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This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

The Oncology Nursing Society (ONS) is a professional association that represents 100,000 nurses and is the professional home to more than 35,000 members. ONS is committed to promoting excellence in oncology nursing and the transformation of cancer care. Since 1975, ONS has provided a professional community for oncology nurses, developed evidence-based education programs and treatment information, and advocated for patient care, all in an effort to improve the quality of life and outcomes for patients with cancer and their families.

Evidence-based guidelines for the management of SVCS are not available. Most of the options regarding the therapeutic approach of SVC obstruction are obtained from case series and randomized trials. Management of SVCS should be multidisciplinary with cooperation among different medical specialties such as radiology and interventional radiology, pulmonology, surgery, vascular surgery, and oncology. The therapeutic approach of SVCS has two pillars: to alleviate symptoms related to SVC obstruction and to treat the underlying disease. Treatment approaches for SVC obstruction include radiation therapy, chemotherapy, open surgery, and endovenous recanalization. During the past decades, SVCS was considered a medical emergency. Nowadays, it is well known that SVC obstruction rarely manifests as a life-threatening entity due to laryngeal or cerebral edema. In these cases, initial stabilization of airway, breathing, and circulation (ABC) and urgent recanalization are sine qua non [5,25,26].

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

ZOL is licenced to treat skeletal complications in metastatic prostate cancer (reviewed by Morgans & Smith (2012) and El-Amm et al. (2013)). However, this drug is not routinely administered until bone metastases are confirmed or when the first skeletal-related event (SRE) occurs. A number of in vivo studies have supported that ZOL inhibits prostate cancer-induced bone disease, but the majority of these have focussed on treatment effects of advanced disease with extensive bone destruction, and hence shown limited effects on disease progression (Corey et al. 2003, Thudi et al. 2008, Hung et al. 2011). A recent clinical trial assessing the effects of starting ZOL treatment within 6 months of androgen-deprivation therapy (ADT) in patients with castration-sensitive, metastatic, prostate cancer found no delay in time to first SRE in the ZOL group (Smith et al. 2014). These data demonstrate that ZOL does not prevent the progression of established bone metastases. We have, therefore, investigated the potential benefits of giving ZOL before castration, in order to inhibit resorption-mediated growth of disseminated tumour cells and thus prevent prostate cancer relapse in bone. This is the first in vivo study to demonstrate that castration results in changes to the bone microenvironment, triggering growth of disseminated tumour cells and development of bone metastases.

Although PC3 cells are commonly used as a model for prostate cancer bone metastasis (Thudi et al. 2008, Das et al. 2010, Kim et al. 2013, Lee et al. 2013, Hansen et al. 2014), these cells do not mimic the majority of prostate cancers. PC3 cells do not express androgen receptors and hence are androgen insensitive (Veldscholte et al. 1990). In contrast, the majority of prostate cancers are initially androgen dependent but develop resistance to castration as the disease progresses. This is not mediated by the loss of androgen receptors; instead, the tumours acquire additional mechanisms that enable their survival in an androgen-deprived environment (Veldscholte et al. 1990). The completely androgen-dependent PC3 cells were deliberately used in this study to allow us to independently assess the effects of androgen on the bone microenvironment and the influence of these changes on tumour growth. In addition, bone lesions generated by PC3 cells are strongly osteolytic. Studies of postmortem samples from prostate cancer patients have shown that the majority of bone metastases result in either predominantly osteoblastic (30%), or mixed osteoblastic, and osteolytic diseases (44%), with only 14% of patients having predominantly osteolytic disease (Morrissey et al. 2013). However, bone resorption markers are significantly elevated in patients with metastatic prostate cancer regardless of lesion type (Garnero et al. 2000, Coleman et al. 2013), and the use of anti-resorptive agents such as ZOL is therefore common in this setting (Coleman et al. 2010). Despite these limitations, we found that the PC3 model was the only prostate cancer model to reflect tumour cell colonisation, quiescence and subsequent growth in the bone microenvironment following injection into the circulation (Supplementary Table 1, see section on supplementary data given at the end of this article). The androgen-dependent VCAP and DUCAP lines form osteoblastic lesions in bone following intra-tibial injection and may provide a more clinically relevant model for prostate cancer-induced bone disease. We and others have shown that implanting prostate and breast cancer cells directly into the tibia enables tumours to grow in this environment both in 6-week-old mice with high bone turnover and in 12-week-old mice with low bone turnover (Ottewell et al. 2009, Herroon et al. 2013, Graham et al. 2014). This method of tumour cell injection is not appropriate for studies of disseminated tumour cells in bone and effects of therapies on early stage disease, as it involves introduction of a large number of tumour cells directly into the bone marrow. We were therefore limited in our choice of model for this study as PC3 cells are the only prostate cancer cell line that could be used to investigate seeding and dormancy in the bone environment.

We found significantly decreased bone turnover in mice treated with ZOL, and this was associated with inhibition of castration-induced proliferation of disseminated prostate cancer cells. Emerging data strongly suggest that administration of ZOL, before detection of bone metastases, may have significant anti-tumour benefit. We and others have shown that administration of ZOL, in the absence of anti-cancer therapies, does not reduce existing bone metastases from solid tumours, including prostate and breast (Ottewell et al. 2009, 2012, Hung et al. 2011). However, when given in a preventive setting, i.e. ZOL is administered before tumour cells are introduced, this results in a significant reduction in metastatic tumour growth in bone from both osteoblastic LnCAP and osteolytic PC3 prostate cancer cells, as well as from MDA-MB-231 breast cancer cells (Daubiné et al. 2007, Hung et al. 2011). Our data suggest that this is due to inhibition of processes in the metastatic niche, causing disseminated tumour cells to be held in a quiescent state. Recent evidence has suggested that inhibiting bone turnover with ZOL may have limited usefulness for specific tumour types. Studies in which dog (Ace-1) and mouse (RM1) prostate cancer cells have been injected i.c. into mice showed no difference in tumour growth between mice that had received ZOL before or after tumour cell injection, or in untreated control mice (Thudi et al. 2008, Hung et al. 2011). These findings warrant further investigation involving clinical trials of prostate cancer metastasis to bone.

The use of ADT in prostate cancer causes marked changes in hormone levels, most notably a drop in circulating androgens. As male oestrogen production is mediated by the aromatisation of testosterone, ADT also reduces circulating oestrogen levels. This leads to loss of bone mineral density (BMD; Smith et al. 2001) and is associated with increased risk of fractures (Shahinian et al. 2005). Clinical trials have reproducibly shown that treatment with a bisphosphonate, including ZOL, improves BMD in prostate cancer patients undergoing ADT (Smith 2003, Michaelson et al. 2007). However, these trials did not record data on effects on future development of bone metastasis. Only two phase III clinical trials have aimed to investigate whether ZOL treatment can prevent development of bone metastasis in men with castrate-resistant and castrate-sensitive prostate cancer. However, both studies were stopped early: the castrate-resistant prostate cancer trial due to poor accrual and lower than expected rate of bone metastasis (Smith et al. 2005), and the trial of castrate-sensitive prostate cancer due to withdrawal of drug supply by the corporate sponsor (Smith et al. 2003). A recently published clinical trial has shown that ZOL treatment initiated within 6 months of ADT did not reduce the time to first SRE in patients with established bone metastasis (Smith et al. 2014). This supports our hypothesis that ADT induces rapid changes to the bone microenvironment and that ZOL therefore must be given at the time of ADT in order to modify disease progression. For now the benefits of early intervention with ZOL remain inconclusive. However, ZOL is currently under study for use in men with castrate-sensitive prostate cancer without evidence of metastasis in a phase III trial that has not yet reported its results (NCT00242567). The primary endpoint of this study is skeletal event free survival at 18 months and 3 years (Saylor 2014). The findings from this small study involving 522 men are currently being analysed and should give an indication into the effectiveness of ZOL as a preventative treatment for prostate cancer-induced bone metastasis. 2b1af7f3a8