A qualitative evaluation of factors influencing Tumor Treating fields (TTFields) therapy decision making among brain tumor patients and physicians.

BACKGROUND: Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine patient and clinician views of TTFields and factors shaping utilization of TTFields through a unique research partnership with medical neuro oncology and medical social sciences. METHODS: Adult glioblastoma patients who were offered TTFields at a tertiary care academic hospital were invited to participate in a semi-structured interview about their decision to use or not use TTFields. Clinicians who prescribe TTFields were invited to participate in a semi-structured interview about TTFields. RESULTS: Interviews were completed with 40 patients with a mean age of 53 years; 92.5% were white and 60% were male. Participants who decided against TTFields stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. The most influential factors for use of TTFields were the efficacy of the device and their clinician's opinion. Clinicians (N = 9) stated that TTFields was a good option for glioblastoma patients, but some noted that their patients should consider the burdens and benefits of TTFields as it may not be the desired choice for all patients. CONCLUSIONS: This is the first study to examine patient decision making for TTFields. Findings suggest that clinician support and efficacy data are among the key decision-making factors. Properly understanding the path to patients' decision making is crucial in optimizing the use of TTFields and other therapeutic decisions for glioblastoma patients.

Photosensitizing antihypertensive medication and risk of skin cancer among postmenopausal women.

BACKGROUND: Few prospective studies exist with an evaluation of a dose-response relationship between use of some photosensitizing antihypertensive medications and skin cancer. PATIENT AND METHODS: We used prospective data from the Women's Health Initiative Observational Study to investigate the association between antihypertensive use and risk of non-melanoma skin cancer (NMSC) and melanoma in postmenopausal women aged 50-79 years at baseline (n  =  64,918). Multivariable Cox proportional hazards regression models were used and hazard ratios (HRs) and 95 confidence intervals (CIs) were calculated. RESULTS: 8,777 NMSC and 1,227 melanoma cases were observed. Use of antihypertensives (HR [95% CI]: 1.12 [1.07-1.18]), ACE inhibitors (1.09 [1.01-1.18]), calcium channel blockers (1.13 [1.05-1.22]), diuretics (1.20 [1.12-1.27]), loop diuretics (1.17 [1.07-1.28]), and thiazides (1.17 [1.03-1.33]) were each associated with higher NMSC risk. NMSC risk linearly increased with use of multiple antihypertensives (p-trend  =  0.02) and with longer duration of use (p-trend < 0.01). Antihypertensives (1.15 [1.00-1.31]), angiotensin-II receptor blockers (1.82 [1.05-3.15]), and diuretics (1.34 [1.13-1.59]) were each associated with elevated melanoma risk. Effect modification by solar radiation exposure was found between antihypertensive use and incidence of melanoma (p-interaction  =  0.02). CONCLUSIONS: Use of antihypertensives overall, and several individual classes thereof, were associated with higher incidence of NMSC and melanoma with dose-response relationship.

PEAK1 Acts as a Molecular Switch to Regulate Context-Dependent TGFß Responses in Breast Cancer.

Transforming Growth Factor ß (TGFß) has dual functions as both a tumor suppressor and a promoter of cancer progression within the tumor microenvironment, but the molecular mechanisms by which TGFß signaling switches between these outcomes and the contexts in which this switch occurs remain to be fully elucidated. We previously identified PEAK1 as a new non-receptor tyrosine kinase that associates with the cytoskeleton, and facilitates signaling of HER2/Src complexes. We also showed PEAK1 functions downstream of KRas to promote tumor growth, metastasis and therapy resistance using preclinical in vivo models of human tumor progression. In the current study, we analyzed PEAK1 expression in human breast cancer samples and found PEAK1 levels correlate with mesenchymal gene expression, poor cellular differentiation and disease relapse. At the cellular level, we also observed that PEAK1 expression was highest in mesenchymal breast cancer cells, correlated with migration potential and increased in response to TGFß-induced epithelial-mesenchymal transition (EMT). Thus, we sought to evaluate the role of PEAK1 in the switching of TGFß from a tumor suppressing to tumor promoting factor. Notably, we discovered that high PEAK1 expression causes TGFß to lose its anti-proliferative effects, and potentiates TGFß-induced proliferation, EMT, cell migration and tumor metastasis in a fibronectin-dependent fashion. In the presence of fibronectin, PEAK1 caused a switching of TGFß signaling from its canonical Smad2/3 pathway to non-canonical Src and MAPK signaling. This report is the first to provide evidence that PEAK1 mediates signaling cross talk between TGFß receptors and integrin/Src/MAPK pathways and that PEAK1 is an important molecular regulator of TGFß-induced tumor progression and metastasis in breast cancer. Finally, PEAK1 overexpression/upregulation cooperates with TGFß to reduce breast cancer sensitivity to Src kinase inhibition. These findings provide a rational basis to develop therapeutic agents to target PEAK1 expression/function or upstream/downstream pathways to abrogate breast cancer progression.

