Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

Pain patterns and descriptions in patients with radicular pain: Does the pain necessarily follow a specific dermatome?

<p>Abstract</p> <p>Background</p> <p>It is commonly stated that nerve root pain should be expected to follow a specific dermatome and that this information is useful to make the diagnosis of radiculopathy. There is little evidence in the literature that confirms or denies this statement. The purpose of this study is to describe and discuss the diagnostic utility of the distribution of pain in patients with cervical and lumbar radicular pain.</p> <p>Methods</p> <p>Pain drawings and descriptions were assessed in consecutive patients diagnosed with cervical or lumbar nerve root pain. These findings were compared with accepted dermatome maps to determine whether they tended to follow along the involved nerve root's dermatome.</p> <p>Results</p> <p>Two hundred twenty-six nerve roots in 169 patients were assessed. Overall, pain related to cervical nerve roots was non-dermatomal in over two-thirds (69.7%) of cases. In the lumbar spine, the pain was non-dermatomal in just under two-thirds (64.1%) of cases. The majority of nerve root levels involved non-dermatomal pain patterns except C4 (60.0% dermatomal) and S1 (64.9% dermatomal). The sensitivity (SE) and specificity (SP) for dermatomal pattern of pain are low for all nerve root levels with the exception of the C4 level (Se 0.60, Sp 0.72) and S1 level (Se 0.65, Sp 0.80), although in the case of the C4 level, the number of subjects was small (n = 5).</p> <p>Conclusion</p> <p>In most cases nerve root pain should not be expected to follow along a specific dermatome, and a dermatomal distribution of pain is not a useful historical factor in the diagnosis of radicular pain. The possible exception to this is the S1 nerve root, in which the pain does commonly follow the S1 dermatome.</p

Sexual dimorphism in cancer.

The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment

Generation and Culture of Human Pancreatic Ductal Adenocarcinoma Organoids from Resected Tumor Specimens

The recent development of human organoids as patient-specific models of pancreatic ductal adenocarcinoma (PDA) has helped set the stage for a new era of personalized medicine. Organoids can be generated from a resected PDA tumor in as little as 2-4 weeks, and are amenable to therapeutic screening as well as genetic and biochemical perturbation. Moreover, because these models promote the propagation of the neoplastic PDA cells at the expense of the stromal cells, transcriptome and genome-wide sequencing of organoids offers an unprecedented view of the genetic and expression changes occurring in the neoplastic cells of individual tumors. Here, we describe methods to generate PDA organoid cultures from resected human tumor specimens. We also describe how to propagate, cryopreserve, and thaw human PDA organoid cultures

Generation and Culture of Tumor and Metastatic Organoids from Murine Models of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that is refractory to all current therapies. Research into the mechanisms driving this cancer is the key to developing better diagnostic and treatment options which are urgently needed in the clinic. Genetically engineered mouse models of PDA have been valuable research tools, enabling studies of all stages of PDA progression. However, these models are difficult and time-consuming to breed, and engineering further mutations into these models requires additional time. Recently, organoid cultures of PDA have emerged as alternative models for this disease. Organoids can be rapidly generated from mouse models of PDA and enable genetic and biochemical perturbation of all stages of PDA progression. Here, we describe the generation and propagation of organoid models from PDA tumors and metastases harvested from genetically engineered mouse models