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

Comparison of three different mediastinal radiotherapy techniques in female patients: Impact on heart sparing and dose to the breasts

Prediction of short survival in patients with brain metastases based on three different scores: a role for 'triple-negative' status?

Purpose This study attempts to improve our understanding of the role of salvage radiotherapy (SRT) in patients with prostate-specific antigen (PSA) relapse after radical prostatectomy with regard to biochemical control, rate of distant metastasis, and survival. Methods and Materials We performed a retrospective analysis of 96 men treated with conformal prostate bed SRT (median, 64.8 Gy) at a single institution (median follow-up, 70 months). The majority had intermediate- or high-risk prostate cancer. Fifty-four percent underwent a resection with positive margins (R1 resection). The median time interval between surgery and SRT was 22 months. Results After SRT, 66% of patients reached a PSA nadir of less than 0.2 ng/mL. However, the 5-year biochemical no evidence of disease rate was 35%. Seminal vesicle involvement was predictive for a significantly lower biochemical no evidence of disease rate. All patients with a preoperative PSA level greater than 50 ng/mL relapsed biochemically within 2 years. The 5-year distant metastasis rate was 18%, the 5-year prostate cancer–specific survival rate was 90%, and the 5-year overall survival rate was 88%. Significantly more distant metastases developed in patients with a PSA nadir greater than 0.05 ng/mL after SRT, and they had significantly inferior prostate cancer–specific and overall survival rates. Resection status (R1 vs. R0) was not predictive for any of the endpoints. Conclusions Men with postoperative PSA relapse can undergo salvage treatment by prostate bed radiotherapy, but durable PSA control is maintained only in about one-third of the patients. Despite a high biochemical failure rate after SRT, prostate cancer–specific survival does not decrease rapidly.

Outcome After Conformal Salvage Radiotherapy in Patients With Rising Prostate-Specific Antigen Levels After Radical Prostatectomy

Purpose Improvement of the relapse rate by locally increasing the tumor dose. Methods To increase the dose in the tumor bed a method for intraoperative radiation therapy has been developed. The radiation is applied using a high-dose-rate afterloading system. Flexible plastic flabs are used as applicators. Each flab contains tubes for the alterloading source. The size of the applicator is chosen to correspond to the size of the target volume. In the dosage system we use the dwell times at all source positions are equal. The dwell time has been precalculated to give the reference dose at the reference position which is located at the surface of the flab in the center of the target volume. Results The dose distributions around the flab have been calculated as a function of the thickness of the flab. If the source is not placed on a regular grid within the applicator due to a non ideal positioning of the tubes within the applicator, the dose distribution is not altered too much, if the positioning error is not larger than +/- 2 mm. The influence of a curvature of the flab has been evaluated and methods to decrease the dose at critical organs are discussed. Conclusion The flab methods for IORT is safe and easy and has been demonstrated for more than 150 cases. This method allows the increase in tumor dose even in regions which are not easily treated by electron IORT due to the rigid electron applicators. Because of the rapid dose fall off, the flab method can only be used for flat target volumes like the tumor bed.

The flab method of intraoperative radiotherapy

Background. The purpose of this study is to evaluate the performance of the new “Graded Prognostic Assessment” (GPA) index, which recently was developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients with brain metastases treated outside of randomized clinical trials. Material and methods. The authors analyzed 232 patients with brain metastases and assigned these patients to the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases, and GPA). Results. The present data confirm the results of the RTOG analysis. Each of the four indices splits the data set into prognostically different groups. In the GPA groups, median survival was 10.3, 5.6, 3.5, and 1.9 months, respectively (p<0.01). In the RTOG analysis, these figures were 11.0, 6.9, 3.8, and 2.6 months, respectively. Conclusion. These results confirm the validity of the GPA index in a patient population that most likely is more r...

Michael Molls

Papers

Comparison of three different mediastinal radiotherapy techniques in female patients: Impact on heart sparing and dose to the breasts

Prediction of short survival in patients with brain metastases based on three different scores: a role for 'triple-negative' status?

Outcome After Conformal Salvage Radiotherapy in Patients With Rising Prostate-Specific Antigen Levels After Radical Prostatectomy

The flab method of intraoperative radiotherapy

Validation of the graded prognostic assessment index for patients with brain metastases