Impact of duplex arteriography in the evaluation of acute lower limb ischemia from thrombosed popliteal aneurysms.

Acute limb-threatening ischemia from thrombosis may be the initial presentation of popliteal artery aneurysms (PAA) and is associated with amputation rates of 20-30%. Since contrast angiography may miss the diagnosis, the authors suspect that thrombosis of PAA may be an underappreciated cause of acute ischemia. Routine use of duplex arteriography (DA) may aid in the diagnosis and may help identify the outflow vessels with improved results. One hundred and nine patients (group 1) from 1994 to 1997 and 201 patients from 1998 to 2001 (group 2) presenting with acute limb-threatening ischemia were studied. None of the group 1 patients underwent preoperative DA and no diagnosis of acute popliteal artery aneurysm thrombosis was made. Ten patients with acute ischemia due to thrombosed popliteal artery aneurysms were identified in group 2 when preoperative DA was routinely performed. Urgent revascularization based on the results from DA was performed with use of autogenous saphenous vein in all patients. Six patients had functioning bypasses with a mean follow-up of 15.6 months. There were 3 deaths, 2 within 30 days and 1 after 2(1/2) years with functioning grafts. One patient was lost to follow-up. No major amputations were performed. Incidence of thrombosed popliteal artery aneurysms as the cause of acute limb-threatening ischemia is probably underestimated. Routine use of DA may provide the diagnosis and identifies the available outflow vessels. Contrary to previously published reports, urgent revascularization of an acutely ischemic extremity from thrombosed popliteal aneurysm can provide excellent rates of limb salvage.

Duplex arteriography prior to femoral-popliteal reconstruction in claudicants: a proposal for a new shortened protocol.

The standard preoperative duplex arteriography (DA) from the aorta to the pedal vessels is time consuming and may be unnecessary in patients presenting with calf claudication alone. The feasibility of a shortened protocol was evaluated. Of 286 femoral-popliteal reconstruction based on DA during the last 4A years, 79 (28%) were primary operations for calf claudication. Eliminating the aortoiliac portion of the test except for the distal external iliac artery and limiting the scanning of the infrapopliteal vessels to one or two arteries in the leg would significantly shorten the exam. To confirm the adequacy of the inflow tract, we relied on the common femoral artery Doppler waveform analysis and the intraoperative graft pressure upon completion of the bypass. Of the 79 primary femoral-popliteal bypasses, 53 (67%) had triphasic common femoral artery waveform and the remaining 26 had monophasic or biphasic waveforms. Three (6%) of the 53 femoral-popliteal bypasses in the former group had significant pressure gradients measured intraoperatively and were treated with iliac angioplasties and stents for unsuspected stenoses in 2 cases and a covered stent for a common iliac aneurysm in 1 case. Three, two, and one infrapopliteal vessel runoff was observed in 24 (45%), 16 (30%), and 9 (17%) extremities, respectively. Four patients (8%) had significant stenoses (>50%) or occlusion of all three infrapopliteal arteries. Eighty-one percent of the patients would have completed the short protocol had we scanned the peroneal artery initially. An additional 8% would have required scanning of a second vessel (anterior tibial) and only 11%, scanning of all three infrapopliteal vessels. The time interval for completion of short-protocol DA was significantly less than the time for the standard DA (16.2 A+/- 5.2A min vs. 35.1 A+/- 10.6 min) ( p < 0.01). We believe that the proposed short DA protocol combined with intraoperative graft pressure measurements can be used in 94% of the patients who have a patent popliteal artery (>/= 7 cm). It is a totally noninvasive approach that is particularly suitable for vascular technologists and surgeons who wish to start utilizing DA instead of contrast arteriography prior to infrainguinal reconstructions. However, the short protocol does not avert the need for completion arteriography of the inflow arteries and readiness to perform endovascular procedures to correct lesions not suspected by common femoral artery waveform analysis.

Deep venous thrombosis after radiofrequency ablation of greater saphenous vein: a word of caution.

PURPOSE: Radiofrequency ablation (RFA) of the greater saphenous vein (GSV; "closure") is a relatively new option for treatment of venous reflux. However, our initial enthusiasm for this minimally invasive technique has been tempered by our preliminary experience with its potentially lethal complication, deep venous thrombosis (DVT). METHODS: Seventy-three lower extremities were treated in 66 patients with GSV reflux, between April 2003 and February 2004. There were 48 (73%) female patients and 18 (27%) male patients, with ages ranging from 26 to 88 years (mean, 62 +/- 14 years). RFA was combined with stab avulsion of varicosities in 55 (75%) patients and subfascial ligation of perforator veins in 6 (8%) patients. An ATL HDI 5000 scanner with linear 7-4 MHz probe and the SonoCT feature was used for GSV mapping and procedure guidance in all procedures. GSV diameter determined the size of the RFA catheter used. Veins less than 8 mm in diameter were treated with a 6F catheter (n = 54); an 8F catheter was used for veins greater than 8 mm in diameter (n = 19). The GSV was cannulated at the knee level. The tip of the catheter was positioned within 1 cm of the origin of the inferior epigastric vein (first GSV tributary). All procedures were carried out according to manufacturer guidelines. RESULTS: All patients underwent venous duplex ultrasound scanning 2 to 30 days (mean, 10 +/- 6 days) after the procedure. The duplex scans documented occlusion of the GSV in 70 limbs (96%). In addition, DVT was found in 12 limbs (16%). Eleven patients (92%) had an extension of the occlusive clot filling the treated proximal GSV segment, with a floating tail beyond the patent inferior epigastric vein into the common femoral vein. Another patient developed acute occlusive clots in the calf muscle (gastrocnemius) veins. Eight patients were readmitted and received anticoagulation therapy. Four patients were treated with enoxaparin on an ambulatory basis. None of these patients had pulmonary embolism. Initially 3 patients with floating common femoral vein clots underwent inferior vena cava filter placement. Of the 19 limbs treated with the 8F RFA catheter, GSV clot extension developed in 5 (26%), compared with 7 of 54 (13%) limbs treated with the 6F RFA catheter (P =.3). No difference was found between the occurrence of DVT in patients who underwent the combined procedure (RFA and varicose vein excision) compared with patients who underwent GSV RFA alone (P =.7). No statistically significant differences were found in age or gender of patients with or without postoperative DVT (P = NS). CONCLUSION: Patients who underwent combined GSV RFA and varicose vein excision did not demonstrate a higher occurrence of postoperative DVT compared with patients who underwent RFA alone. Early postoperative duplex scans are essential, and should be mandatory in all patients undergoing RFA of the GSV.

Role of duplex arteriography as the sole preoperative imaging modality prior to lower extremity revascularization surgery in diabetic and renal patients.

The limitations and complications associated with contrast angiography (CA) prior to lower extremity revascularization have led to an increased interest in duplex arteriography (DA) as a potential replacement. We report our experience with DA in patients with diabetes and/or chronic renal insufficiency (CRI) that would particularly benefit from a noninvasive approach to preoperative evaluation of the arterial tree. From January 1998 to November 2000, DA was performed in 145 patients with diabetes mellitus and/or CRI prior to 180 arterial reconstructions. One hundred twenty-one procedures were performed on 91 patients with diabetes alone, 41 on 33 patients with diabetes and CRI, and 18 on 15 patients with CRI alone. Patient ages ranged from 36 to 98 years (mean 72 +/- 12 years). Indications for surgery were severe claudication in 33 (18%), rest pain in 37 (21%), nonhealing ischemic ulcers in 52 (29%), and limb gangrene in 58 (32%). Optimal inflow and outflow anastomotic sites were selected according to a diagram based on DA that included arterial tree imaging from mid-aorta to the pedal vessels. Preoperative contrast arteriography was performed in 16 cases (9%) because of extremely poor runoff based on DA and limited visualization of outflow vessels. The distal anastomosis was to the popliteal artery in 89 cases (49%) and to the tibial and pedal arteries in 91 (51%). Intraoperative findings confirmed the preoperative DA results with the exception of one (0.6%) where the distal anastomosis was placed proximal to a significant stenosis requiring an extension graft. The use of DA presents a safe and reliable option to prebypass CA for many patients with diabetes or CRI. The ease of use and favorable patient outcomes achieved by this imaging modality may rival the use of CA for these patients.

Endovascular management of axillofemoral bypass graft stump syndrome.

OBJECTIVE: Upper extremity embolic complications of occluded axillofemoral bypass grafts are infrequent. However, traditional management of dissection of axillary anastomosis for removal of the stump can be challenging. We report two patients with critical upper extremity ischemia secondary to stump syndrome and its successful management with endovascular techniques. METHODS: One hundred fifty-two patients underwent axillofemoral bypass grafting over 10 years from 1991-2001. Two patients from this series had acute ischemia involving the ipsilateral upper extremity of occluded axillofemoral bypass graft. Duplex ultrasound scans revealed occlusion of the axillofemoral bypass graft and acute occlusion of ipsilateral upper extremity arteries. Both patients underwent brachial artery exploration and embolectomy. Completion angiograms revealed persistent axillofemoral bypass graft stump as the source of embolus. The stump was obliterated with a 10-mm/40-mm Wallgraft introduced through the same arteriotomy made for brachial embolectomy. Transesophageal echocardiography and magnetic resonance angiography of the arch and great vessels were performed to exclude other sources of origin for the embolus. RESULTS: Both patients remained symptom-free and with patent stent grafts, as seen on duplex scans at 3, 6, and 9 months of follow-up. CONCLUSIONS: Upper extremity embolism is a rare complication after occlusion of axillofemoral bypass grafts. The endovascular approach to obliterate the stump of occluded axillofemoral bypass grafts is minimally invasive and an effective alternative treatment of this rare condition.