Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

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Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

https://www.unitypoint.org/desmoines/filesimages/Cancer%20Education/Oncology%20Nursing%20Conference/2015/2014%20NCCN%20Clin%20Pract%20Guidelines%20Male%20Sex%20Dysf.pdf

Clinical practice guidelines in oncology

The literature is reviewed to identify the main clinical and dose-volume predictors for acute and late radiation-induced heart disease. A clear quantitative dose and/or volume dependence for most cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury.

/pdf/radiation-dose-volume-effects-in-the-brain-weug9uqa6a.pdf

Radiation Dose–Volume Effects in the Brain

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is activated in the majority of human cancers. This pathway is known to play a key role in numerous cellular functions including proliferation, adhesion, migration, invasion, metabolism, and survival, but in the current review we focus on its role in angiogenesis. PI3K activation may occur via RAS mutation, loss of phosphatase and tensin homolog (PTEN), or by increased expression of growth factor receptors such as epidermal growth factor receptor. There is a connection between the PI3K pathway and angiogenesis. Hypoxia leads to HIF-1α stabilization and is a major stimulus for increased vascular endothelial growth factor (VEGF) production by tumor cells. However, activation of the PI3K/AKT pathway in tumor cells can also increase VEGF secretion, both by hypoxia-inducible factor 1 (HIF-1) dependent and independent mechanisms. The PI3K/AKT pathway also modulates the expression of other angiogenic factors such as nitric oxide and angiopoietins. Numerous inhibitors targeting the PI3K/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiogenesis. The effect of these inhibitors on tumor vasculature can be difficult to predict. The vasculature of tumors is aberrant, leading to sluggish bloodflow and elevated interstitial blood pressure, which can be perpetuated by the high levels of VEGF. Hence, decreasing VEGF expression can paradoxically lead to vascular normalization and improved bloodflow in some tumors. In addition to its importance in cancer, the PI3K pathway also plays an essential role in the formation of normal blood vessels during development. Embryos with kinase-dead p110α catalytic subunit of PI3K develop vascular defects. Stimulation of endothelial cells by VEGF leads to activation of the PI3K pathway within these cells, which is important for cell migration. Sustained endothelial activation of AKT1 has been shown to induce the formation of structurally abnormal blood vessels that recapitulate the aberrations of tumor vessels. Hence, the PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers.

PI3K/AKT/mTOR Pathway in Angiogenesis

Purpose: To update a combined analysis of all published clinical data. Methods and Materials: We collected data from 38 additional patients treated in our department or published in four different reports and calculated the biologically effective dose (BED) according to the linear-quadratic model using an α/β value of 2 Gy for cervical and thoracic cord and 4 Gy for lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy 2 or 75 Gy 4 . Results: The 2005 risk score based on three variables (cumulative BED, highest BED of all treatment series in a particular individual, and interval), which discriminate three different risk groups, does not require modification. The low-risk group now contains 1 case of radiation myelopathy (RM) after hypofractionated stereotactic reirradiation. Therefore, the rate increased from 0% to 3%. Intermediate-risk patients developed RM in 25%, and high-risk patients in 90%. When the interval between the two treatment courses is not shorter than 6 months and the dose of each course is ≤98 Gy 2 , the cumulative BED where no case of RM has yet been reported is 120 Gy 2 . Conclusions: Based on these updated results, the risk of RM appears small after ≤135.5 Gy 2 when the interval is not shorter than 6 months and the dose of each course is ≤98 Gy 2 . We would recommend limiting the dose to the lowest feasible level. The influence of very steep dose gradients from stereotactic and intensity-modulated approaches (i.e., a more complex volume-effect) requires further evaluation.

Update of human spinal cord reirradiation tolerance based on additional data from 38 patients

Current status of angiogenesis inhibitors combined with radiation therapy

The aim of this study was to evaluate fatigue 2.5 years after adjuvant radiation therapy (RT) in patients with localized breast cancer and to assess its relation to pre- and immediate post-treatment fatigue values. The association of fatigue with psychological distress and functional impairment was analyzed as well as pretreatment predictors for chronic fatigue. Of a set of 41 patients whose fatigue was evaluated during adjuvant radiation therapy, 38 patients alive and free of cancer at 2.5 years (t2) after RT were assessed in this study. Patients received the Fatigue Assessment Questionnaire (FAQ), a visual analog scale on fatigue intensity (VAS-F) as well as on cancer-related distress (VAS-D), the Hospital Anxiety and Depression Scale (HADS), and three questions of the Short-Form 36-Item Health Survey (SF-36) per mail. All 38 patients returned their questionnaires. The values were compared to pretreatment (t0) and immediate post-treatment levels (2 months after RT, t1). There was no significant difference between chronic fatigue levels at 2.5 years after RT and pretreatment values. When compared to immediate post-treatment levels the FAQ global score and the HADS anxiety score displayed a significant increase. Cancer-related distress correlated closely with fatigue scores. Patients with functional impairment had slightly higher fatigue values. Age or hormonal therapy were not associated with chronic fatigue levels. Pretreatment fatigue and pretreatment HADS anxiety and depression scores were good predictors of fatigue at 2.5 years after RT explaining 60% (FAQ) and 49% (VAS-F) of its variance. Fatigue 2.5 years after RT did not increase above baseline levels before RT in conservatively operated breast cancer patients. Chronic fatigue correlated closely with psychological distress. Patients with pretreatment elevated fatigue, anxiety or depression levels are at risk for chronic fatigue.

Fatigue in patients with adjuvant radiation therapy for breast cancer: long-term follow-up

This is a summary of knowledge on blood perfusion and the microenvironment of human tumours, designed to enable the reader to gain a deeper insight into the physiological components of malignant tumours. Among a range of topics, consideration is given to circulatory parameters, including blood and nutrient supply, transvascular and interstitial transport, and oxygenation, as well as to bioenergetic status and the influence of pH on the responsiveness of malignant tumours to nonsurgical treatments such as radiotherapy and chemotherapy. The clinician may find it useful to read about the various invasive and non-invasive methods (including MR and PET) that allow the tumour physiology and microenvironment of an individual patient to be characterized.

Michael Molls

Papers

Update of human spinal cord reirradiation tolerance based on additional data from 38 patients

Current status of angiogenesis inhibitors combined with radiation therapy

Fatigue in patients with adjuvant radiation therapy for breast cancer: long-term follow-up

Blood perfusion and microenvironment of human tumors : implications for clinical radiooncology

Changes in tumor oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer