Can obesity be an advantage for febrile neutropenia?

There are numerous factors affecting febrile neutropenia. Obese cancer patient management and especially chemotherapeutic dosages may be more problematic than in normal weight patients.     

Can cancer be reversed by engineering the tumor microenvironment?

To advance cancer research in a transformative way, we must redefine the problem. Although epithelial cancers, such as breast cancer, may be caused by random somatic gene mutations, the reality is that this is only one of many ways to induce tumor formation. Cancers also can be produced in experimental systems in vitro and in vivo, for example, by inducing sustained alterations of extracellular matrix (ECM) structure. Moreover, certain epithelial cancers can be induced to 'reboot' and regenerate normal tissue morphology when combined with embryonic mesenchyme or exogenous ECM scaffolds that are produced through epithelial-stromal interactions. At the same time, work in the field of Mechanical Biology has revealed that many cell behaviors critical for cancer formation (e.g., growth, differentiation, motility, apoptosis) can be controlled by physical interactions between cells and their ECM adhesions that alter the mechanical force balance in the ECM, cell and cytoskeleton. Epithelial tumor progression also can be induced in vitro by changing ECM mechanics or altering cytoskeletal tension generation through manipulation of the Rho GTPase signaling pathway. Mechanical interactions between capillary cells and ECM that are mediated by Rho signaling similarly mediate control of capillary cell growth and angiogenesis, which are equally critical for cancer progression and metastasis. These findings question basic assumptions in the cancer field, and raise the intriguing possibility that cancer may be a reversible disease that results from progressive deregulation of tissue architecture, which leads to physical changes in cells and altered mechanical signaling. This perspective raises the possibility of developing a tissue engineering approach to cancer therapy in which biologically inspired materials that mimic the embryonic microenvironment are used to induce cancers to revert into normal tissues.     

How DNA lesions are turned into mutations within cells?

Genomes of all living organisms are constantly injured by endogenous and exogenous agents that modify the chemical integrity of DNA and in turn challenge its informational content. Despite the efficient action of numerous repair systems that remove lesions in DNA in an error-free manner, some lesions, that escape these repair mechanisms, are present when DNA is being replicated. Although replicative DNA polymerases are usually unable to copy past such lesions, it was recently discovered that cells are equipped with specialized DNA polymerases that will assist the replicative polymerase during the process of Translesion Synthesis (TLS). These TLS polymerases exhibit relaxed fidelity that allows them to copy past lesions in DNA with an inherent risk of generating mutations at high frequency. We present recent aspects related to the genetics and biochemistry of TLS and highlight some of the remaining hot topics of this field.     

Is F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer C-EF3 in animal tumor models

Introduction

Fluorodeoxyglucose (FDG) has been reported as a surrogate tracer to measure tumor hypoxia with positron emission tomography (PET). The hypothesis is that there is an increased uptake of FDG under hypoxic conditions secondary to enhanced glycolysis, compensating the hypoxia-induced loss of cellular energy production. Several studies have already addressed this issue, some with conflicting results. This study aimed to compare the tracers ¹⁴C-EF3 and ¹⁸F-FDG to detect hypoxia in mouse tumor models.

Materials and methods

C3H, tumor-bearing mice (FSAII and SCCVII tumors) were injected iv with ¹⁴C-EF3, and 1 h later with ¹⁸F-FDG. Using a specifically designed immobilization device with fiducial markers, PET (Mosaic®, Philips) images were acquired 1 h after the FDG injection. After imaging, the device containing mouse was frozen, transversally sliced and imaged with autoradiography (AR) (FLA-5100, Fujifilm) to obtain high resolution images of the ¹⁸F-FDG distribution within the tumor area. After a 48-h delay allowing for ¹⁸F decay a second AR was performed to image ¹⁴C-EF3 distribution. AR images were aligned to reconstruct the full 3D tumor volume, and were compared with the PET images. Image segmentation with threshold-based methods was applied on both AR and PET images to derive various tracer activity volumes. The matching index DSI (dice similarity index) was then computed. The comparison was performed under normoxic (ambient air, FSAII: n = 4, SCCVII, n = 5) and under hypoxic conditions (10% O₂ breathing, SCCVII: n = 4).

Results

On AR, under both ambient air and hypoxic conditions, there was a decreasing similarity between ¹⁴C-EF3 and FDG with higher activity sub-volumes. Under normoxic conditions, when comparing the 10% of tumor voxels with the highest ¹⁸F-FDG or ¹⁴C-EF3 activity, a DSI of 0.24 and 0.20 was found for FSAII and SCCVII, respectively. Under hypoxic conditions, a DSI of 0.36 was observed for SCCVII tumors. When comparing the ¹⁴C-EF3 distribution in AR with the corresponding ¹⁸F-FDG-PET images, the DSI reached values of 0.26, 0.22 and 0.21 for FSAII and SCCVII under normoxia and SCCVII under hypoxia, respectively.

Conclusion

This study showed that FDG is not a good surrogate tracer for tumor hypoxia under either ambient or hypoxic conditions. Only specific hypoxia tracers should be used to measure tumor hypoxia.     

Can 5' nucleotidase estimation be a predictor of liver metastases?

