When the tumour is not the culprit: avascular necrosis of the hip in a patient with castration-resistant prostate cancer.

Avascular necrosis (avn) of the hip is a well-documented side effect of corticosteroid therapy, but it has also been described as a complication of radiation and chemotherapy. Many prostate cancer patients undergo treatment with all three of those therapeutic modalities, and yet reported cases of avn of the hip in prostate cancer patients are rare. Symptoms that might potentially alert physicians to this complication are nonspecific and may be attributed to cancer progression, in particular to progressive bone metastasis.Here, we report on a 79-year-old man diagnosed with castration-resistant prostate cancer whose diagnosis of avn of the hip was confounded by his underlying malignancy. We discuss risk factors and diagnostic clues in this differential diagnosis of acute hip pain in patients with castration-resistant prostate cancer. Physicians might maintain a high index of suspicion for avn of the hip in prostate cancer patients presenting with new-onset hip pain. Surgical intervention may help to prevent the appearance of avn-associated pain and the negative impact of advanced avn on overall quality of life.

Growth-inhibitory activity and downregulation of the class II tumor-suppressor gene H-rev107 in tumor cell lines and experimental tumors.

The H-rev107 gene is a new class II tumor suppressor, as defined by its reversible downregulation and growth-inhibiting capacity in HRAS transformed cell lines. Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation. Cell populations of H-rev107 transfectants showed an attenuated tumor formation in nude mice. Cells explanted from tumors or maintained in cell culture for an extended period of time no longer exhibited detectable levels of the H-rev107 protein, suggesting strong selection against H-rev107 expression in vitro and in vivo. Expression of the truncated form of H-rev107 lacking the COOH-terminal membrane associated domain of 25 amino acids, had a weaker inhibitory effect on proliferation in vitro and was unable to attenuate tumor growth in nude mice. The H-rev107 mRNA is expressed in most adult rat tissues, and immunohistochemical analysis showed expression of the protein in differentiated epithelial cells of stomach, of colon and small intestine, in kidney, bladder, esophagus, and in tracheal and bronchial epithelium. H-rev107 gene transcription is downregulated in rat cell lines derived from liver, kidney, and pancreatic tumors and also in experimental mammary tumors expressing a RAS transgene. In colon carcinoma cell lines only minute amounts of protein were detectable. Thus, downregulation of H-rev107 expression may occur at the level of mRNA or protein.

New multidisciplinary prostate bone metastases clinic: first of its kind in Canada.

Prostate cancer is the most common non-skin malignancy in men. Almost all men who die from prostate cancer have hormone-refractory prostate cancer with metastasis to bone. Emerging supportive treatments-including chemotherapy, bisphosphonates, and surgery-require integration that is optimized in a multidisciplinary setting. A multidisciplinary clinic for bone metastases has been in place at Toronto-Sunnybrook Regional Cancer Centre since 1999, combining orthopedic surgery, radiation oncology, interventional radiology, and palliative medicine for all patients with bone metastases. The addition of a prostate-focused multidisciplinary clinic integrates these services for patients with advanced prostate cancer.

Bone Health and Bone-targeted Therapies for Prostate Cancer: a Programme in Evidence-based Care - Cancer Care Ontario Clinical Practice Guideline.

AIMS: To make recommendations with respect to bone health and bone-targeted therapies in men with prostate cancer. MATERIALS AND METHODS: A systematic review was carried out by searching MEDLINE, EMBASE and the Cochrane Library from inception to January 2016. Systematic reviews and randomised-controlled trials were considered for inclusion if they involved therapies directed at improving bone health or outcomes such as skeletal-related events, pain and quality of life in patients with prostate cancer either with or without metastases to bone. Therapies included medications, supplements or lifestyle modifications alone or in combination and were compared with placebo, no treatment or other agents. Disease-targeted agents such as androgen receptor-targeted and chemotherapeutic agents were excluded. Recommendations were reviewed by internal and external review groups. RESULTS: In men with prostate cancer receiving androgen deprivation therapy, baseline bone mineral density testing is encouraged. Denosumab should be considered for reducing the risk of fracture in men on androgen deprivation therapy with an increased fracture risk. Bisphosphonates were effective in improving bone mineral density, but the effect on fracture was inconclusive. No medication is recommended to prevent the development of first bone metastasis. Denosumab and zoledronic acid are recommended for preventing or delaying skeletal-related events in men with metastatic castration-resistant prostate cancer. Radium-223 is recommended for reducing symptomatic skeletal events and prolonging survival in men with symptomatic metastatic castration-resistant prostate cancer. CONCLUSIONS: The recommendations represent a current standard of care that is feasible to implement, with outcomes valued by clinicians and patients.

Interleukin-1 and experimental gastric ulcer healing in the rat.

The involvement of inflammation in peptic ulcer development and healing attracts growing interest. Since lymphokines, in particular interleukin-1 (IL-1), as ubiquitous mediators of inflammation are currently intensively studied in the gastrointestinal tract, we assessed the effect of this cytokine as well as that of a specific IL-1 release inhibitor (IX 207-887 (IX)) on development and healing of experimental gastric ulcers. After a single dose of IL-1, 4 micrograms/kg, i. p., basal acid secretion was almost completely inhibited for 4 hours in conscious chronic gastric fistula rats. In a first study, following induction of a 7 mm wide cryo-ulcer in the gastric corpus, three groups of 24 rats were treated either with a non-acid inhibitory dose of IL-1 (0.4 microgram/kg) or with an antisecretory regimen (4 micrograms/kg) b.i.d. or saline control. Ulcer size did not differ from that of control animals, neither after 24h nor 7 days. Similarly, IX applied daily (20 mg/kg/s.c) from 5 days before ulcer induction and continued thereafter for 15 days had no effect on ulcer development or healing. Despite its anti-inflammatory property IX produced no macroscopically visible damage on the gastric or intestinal mucosa and may therefore offer a higher safety profile within the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs.

Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation.

QUESTIONS UNDER STUDY: starting treatment of reactive macrophage activation syndromes as early as possible (rMAS, haemophagocytic lymphohistiocytosis), e.g., with intravenous immunoglobulins (IVIG), seems to be essential for optimal outcome. However, there is no diagnostic gold standard which reliably indicates need for early treatment. We used a simple screening strategy consisting of serum ferritin measurements and/or morphological assessment of haemophagocytosis and compared the studied patient population with published series. METHODS: Retrospective analysis of clinical and laboratory data of 57 patients experiencing 60 episodes of rMAS. RESULTS: Screening by serum ferritin measurements and/or morphological assessment of haemophagocytosis of patients presenting with a systemic inflammatory response syndrome (SIRS) indicates that rMAS might be considerably more frequent than stated in the literature. Serum ferritin exceeded >10,000 microg/L in 91% rMAS episodes. Although the patient population studied was otherwise similar in most aspects to the published rMAS series, the fact that 40% of patients fulfilled the criteria for Still's disease (SD) as the disorder underlying rMAS is remarkable and questions the distinct nature of the two diseases. IVIG responders and non-responders did not differ regarding their initial characteristics with exception to the timepoint of IVIG administration, confirming the importance of early treatment initiation. Malignancy-associated rMAS however, has a poor prognosis and seems to be refractory to manipulation with IVIG in most instances, even when responding initially. CONCLUSIONS: rMAS has to be considered in patients with a SIRS- or SD-like clinical presentation. Hyperferritinaemia >or=10,000 microg/l seems to be a good marker for defining patients with or at risk for developing rMAS and should be completed with a morphological assessment of haemophagocytosis. The perception of acute SD and rMAS as two distinct entities has to be questioned at least in a subgroup of patients.

Low-dose metronomic chemotherapy: a systematic literature analysis.

Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is an emerging alternative to conventional chemotherapy. While promising tumour control rates and excellent safety profiles have been observed, there are no definitive phase III trial results. Furthermore, the selection of patients, drug dosages and dosing intervals is empirical. To systematically review the current state of knowledge regarding LDM chemotherapy, we searched the MEDLINE, EMBASE, CENTRAL and PubMed databases for fully published LDM chemotherapy trials. We calculated the relative dose-intensity (RDI, mg/m(2)/week) of each LDM regimen as compared to conventional maximum tolerated dose (MTD) dosages and the 'dosing-density' (DD, % of days with chemotherapy administration per cycle). Meta-regression was performed to examine factors associated with disease control rate (DCR; complete response (CR)+partial response (PR)+stable disease (SD)). Eighty studies involving mainly pretreated patients with advanced/metastatic breast (26.25%) and prostate (11.25%) cancers were retrieved. The most commonly used drug was cyclophosphamide (43%). LDM chemotherapy was frequently combined with other therapies (64.5%). Response rate (RR) and progression-free survival (PFS) were the most frequent primary end-points (24% and 19%). Mean RR was 26.03% (95% confidence interval (CI): 21.4-30.7), median PFS was 4.6months (interquartile range (IQR): 2.9-7.0) and mean DCR was 56.3% (95% CI: 50.9-61.6). RDI, DD and metronomic drug used were not associated with DCR. Grade 3/4 adverse events were rare (anaemia 7.78%, fatigue 13.4%). Thus, LDM therapy appears to be clinically beneficial and safe in a broad range of tumors. However, meta-regression analysis did not identify predictive factors of response.

Incidence of skeletal-related events over time from solid tumour bone metastases reported in randomised trials using bone-modifying agents.

AIMS: Skeletal-related events (SREs) in patients with bone metastases decrease a patient's quality of life and functional status. Although bone-modifying agents have been found to reduce the time to first on-trial SRE and decrease the total incidence of SREs in randomised clinical trials, standard practice in the management of bone metastases has changed concurrently. The purpose of this study was to investigate if advances in bone-targeted therapies have decreased the incidence of individual types of SREs and to delineate the trend of SREs. MATERIALS AND METHODS: A literature review was conducted in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to identify phase III, randomised bisphosphonate and other bone-targeted therapy trials from 1980 to September 2011. For all studies, a mean year of enrolment ([start of enrolment + end of enrolment]/2) was calculated. The incidences of SREs were tabulated and expressed as percentages of on-trial patients. Generalised linear mixed models were used to search for the trends of SREs over time for all placebo and intervention arms. Regression coefficients were interpreted as the odds ratio, which was calculated using the exponential of the slope. Ninety-five per cent confidence intervals were also calculated. RESULTS: In total, 20 eligible studies were identified that reported SRE data from phase III trials, of which 11 were suitable for the quantitative analysis. Most of the articles included patients with breast cancer and the remaining involved patients with prostate, renal cell, bladder and lung cancer or other solid tumours. Enrolment periods for all included data ranged from 1990 to 2009. Statistically significant overall downward trends in pathological fractures and the need for surgery were seen over time. Also significant differences between intervention and placebo were seen with all SREs. CONCLUSION: The decrease in SREs over time may not only be a result of the development of new generation bone-targeted agents, but also due to better systemic management and awareness of events associated with bone metastases.

Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation.

BACKGROUND: Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potentially novel approach to the control of advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has, as an advantage, the property of significantly reducing undesirable toxic side-effects. The aim of the present study was to evaluate the cost effectiveness of cyclophosphamide-methotrexate 'metronomic' chemotherapy in the palliative treatment of pretreated metastatic breast cancer. METHODS: Low-dose cyclophosphamide-methotrexate 'metronomic' chemotherapy was compared with outcome and resource utilisation data of published phase II trials regarding metastatic breast cancer, performed in western countries, mostly in Europe. All direct costs associated with metastatic breast cancer treatment were included and adjusted to year 2003 values. Sensitivity analyses were performed and variations to the values of key parameters were assessed. RESULTS: Low-dose cyclophosphamide-methotrexate 'metronomic' therapy was assessed to be a cost-effective/cost-saving therapy for palliative treatment for metastatic breast cancer when compared with novel chemotherapy strategies (phase II trials). Compared with the 11 phase II mono- and combination chemotherapies, metronomic treatment showed marked cost savings in each case and improved cost effectiveness. Sensitivity analyses showed the results were robust to variations to the values of key parameters with very few exceptions. CONCLUSIONS: Metronomic cyclophosphamide-methotrexate is significantly cost effective. If validated by prospective randomized trials, the treatment concept could reduce healthcare costs, especially those associated with the combined use of new, highly expensive, molecularly targeted therapies.

