Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

Activity-based anorexia: A biobehavioral perspective

A biobehavioral model of activity-based anorexia is examined in terms of recent evidence. Strenuous exercise reduces the value of food reinforcement and results in decreased food intake. Reduction of food intake increases the motivational value of physical exercise. This produces an escalation in activity that further suppresses appetite. Cultural practices of diet and exercise initiate this anorexic cycle, and once started the process is resistant to change. These anorexias may be the result of natural selection favoring those organisms that became active in times of food scarcity. Proximate physiological mechanism(s) appear to involve the endogenous opiate system that mediates the relationshp between running and eating. It is argued that classification of human self-starvation should be based on environmental and/or biological conditions that control food regulation. Activity anorexia may be one instance of such a classification that could account for many instances of “an orexia nervosa”.     

A comparison of diabetics and nondiabetics with threatened limb loss

One hundred seventeen patients with threatened limb loss were evaluated. Seventy-three of these patients underwent vascular reconstruction. Diabetics had a significantly higher incidence of ischemic ulceration and gangrene when compared with nondiabetics. Nondiabetics typically presented with rest pain. The outcome of foot salvage surgery was evaluated by postoperative ankle-branchial indices as well as limb salvage rates. Ankle-brachial indices increased significantly in both groups. Fifty-five percent of the diabetics and 67 percent of the nondiabetics had a postoperative ankle-brachial index of 0.8 or greater. Overall foot salvage at 1 year was 84 percent. Foot salvage in patients with diabetes was 78 percent compared with 86 percent in nondiabetics. In this subset of patients with threatened limb loss confirmed by hemodynamic measurements, the results of vascular reconstruction were comparable in both diabetic and nondiabetic patients.     

Radiosensitivity of permanent human bone marrow stromal cell lines: effect of dose rate

In contrast to the dose-rate independent X ray killing observed with human bone marrow hematopoietic stem cells, bone marrow adherent stromal cells from the same fresh marrow harvests demonstrate increased radiation resistance at low dose rate (LDR) (5 cGy/min), compared to high dose rate (HDR) irradiation (120-200 cGy/min). Physiologic changes observed in plateau phase bone marrow cells after LDR irradiation in vivo and in vitro suggested that marrow stromal cells might be heterogeneous in LDR irradiation repair. Five permanent clonal bone marrow stromal lines were derived from a single human marrow donor. Each cell line was positive for markers of fibroblasts including: immunohistochemically detectable fibronectin, collagen, acid phosphatase, and nonspecific esterase, and was negative for Factor VIII, alkaline phosphatase, lysozyme and several markers of marrow macrophages. The x-irradiation survival curve of each cell line was determined at LDR and HDR in vitro. Cell lines KM102, KM103, KM104, and KM105 each demonstrated a significant (p less than .05) increase in radioresistance at LDR (D0 = 142, n = 2.9; D0 = 131, n = 2.5; D0 = 145, n = 2.1 and D0 = 127, n = 2.1 respectively) compared to HDR: (D0 = 111, n = 2.1; D0 = 94, n = 3.5; D0 = 99, n = 3.5 and D0 = 95, n = 2.1 respectively). In contrast, cell line KM101 demonstrated no significant change in radiosensitivity relative to dose rate at LDR (D0 = 113, n = 3.3) compared to HDR, D0 = 114, n = 3.3. Cell line KM101 was more supportive than the other lines of cocultivated hemopoietic cells in vitro. Subclones of KM101 and KM104 selected by retroviral vector transfer of the neor gene for growth in the antibiotic neomycin-analogue G418, maintained the stably associated radiobiologic properties of each parent clonal line. These data indicate significant heterogeneity in the LDR irradiation response of clonal stromal cell lines derived from human bone marrow.     

Determinants of response to pentoxifylline therapy in patients with intermittent claudication

Eighty-three patients receiving pentoxifylline for stable claudication were evaluated to identify factors associated with response to treatment. Patients with isolated aortoiliac occlusive disease and those with arterial occlusive disease of moderate severity were more likely to have an improvement in claudication distance.     