The diagnosis of hepatic metastases is important and has prognostic significance in clinical medicine. A variety of biochemical tests have been used to diagnose liver metastases before surgery and during follow up. However, recently, with the introduction of high resolution imaging modalities like CT Scan/Ultrasonography, the value of these biochemical tests declined. Ultrasonography/CT Scan can pick up liver metastases upto 0.5 cm diameter. Many a times bigger lesions and obviously smaller lesions can be missed by these screening methods. Various biochemical markers were proposed to pick up liver metastases. In this study, the estimation of 5'nucleotidase is found to be the most sensitive predictor of liver metastases when compared to conventional markers and imaging modalities.     

Can a phenotype for recessive inheritance in breast cancer be defined?

While a dominant inheritance of breast cancer (vertical inheritance) is well known, less is known about a possible recessive inheritance (horizontal inheritance). In a clinical series of 1676 breast cancer patient’s family history was scored as vertical (grandmother-aunt-mother-sister-daughter) or horizontal (sister-sister) and related to histopathological tumor type, presence of germline mutations, bilaterality, multifocality, screening, parity, hormone replacement therapy (HRT) use and age at diagnosis. Prognosis was estimated by also adding tumor size, lymph node status, distant metastases and hormone receptor status at diagnosis into a Cox proportional hazard model. Excluding mutations carriers, a horizontal family history (5% of all cases) was significantly associated with tubular tumor type [OR = 3.87(1.44–10.41)]. A vertical family history (23% of all cases) was significantly related to tumor multifocality [OR = 2.30(1.51–3.50)], tumor bilaterality [OR = 2.08(1.44–3.00)] and screening detection [OR = 1.50(1.10–2.05)]. No significant difference in survival could be seen between patients with none, horizontal or vertical family history. However, germline mutation carriers (BRCA1/2, TP53 or CDKN2A, present in 0.95% of the cases) had a significantly worse survival. Screening detected cases, HRT ever users and patients with estrogen receptor positive tumors had a significantly better survival adjusting for age at diagnosis, tumor size, lymph node status and presence of distant metastases at diagnosis. Factors associated with a horizontal family history were found, defining a possible phenotype for a recessive inheritance: tubular breast cancer.     

Can 8-oxo-dG be used as a predictor for individual radiosensitivity?

PURPOSE: To develop predictive tests for individual radiosensitivity of tumor patients. METHODS AND MATERIALS: Acute skin reactions were clinically scored among 40 women after 46 Gy, given with 2 Gy fractions to breast and regional lymph nodes, adjuvant after surgery. The acute skin reactions were compared to the excretion of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) in urine, determined by high-performance liquid chromatography (HPLC) with electrochemical detector. Specimens of urine were collected before and during postoperative radiation treatment at given intervals. We compared a group of 9 patients with the most pronounced skin reactions with another group of 8 patients with almost no skin reactions at 46 Gy. RESULTS: The level of 8-oxo-dG excreted in urine during 8 h was measured. After normalizing the excretion to irradiated volumes, dose per volume and excretion before irradiation, the 8-oxo-dG level in urine was significantly (p < 0.001) lower for the patients with pronounced skin reactions as compared to patients with minor skin reactions, at an accumulated dose of 12 Gy. In addition, the background level of 8-oxo-dG excreted before treatment started, was significantly (p = 0.043) lower for patients with minor skin reactions as compared to patients with pronounced skin reactions. The background level of 8-oxo-dG was corrected for body weight and normalized to BMI. CONCLUSION: We suggest that the excretion of 8-oxo-dG into urine of breast cancer patients is a possible marker for acute radiosensitivity.     

Can metastatic colorectal cancer be cured?

Significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). Development of the targeted biologic agents and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of these combination regimens in mCRC therapy has been relatively modest. While 2-year survival has improved, substantive gains have yet to be made in 5-year survival. However, a small subset of patients can be cured of their metastatic disease, with prolonged 5- and 10-year overall survival. This select group of patients includes those with metastatic disease limited to the liver or other organ-specific sites, as these patients are able to undergo surgical resection at the time of diagnosis or following conversion therapy with the appropriate integration of chemotherapy. A multimodality team-based approach involving medical oncologists, surgical oncologists, radiologists, and other healthcare providers is absolutely critical for the success of this therapeutic approach. This article reviews the main issues that must be considered from the surgical oncology and medical oncology perspectives, respectively.     

Can recurrence of meningiomas be predicted?

After resection of meningiomas the clinical evolution remains problematic, as no clear-cut predictive criteria are available. In vitro evaluation of meningiomas might help to predict their evolution in vivo after resection. For this goal a confrontation model was tested. A group of 105 patients operated for meningiomas between 1986 and 1997 were reviewed at 3, 5, 10 and 15 years for tumour evolution by tomodensitometry or magnetic resonance. At operation a fragment of these resected tumours was explanted for cell culture and was confronted with embryonic chick heart as a host tissue. The confrontation between tumour- derived cells and host tissue resulted in three different patterns: respectively a regressive, a non-invasive and an invasive pattern. Resection type, proliferation markers (Ki67 and PCNA) and in vitro confrontation patterns were significant (p<0.05) factors in predicting the postsurgical evolution of meningiomas. No correlation was found between proliferation markers and the behaviour in vitro, but invasion in vitro was strictly correlated with recurrence and malignancy of meningiomas.