Antitumour effects of bisphosphonates: first evidence and possible mechanisms

Bisphosphonates have been used successfully for many years in the treatment of hypercalcaemia and to reduce skeletal complications of metastases. In the first years of bisphosphonate use the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumour effect may also play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumour cells. Whether this effect (at low doses) also plays a role in vivo remains unclear and requires further investigation. Improvements in the survival time of certain subpopulations have been found in many phase III studies with bisphosphonates to date, both in the setting of metastatic breast cancer and in multiple myeloma. However, because survival time in subgroups of patients was neither a primary nor a secondary objective in these studies, these advantages could only be seen as important pointers for future studies. Some preclinical studies have shown that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of non-osseous metastases. The results of 3 randomised studies in patients with primary breast cancer who received clodronate 1600 mg/day orally have now been evaluated and presented. All 3 studies arrived at different results. In the Heidelberg study there was a reduction in both osseous and non-osseous metastases, whereas in a much larger study performed in Great Britain, Canada and Scandinavia there was a reduction only in the incidence of skeletal metastases. A third study from Finland found no effect on bone metastases, but an increase in the number of visceral metastases and a deterioration in overall survival. Because the dosage was identical in all 3 studies, the differing results can only be either random or methodological (for example inclusion criteria or sample size). Overall, the results are very promising, but there is a need for further studies.     

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma

To test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P< 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P< 0.001), and serum beta2-microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P< 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P< 0.001, log rank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM.     

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases

BackgroundOsteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies.Patients and methodsPatients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts.ResultsOf 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab).ConclusionsIn this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.     

Severe SARS-CoV-2 Infection in a Cat with Hypertrophic Cardiomyopathy

Coronavirus disease 19 (COVID-19), has claimed millions of human lives worldwide since the emergence of the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China in December 2019. Notably, most severe and fatal SARS-CoV-2 infections in humans have been associated with underlying clinical conditions, including diabetes, hypertension and heart diseases. Here, we describe a case of severe SARS-CoV-2 infection in a domestic cat (Felis catus) that presented with hypertrophic cardiomyopathy (HCM), a chronic heart condition that has been described as a comorbidity of COVID-19 in humans and that is prevalent in domestic cats. The lung and heart of the affected cat presented clear evidence of SARS-CoV-2 replication, with histological lesions similar to those observed in humans with COVID-19 with high infectious viral loads being recovered from these organs. The study highlights the potential impact of comorbidities on the outcome of SARS-CoV-2 infection in animals and provides important information that may contribute to the development of a feline model with the potential to recapitulate the clinical outcomes of severe COVID-19 in humans.     

有症状门诊病人深静脉血栓形成的诊断,临床评价和D-二聚体分析可能减少对影像学诊断的需要

深静脉血栓形成(DVT)的年发病率为48-182／10万,一般估计为1／1000。DVT病死率为1%-5%,发病率和病死率与年龄密切相关。慢性疼痛、肿胀、偶尔腿部皮肤溃疡等血栓后综合征见于1／3发生过DVT的患者。血栓后综合征可出现较早,也可迟至10年才出现,总的发病率为2年23%,5年28%。患者如使用弹力加压袜至少2年以上,腿部病变的发生率可     

Anabolic and andogenic activity of 19-norandrostenedione after oral and subcutaneous administration—Analysis of side effects and metabolism

One of the most frequently misused steroid precursors (prohormones) is 19-norandrostenedione (estr-4-ene-3,17-dione, NOR). Recently we have show that NOR stimulates skeletal muscle growth after s.c. administration in a highly selective manner but exhibits only weak androgenic activity in rats. Because most abusers take NOR orally, the aim of this study was to compare the anabolic and androgenic potency of NOR between s.c. and oral application. Orchiectomised rats were treated with NOR either s.c. (1 mg/kg BW/day) or orally (0.1, 1 and 10 mg/kg BW/day). The tissue weights of the levator ani, the seminal vesicle and the prostate were analysed to determine the anabolic and androgenic activity. Heart and liver wet weights were examined to identify side effects. Serum concentrations of NOR and its metabolite nandrolone (NT) were determined.     

A relapse of paratyphoid fever after treatment with ciprofloxacin in a child with congenital biliary atresia

This report describes a relapse of Salmonella paratyphi B infection in a child with biliary atresia, following 2 weeks of treatment with ciprofloxacin. The recrudescence was complicated by the development of osteomyelitis and was treated with chloramphenicol, trimethoprim, ceftriaxone and ampicillin in succession.     

雌二醇对动情间期切除卵巢母羊黄体生成素分泌脉冲的抑制作用

动情间期母羊切除卵巢并皮下植入持续释放的E_2后,平均LH基础分泌水平和LH脉冲幅高比对照组显著减低,LH脉冲频率无明显改变。LH的平均基础分泌水平和脉?中幅高显著相关。表明植入E_2对垂体LH分泌的抑制作用主要是抑制LH对GnRH的反应,作用部位在垂体,不在下丘脑。LH基础分泌水平的下降,亦可能是E_2的抑制作用所致。     

The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma

Melanocyte stimulating hormone (MSH) plays an important role in determining the cutaneous response to ultraviolet radiation and may also influence melanoma progression. We have previously shown that variants of the melanocortin receptor present on melanocytes, MC1R, are associated with sun sensitivity and red hair in a UK population and therefore now consider the gene as a candidate for melanoma susceptibility. We have compared the frequency of known MC1R variants in the second and seventh transmembrane domains in 43 melanoma cases and 44 controls. MC1R variants were more common in cases than controls (chi 2 = 6.75, 1 d.f.; P = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91 (95% c.l.: 1.48-10.35), and a population risk attributable to carriers of 34.6% (95% c.i. 10.7-52.1%). The Asp84Glu variant was only present in melanoma cases and appears to be of particular significance. The contribution of variant MC1R alleles was largely independent of skin type. Variants of the MC1R gene are likely to be causally associated with the development of melanoma.      

Ongoing outbreak of tuberculosis in a low-incidence community: a molecular-epidemiological evaluation.

SETTING: Federal State of Hamburg, Germany, 1997-2002. OBJECTIVE: To identify the pathways of tuberculosis (TB) transmission and to evaluate possible risk factors for recent transmission in Hamburg. DESIGN: A prospective, molecular-epidemiological study was performed. Conventional contact tracing and an indepth epidemiological analysis were conducted. RESULTS: A predominant cluster of Mycobacterium tuberculosis strains was identified by IS6110 DNA fingerprinting of 828 TB cases notified during the study period. The cluster expanded from seven cases in 1997 to 38 in June 2002. A single source case could not be identified. Transmission links were confirmed in 20 cases. Twenty-five patients were regular customers at a bar close to the red-light district. Seven patients, including one regular customer in the bar, were staying at a nearby hostel for homeless men, and four were living in a far-away hostel for alcoholic men. Of the 421 close contact persons investigated, 169 (40.1%) had positive tuberculin skin tests, and eight became ill (1.9%). Twelve of 20 cases with confirmed recent transmission could only be determined a posteriori by fingerprinting. CONCLUSIONS: An ongoing outbreak at a local bar indicates chronic alcoholism as a high-risk factor for the dissemination of TB in a large metropolitan area. The fact that conventional contact tracing is insufficient for the detection of chains of transmission in this milieu indicates the need for an improved, location-based approach, e.g., the implementation of an outreach strategy.