Diagnostic value of open lung biopsy in immunocompromised patients

The records of 46 immunocompromised patients who presented with diffuse pulmonary infiltrates were reviewed to determine the role of open lung biopsy in their management. Fifty-two percent of these patients had underlying hematologic malignancies and 54 percent had received chemotherapy within 3 months prior to biopsy. Forty-six percent were receiving immunosuppressive doses of corticosteroids. A specific diagnosis was obtained in 30 of the 46 patients (65 percent). Fifteen of these patients had pulmonary infections. Nonspecific diagnoses were obtained in 16 of the 46 patients (45 percent). Therapy was altered in a total of 27 patients and 17 of these patients responded to treatment. Overall survival at 1 year was 41 percent. Forty-eight percent of the patients in whom therapy was changed survived 1 year, and 31 percent of the patients in whom therapy was not changed survived 1 year. No deaths were attributable to the operative procedure. The complication rate was acceptable. Open lung biopsy is an important technique in evaluating and determining therapy in immunocompromised patients who present with diffuse pulmonary infiltrates.     

The critical hypogastric circulation

Eleven patients had ischemic complications secondary to ligation, hypoperfusion, exclusion, or thrombosis of the hypogastric arteries after aortoiliac reconstruction or spontaneous aortoiliac thrombosis. Ligation of one hypogastric artery resulted in persistent ipsilateral buttock claudication in three patients. Bilateral acute hypogastric artery ischemia occurred in eight patients and resulted in paralysis in all eight patients, buttock necrosis in four patients, anal and bladder sphincteric dysfunction in two patients, and colorectal ischemia in three patients. Five of these patients (63 percent) died. The mortality rate was 100 percent when buttock necrosis developed. In most of these patients, the neurologic deficit suggested ischemic injury of the lumbosacral plexus rather than spinal cord ischemia. These complications occurred despite patent bypass grafts to the iliac or femoral vessels. These observations suggest that it is essential to maintain patency of the hypogastric vessels in all aortoiliac reconstructions.     

The endovascular management of visceral artery aneurysms and pseudoaneurysms

OBJECTIVE: Visceral artery aneurysms may be treated by aneurysm exclusion, excision, revascularization, and endovascular techniques. The purpose of this study was to review the outcomes of the management of visceral artery aneurysms with catheter-based techniques. METHODS: Between 1997 and 2005, 90 patients were identified with a diagnosis of visceral artery aneurysm. This was inclusive of aneurysmal disease of the celiac axis, superior mesenteric artery (SMA), inferior mesenteric artery, and their branches. Surveillance without intervention occurred in 23 patients, and 19 patients underwent open aneurysm repair (4 ruptures). The endovascular treatment of 48 consecutive patients (mean age 58, 60% men) with 20 visceral artery aneurysms (VAA) and 28 visceral artery pseudoaneurysms (VAPA) was the basis for this study. Electronic and hardcopy medical records were reviewed for demographic data and clinical variables. Original computed tomography (CT) scans and fluoroscopic imaging were evaluated. RESULTS: The endovascular treatment of visceral artery aneurysms was technically successful in 98% of 48 procedures, consisting of 3 celiac axis repairs, 2 left gastric arteries, 1 SMA, 12 hepatic arteries, 20 splenic arteries, 7 gastroduodenal arteries, 1 middle colic artery, and 2 pancreaticoduodenal arteries. Of these, 29 (60%) were performed for symptomatic disease (5 ruptured aneurysms). Procedures were performed in the endovascular suite under local anesthesia with conscious sedation (94%). The femoral artery was used as the preferential access site (90%). Coil embolization was used for aneurysm exclusion in 96%. N-butyl-2-cyanoacrylate (glue) was used selectively (19%) using a triaxial system with a 3F microcatheter for persistent flow or multiple branches. The 30-day mortality was 8.3% (n = 4). One patient died from recurrent gastrointestinal bleeding after gastroduodenal embolization, and the remaining died of unrelated causes. All perioperative deaths occurred in patients requiring urgent or emergent intervention in the setting of hemodynamic instability. No patients undergoing elective intervention died in the periprocedural period. Postprocedural imaging was performed after 77% of interventions at a mean of 16 months. Complete exclusion of flow within the aneurysm sac occurred in 97% interventions with follow-up imaging, but coil and glue artifact complicated CT evaluation. Postembolization syndrome developed in three patients (6%) after splenic artery embolization. There was no evidence of hepatic insufficiency or bowel ischemia after either hepatic or mesenteric artery aneurysm treatment. Three patients required secondary interventions for persistent flow (n = 1) and recurrent bleeding from previously embolized aneurysms (n = 2). CONCLUSION: Visceral artery aneurysms and pseudoaneurysms can be successfully treated with endovascular means with low periprocedural morbidity; however, the urgent repair of these lesions is still associated with elevated mortality rates. Aneurysm exclusion can be accomplished with coil embolization and the selective use of N-butyl-2-cyanoacrylate. Current catheter-based techniques extend our ability to exclude visceral artery aneurysms, but imaging artifact hampers postoperative CT surveillance.