Elevation of soluble Fas and soluble Fas ligand in reactive macrophage activation syndromes.

Derailed T-cell activation can give rise to life-threatening macrophage activation, the final common pathway of the different forms of reactive macrophage activation syndromes (rMAS). Besides inappropriate activation of the immune system, impaired termination of immune responses might be another mechanism leading to rMAS. The Fas (CD95)/Fas ligand (CD95 ligand) system functions in turning off immune responses by executing activation-induced cell death (AICD). Soluble Fas (sFas) and Fas ligand (sFasL) can interfere with their corresponding membrane-bound counterparts, qualifying them as potential parameters of impaired immune termination. Hence, sFas and sFasL were analyzed in sera of rMAS patients. We show that soluble Fas/CD95 (sFas) is elevated >2 SD over the mean of controls in all 8 rMAS episodes studied (mean 12.08 +/- 6.12 ng/mL, range 3.7-20.2; controls 2.46 +/- 0.49, range 1.5-2.9). sFasL was detected during five rMAS episodes (0.70 +/- 0.49 ng/mL, range 0.16-1.28; controls all below the limit of detection of 0.1). In addition, both parameters decrease during convalescence, reflecting clinical evolution. In conclusion, sFas seems to be consistently elevated during acute rMAS. sFasL is detected only in a subgroup of our adult rMAS patients extending the recent finding of sFasL elevation in a majority of children with macrophage activation syndromes (Hasegawa et al. Blood 1998;91(8):2793-2799). By interfering with AICD, sFas and sFasL might contribute to the pathogenesis of at least a subset of rMAS.

Inflammation, capillary leakage and healing of experimental gastric ulcers in the rat.

Little information is available on the role of inflammation and small vessel alteration in the development and healing of peptic ulcers. We studied the spontaneous healing of experimental ulcers in the rat stomach with a novel radio-isotope technique for the monitoring of capillary damage in ulcer-related inflammation. Following ulcer induction, healing was assessed on days 1, 7 and 15 by macroscopical and histological determinations of ulcer size and lesion area, parietal cell counts in the ulcer margin and nuclear imaging of the lesion area using Nanocoll, a 99mTc-labelled colloid. The ulcers were re-epithelized after 15 days. However, Nonocoll activity was still significantly enhanced in the ulcer area, and regression of the microscopically visible lesion area, which, from day 1 on, occupied a zone considerably larger than the ulcer itself, was delayed and still incomplete at the end of the study. Compared to the intact mucosa, parietal cells were reduced in the scar tissue up to 15 days (24-40%). However, despite macroscopical and histological re-epithelization, small vessel leakage and substantial tissue alteration persisted in the ulcer scar.

Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes.

The underlying mechanisms of reactive macrophage activation syndromes (rMAS) are not understood in detail, and there is no specific treatment. This observational study was prompted by intravenous immunoglobulin (IVIG), dramatically halting two distinct rMAS episodes in the same patient. We evaluated the potential benefits of IVIG administration in treating fulminant rMAS and the usefulness of monitoring serum ferritin levels as an indication for emergency treatment with IVIG. Ten females and 10 males experiencing 22 episodes of rMAS were recruited on the basis of serum ferritin levels >or=10,000 microg/l and/or direct evidence of haemophagocytosis in 11 intensive care units in secondary and tertiary care hospitals in Switzerland between October 1993 and May 2000. In individual patients, serially measured ferritin was closely related to disease activity. Abrupt increases of up to >100,000 microg/l could be observed within hours. Rapid and profound beneficial effects of emergency IVIG treatment were seen in 12 episodes of rMAS accompanied by a prompt decrease of serum ferritin. IVIG produced partial or delayed improvements in 5 patients. No apparent effects were seen in 5 patients. IVIG was only successful if started early during the ferritin run-up to peak values. In conclusion, IVIG is effective in at least a subgroup of adult rMAS when started at the beginning of the macrophage activation process. The monitoring of serum ferritin levels might be helpful in detecting macrophage activation in order to commence IVIG treatment early enough.