A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an Eastern Cooperative Oncology Group study (PB687)

Purpose: Didemnin B is a novel marine natural product cyclic depsipeptide containing unusual amino acid moieties. This agent demonstrates promising preclinical antitumor activity, including activity against B16 melanoma and against melanoma isolates in the human tumor stem cell assay.Methods: We conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced malignant melanoma were eligible. All patients were previously untreated with chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and 5.6 mg/m2 in cycles 2 and 3, respectively.Results: Nineteen patients were entered and treated with a median of one cycle per patient. Eight of these patients went off study for toxicity including 7 with anaphylactoid reactions in the first or second cycle. One patient went off study after 3 cycles with severe myopathy, a newly described toxicity. Two were not evaluable for response and five were considered stable, including one patient with a transient PR of soft tissue disease in the first cycle. Another patient had stable disease for twelve cycles before progressing and one went off study electively after 3 cycles, for a total of 7 patients with stable disease. One patient with a measurable partial remission (PR) and went off study after three cycles due to severe myopathy, a then newly-described toxicity. No hematologic toxicity was seen. Nausea and vomiting were controlled with anti-emetics.Conclusions: This study was indeterminate with respect to the activity of Didemnin B in melanoma. Signs of activity were seen, particularly in soft tissue masses, though a large number of patients could not be evaluated fully for activity due to the occurrence of anaphylactoid reactions. This study does not preclude a clinically important level of activity for Didemnin B.     

Excisional Plication of the Ileocecal Valve: A Useful Adjunct for the Construction of Continent Urinary Diversions

Purpose

A variety of techniques exist to reinforce the ileocecal valve for use as a nonrefluxing mechanism in continent urinary diversion. We report short-term and long-term followup for a new technique of excisional plication of the valve.

Materials and Methods

Since 1988 we performed 16 procedures in 15 patients. The technique was used for repair of an incompetent ileocecal valve to restore continence in 2 patients in whom continent cutaneous diversion failed, and to correct a massively refluxing ileocecal valve following previous augmentation with an ileocecal segment in 1. The remaining patients underwent the procedure in conjunction with continent cutaneous ileocecal diversion with a modified Indiana pouch.

Results

To date no patient undergoing continent cutaneous diversion required reoperation to correct incontinence. Two patients wear a protective pad during the day, while the remainder have been completely dry during followup.

Conclusions

Excisional plication is a versatile and simple procedure that may be used to assist construction and repair of ileocecal valves in conjunction with continent urinary diversion.     

Soft tissue sarcomas of adults: state of the translational science.

Sarcomas--like leukemias, which are also mesodermal malignancies--carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality.     

Treatment of tumors involving the optic nerves and chiasm

An approach toward treatment of tumors involving the optic apparatus is presented. When tumors cause mass effect, microsurgical excision or debulking is generally recommended. Radiosurgery has been controversial yet advances in imaging and high speed computer planning allow treatment of lesions involving the optic apparatus with low morbidity. Microsurgical and radiosurgical approaches to tumors involving the globe, orbit, suprasellar region and third ventricle are discussed. Gamma Knife radiosurgery for choroidal melanomas spares orbital excenteration. We have used a marginal dose of 20–25 Gy for choroidal melanomas and generally limit the optic nerves and chiasm to less than 10 Gy in other cases. The effective dose for cavernous hemangiomas remains unclear, however we have had success with marginal doses in the range of 16–20Gy. Lower doses may prove successful yet better spare vision in cases where vision is useful. Our combined microsurgical and radiosurgical approach to tumors involving the apparatus has had an excellent rate of sparing vision, a low overall morbidity and excellent success.     

Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen

Assembly of anthrax toxin complexes at the mammalian cell surface involves competitive binding of the edema factor (EF) and lethal factor (LF) to heptameric oligomers and lower order intermediates of PA(63), the activated carboxyl-terminal 63-kDa fragment of protective antigen (PA). We used sequence differences between PA(63) and homologous PA-like proteins to delineate a region within domain 1' of PA that may represent the binding site for these ligands. Substitution of alanine for any of seven residues in or near this region (R178, K197, R200, P205, I207, I210, and K214) strongly inhibited ligand binding. Selected mutations from this set were introduced into two oligomerization-deficient PA mutants, and the mutants were used in various combinations to map the single ligand site within dimeric PA(63). The site was found to span the interface between two adjacent subunits, explaining the dependence of ligand binding on PA oligomerization. The locations of residues comprising the site suggest that a single ligand molecule sterically occludes two adjacent sites, consistent with the finding that the PA(63) heptamer binds a maximum of three ligand molecules. These results elucidate the process by which the components of anthrax toxin, and perhaps other binary bacterial toxins, assemble into toxic complexes.     

The Early Effects of Medicare's Mandatory Hospital Pay‐for‐Performance Program

Objective

To evaluate the impact of hospital value-based purchasing (HVBP) on clinical quality and patient experience during its initial implementation period (July 2011–March 2012).

Data Sources

Hospital-level clinical quality and patient experience data from Hospital Compare from up to 5 years before and three quarters after HVBP was initiated.

Study Design

Acute care hospitals were exposed to HVBP by mandate while critical access hospitals and hospitals located in Maryland were not exposed. We performed a difference-in-differences analysis, comparing performance on 12 incentivized clinical process and 8 incentivized patient experience measures between hospitals exposed to the program and a matched comparison group of nonexposed hospitals. We also evaluated whether hospitals that were ultimately exposed to HVBP may have anticipated the program by improving quality in advance of its introduction.

Principal Findings

Difference-in-differences estimates indicated that hospitals that were exposed to HVBP did not show greater improvement for either the clinical process or patient experience measures during the program''s first implementation period. Estimates from our preferred specification showed that HVBP was associated with a 0.51 percentage point reduction in composite quality for the clinical process measures (p > .10, 95 percent CI: −1.37, 0.34) and a 0.30 percentage point reduction in composite quality for the patient experience measures (p > .10, 95 percent CI: −0.79, 0.19). We found some evidence that hospitals improved performance on clinical process measures prior to the start of HVBP, but no evidence of this phenomenon for the patient experience measures.

Conclusions

The timing of the financial incentives in HVBP was not associated with improved quality of care. It is unclear whether improvement for the clinical process measures prior to the start of HVBP was driven by the expectation of the program or was the result of other factors.     

Headache with Aura: A case report of ocular melanoma

Background

Headaches and visual complaints are common conditions encountered in the emergency department. While a patient's age, risk factors, and comorbidities often aid in risk stratification and guide emergency department evaluation, atypical presentations of serious disease may still occur in young otherwise healthy patients

Self-assembly properties of a model RING domain.

RING domains act in a variety of essential cellular processes but have no general function ascribed to them. Here, we observe that purified arenaviral protein Z, constituted almost entirely by its RING domain, self-assembles in vitro into spherical structures that resemble functional bodies formed by Z in infected cells. By using a variety of biophysical methods we provide a thermodynamic and kinetic framework for the RING-dependent self-assembly of Z. Assembly appears coupled to substantial conformational reorganization and changes in zinc coordination of site II of the RING. Thus, the rate-limiting nature of conformational reorganization observed in the folding of monomeric proteins can also apply to the assembly of macromolecular scaffolds. These studies describe a unique mechanism of nonfibrillar homogeneous self-assembly and suggest a general function of RINGs in the formation of macromolecular scaffolds that are positioned to integrate biochemical processes in cells.     

Cardiometabolic Impact of Non-Statin Lipid Lowering Therapies

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease.