normalized ratio (INR; <1.00) was significantly associated with a higher risk of late TCC malfunction (RR 5.2 and 4.0, respectively), a higher risk of incipient TCC thrombosis requiring UK (RR 2.0 and 2.8, respectively), and higher rates of UK dosing. Diabetics had a 3.6-fold higher risk of late TCC malfunction and a twofold higher risk of incipient thrombosis requiring UK, although these findings were not statistically significant. Aspirin use, race, age, number of hospitalizations, erythropoietin dose, intradialytic heparin dose, serum albumin, and the number of episodes of TCC-associated infection were not significantly associated with late TCC malfunction. CONCLUSIONS: Thrombosis prophylaxis using fixed minidose warfarin is not efficacious in TCCs used for HD. However, the present data suggest improved TCC survival in patients with an INR> 1.00. Patients with diabetes and those with a low Hgb or INR have a higher risk of late TCC malfunction.

Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone.

To study the complications of renal osteodystrophy in patients with end-stage renal disease, we reviewed the incidence of hip fractures in our outpatient dialysis population from 1988 to 1998. One thousand two hundred seventy-two patients were treated for a total of 4,039 patient-years; 56 hip fractures were documented during this period. The incidence of hip fractures was many times greater in the dialysis patients than in the general population in each of the age-, race-, and sex-matched subgroups. The 1-year mortality rate from the hip fracture event was nearly two and a half times greater in the dialysis patients compared with the general population. The incidence of hip fractures in the first half of the decade was similar to that observed in the second half. When parathyroid hormone (PTH) levels were evaluated, we determined that patients with lower serum PTH levels were more likely to sustain a hip fracture than patients with higher PTH levels (P: < 0.006). In addition, we determined that patients with lower PTH levels had an earlier mortality than patients with higher PTH levels (P: < 0.03). We conclude that despite more aggressive therapy directed toward bone health in our dialysis patients in recent years, the incidence of hip fractures and their devastating morbidity and mortality remained unchanged over the past decade. Lower PTH levels may predispose to earlier mortality.

Women's health issues in a dialysis population.

BACKGROUND: As women receiving hemodialysis are evaluated frequently by the nephrologist, we hypothesized that women's health issues are better addressed in the dialysis patient than in the general population. PATIENTS AND METHODS: We surveyed the female patients in our dialysis population. 97% of the women approached agreed to participate. We found that 55.4% of our cohort had received routine gynecologic care. 50% of the women had undergone a Papanicolaou (Pap) smear in the last year. Of the women aged 40-50, 55% had undergone a mammogram in the last 2 years. In women over age 50, 71% received an annual mammogram. RESULTS: We found that 57% of the women were amenorrheic before starting renal replacement therapy while 16% had become amenorrheic after dialysis was started. 27% were still menstruating at the time of the survey. Only 4% of the amenorrheic women interviewed were currently on hormone replacement therapy (HRT) as compared with 20% of women in our general medical clinics. While 67% stated that they would take hormone replacement if offered, 89% had never been offered HRT. Variables that positively correlated with willingness to take HRT were a history of a hysterectomy and more skilled work history. Although nephrologists surveyed at our academic facility agreed that amenorrheic women with renal disease benefited from HRT, many believed that it is not the role of the nephrologist to prescribe it. CONCLUSION: Despite frequent contacts with medical providers, women's health issues for patients on dialysis may not receive the same attention as women in the general population