A Randomized,Double-Blind,Dose-Finding,Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

Background

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.

Objective

To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.

Design, setting, and participants

In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels.

Outcome measurements and statistical analysis

Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.

Results and limitations

The study met its primary end point with a statistically significant dose–response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.

Conclusions

Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.

Trial registration

ClinicalTrials.gov: NCT00337155.     

ASO Author Reflections: Axillary Management in Mastectomy Patients with Limited Nodal Burden

Annals of Surgical Oncology -     

Hormonal effects on cell proliferation in a human erythroleukemia cell line (K562)

We have investigated the hormonal responsiveness of K562 cells using a serum-substituted in vitro clonogenic assay. Dexamethasone inhibited colony formation by the K562 cells, and the inhibitory effect could be reversed by progesterone (10(-6) M). Fluoxymesterone caused a prominent enhancement of K562 colony growth, whereas estriol had no effect. Stimulation by triiodothyronine was maximal at 10(-7) M, and the thyroid effect could be abrogated by the beta 2-adrenergic antagonist butoxamine in equimolar concentrations. Using standard tissue culture conditions, the beta-adrenergic agent isoproterenol, but not the alpha catecholamine phenylephrine, enhanced the proliferation of K562 cells. When K562 cells were grown under hormone-depleted conditions, they developed responsiveness to phenylephrine and were no longer stimulated by isoproterenol. DbcAMP and prostaglandins of the E series also caused K562 colony enhancement. Prostaglandin F2 alpha had no effect on cell proliferation. Insulin was an effective stimulant of colony formation of K562 cells, as were human growth hormone and ovine prolacin. Bovine growth hormone had no effect. Our results are consistent with the identificaiton of K562 as an erythroid line, and they indicate that K562 cells respond to endocrine hormones in a manner analogous to normal erythroid progenitors.     

Efficacy of red and infrared lasers in treatment of temporomandibular disorders — a double-blind,randomized, parallel clinical trial

Aim:

Low-level laser therapy has still not been well established, and it is important to define a standardized protocol for the treatment of temporomandibular disorders (TMDs) using low level laser. There is no consensus on controlled clinical trials concerning the best option for laser therapy with regard to wavelength. The aim of this study was to evaluate the efficacy of red and infrared laser therapy in patients with TMD, using a randomized parallel-group double-blind trial.

Methodology:

Each hemiface of 19 subjects was randomized to receive intervention, in a total of 116 sensitive points. Pain was measured at baseline and time intervals of 24 hours, 30 days, 90 days, and 180 days after treatment. Irradiation of 4 J/cm² in the temporomandibular joints and 8 J/cm² in the muscles was used in three sessions.

Results:

Both treatments had statistically significant results (P<0·001); there was statistical difference between them at 180 days in favor of the infrared laser (P?=?0·039). There was improvement in 24 hours, which extended up to 180 days in both groups.

Conclusion:

Both lasers are effective in the treatment and remission of TMD symptoms.     

Excitation of upper cervical inspiratory neurons by inspiratory neurons of the nucleus retroambigualis in the cat

The experiments reported here examined inputs from inspiratory neurons of the nucleus retroambigualis to upper cervical inspiratory neurons. Antidromic mapping in contralateral C1 demonstrated the existence of axon collaterals for 9 of 19 nucleus retroambigualis axons tested (47%). Forty nucleus retroambigualis neurons were tested with antidromic mapping for a projection to the ipsilateral C1 segment; 9/40 (22%) had an ipsilateral axon (8 of these also projected contralaterally), and 2/40 (5%) had an axon collateral in ipsilateral C1. Cross-correlation histograms suggested monosynaptic excitation of an upper cervical inspiratory neuron by a contralateral nucleus retroambigualis neuron in 4/69 cases (6%) and common input to the pair in 2/69 cases (3%). Six of the 69 cross-correlograms were computed during antidromic activation of the nucleus retroambigualis neuron, and one of these six demonstrated direct excitation of the upper cervical inspiratory neuron by the retroambigualis neuron. We concluded that at least some upper cervical inspiratory neurons receive monosynaptic excitation from the contralateral, and possibly the ipsilateral, nucleus retroambigualis inspiratory neurons. These results, together with those published elsewhere for inputs from inspiratory neurons in the contralateral ventrolateral nucleus tractus solitarius, suggest that the rhythmic, inspiratory firing pattern of the upper cervical inspiratory neurons is due to excitatory inputs from these two inspiratory bulbospinal neuron populations.     

Nonsentinel node metastasis in breast cancer patients: assessment of an existing and a new predictive nomogram

BACKGROUND: The accurate prediction of nonsentinel node (NSN) metastasis in breast cancer patients remains uncertain. METHODS: The medical records of 574 breast cancer patients from 2 different institutions (Mayo Clinic and University of Michigan) with sentinel lymph node biopsy examination and completion axillary lymph node dissection were reviewed for multiple clinicopathologic variables. The Memorial Sloan Kettering Cancer Center nomogram performance for prediction of NSN metastases was assessed. A new model was developed with clinically relevant variables and possible advantages. RESULTS: The Memorial Sloan Kettering Cancer Center nomogram predicted the likelihood of NSN metastasis with an area under the receiver operating characteristic curve of .72 and .86. For predicted probability cut-off points of 5% and 10%, the false-negative rates were 0% and 14% (Mayo), and 17% and 11% (Michigan). A new model was developed with similar area under the curve but lower false-negative rates for low-probability subgroups. CONCLUSIONS: Predictive models for NSN tumor burden are imperfect.     

Bovine lactoferricin induces caspase-independent apoptosis in human B-lymphoma cells and extends the survival of immune-deficient mice bearing B-lymphoma xenografts

Although current treatments based on the use of B-cell-specific anti-CD20 monoclonal antibodies and aggressive combinatorial chemotherapy have improved the survival of patients suffering from B-cell non-Hodgkin's lymphoma (NHL), some individuals fail to respond to treatment and relapses remain common. New and more effective treatments for B-cell NHL are therefore required. Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that is cytotoxic for several human tumor cell lines but does not harm healthy cells. Here we show that in vitro treatment with LfcinB caused Raji and Ramos human B-lymphoma cells to die by apoptosis, as indicated by DNA fragmentation, chromatin condensation, and nuclear disintegration. LfcinB killed B-lymphoma cells more efficiently at low serum concentrations and was inhibited in the presence of exogenous bovine serum albumin, suggesting partial neutralization of cationic LfcinB by anionic serum components. LfcinB-induced apoptosis in B-lymphoma cells was caspase-independent since caspase-3 activation was not detected by Western blotting and the general caspase inhibitor z-VAD-fmk did not prevent LfcinB-induced DNA fragmentation. Importantly, immune-deficient SCID/beige mice that were inoculated intravenously with Ramos B-lymphoma cells in order to model B-cell NHL exhibited extended survival following systemic administration of LfcinB, indicating that LfcinB warrants further investigation as a novel therapeutic agent for the possible treatment of B-cell NHL.