There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.

Osteoclast differentiation and activation

Background Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

/pdf/sipuleucel-t-immunotherapy-for-castration-resistant-prostate-31dll2jbjc.pdf

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Pamidronate (pamidronic acid) is an aminobisphosphonate that interferes with the mevalonate pathway inducing osteoclast-apoptotic cell death. A 90mg dose of pamidronate administered in a 2- to 24-hour infusion achieves normocalcemia in >90% of unselected patients. Zoledronate (zoledronic acid) is more effective than pamidronate in normalising calcium levels in patients with tumor-induced hypercalcemia, at least in patients without bone metastases; however, zoledronate should be used with caution in patients with renal insufficiency. Pamidronate can be safely administered in hypercalcemic patients with renal insufficiency. Clinically meaningful bone pain relief occurs in about half of patients treated with pamidronate. Pamidronate also achieved significantly better pain control than placebo in patients with breast cancer (bone metastases) or myeloma, in 2-year placebo-controlled trials. Pamidronate 90mg administered over 2 hours every 3–4 weeks for 2 years has been shown to reduce the frequency of skeletal-related events in patients with bone metastases from breast cancer by up to 40% and in patients with multiple myeloma by nearly 50%. In the largest randomized double-blind trial that compared zoledronate 4 or 8mg with pamidronate 90mg every 3–4 weeks in patients with breast cancer or myeloma, the primary efficacy endpoint (proportion of patients experiencing at least one skeletal-related event) was similar in all three treatment groups. The 8mg dose of zoledronate had to be lowered to 4mg during the trial because of renal toxicity. Indeed, concern about the renal toxicity of zoledronate has led authorities to recommend controlling serum creatinine levels before each infusion. When the data were analyzed by a complex multiple-event analysis, the hazard ratio for developing a bone complication was reduced by about 16% in patients treated with zoledronate compared with pamidronate after 2 years of therapy. This superiority of zoledronate was observed in the breast cancer subgroup but not in myeloma patients. However, multiple-event analyses rely on assumptions that are not unanimously accepted. The short duration of zoledronate infusion (15 minutes compared with 1.5–2 hours for pamidronate) is its most evident advantage, but cost savings have not been confirmed so far in limited micro-costing analyses. Positive effects of pamidronate therapy on bone mass have been shown in patients with prostate cancer who are undergoing androgen-blockade therapy; antineoplastic therapy-induced bone loss was prevented. Studies with bisphosphonates are ongoing in breast cancer patients receiving aromatase inhibitors for the prevention of cancer treatment-induced bone loss. Zoledronate appears to be more potent than pamidronate for the prevention of endocrine therapy-induced bone loss.

Bisphosphonates in Oncology

Ibandronate in metastatic bone pain : Ibandronate

The bone isoenzyme of alkaline phosphatase in hypercalcaemic cancer patients

Background: Bone complications, also known as skeletal-related events (SREs), are common in patients with bone metastases secondary to advanced cancers. Objective: To provide a detailed estimate of the health resource utilization (HRU) burden associated with SREs across eight European countries. Methods: Eligible patients from centers in Austria, the Czech Republic, Finland, Greece, Poland, Portugal, Sweden, and Switzerland with bone metastases or lesions secondary to breast cancer, prostate, or lung cancer or multiple myeloma who had experienced at least one SRE (defined as radiation to bone, long-bone pathologic fracture, other bone pathologic fracture, surgery to bone or spinal cord compression) were entered into this study. HRU data were extracted retrospectively from the patients’ charts from 3.5 months before the index SRE until 3 months after the index SRE (defined as an SRE preceded by an SRE-free period of at least 6.5 months). Results: Overall, the mean number of inpatient stays per SRE increased from baseline by approximately 0.5–1.5 stays, with increases in the total duration of inpatient stays of approximately 6–37 days per event. All SREs were associated with substantial increases from baseline in the frequency of procedures and the number of outpatient and day-care visits. Conclusions: SREs are associated with substantial HRU owing to considerable increases in the number and duration of inpatient stays, and in the number of procedures, outpatient visits, and day-care visits. These data collectively provide a valuable summary of the real-world SRE burden on European healthcare systems.

Health resource utilization associated with skeletal-related events: results from a retrospective European study

Sequence-dependent synergistic effects of ibandronate in combination with antiestrogens on growth inhibition of estrogen receptor-positive breast cancer cells

Jean-Jacques Body

Papers

Bisphosphonates in Oncology

Ibandronate in metastatic bone pain : Ibandronate

The bone isoenzyme of alkaline phosphatase in hypercalcaemic cancer patients

Health resource utilization associated with skeletal-related events: results from a retrospective European study

Sequence-dependent synergistic effects of ibandronate in combination with antiestrogens on growth inhibition of estrogen receptor-positive breast cancer cells