Management and survival analysis of elderly patients with a cancer in the digestive system who refused to receive anticancer treatments.

Treatment and management of cancers in elderly patients require some special considerations. A better understanding of how cancers progress in those elderly patients who have not received any anticancer treatments could better help us in treating these patients and in making end-of-life decisions. Over the past years, we had encountered 57 elderly patients, aged 75 to 94 years (87.6 on average), with a cancer in the digestive system, who refused to accept anticancer treatment but who did receive the best available supportive and palliative care. Clinicopathological data of these patients were analyzed. Of these 57 cases, 49 were at an advanced or late stage, while the remaining eight were at an early stage at the time of diagnosis. The median overall survival time of all the patients was 11 months, and almost the entire cohort manifested multiple-organ impairments. The average number of malfunctioning organs per patient was 3.68. After carefully predicting, and then preventing or managing complications, only 54.4% of the patients eventually died of multiple-organ functional failure. Nearly 18% of the single organ dysfunctions were finally well-controlled. Our data provide the first statistical information on the survival time and the direct cause of death of the elderly patients with a cancer in the digestive system not treated with chemotherapy or other direct anticancer interventions, but who did receive the best available supportive and palliative cares. During their struggle with cancer, elderly patients clearly could benefit from prophylactic interventions on organ dysfunction.

Complications of oncologic therapy in the abdomen and pelvis: a review.

Cancer therapy has significantly improved in the past few decades with development of various newer classes of cytotoxic chemotherapy as well as novel, molecularly targeted chemotherapy. Similar to chemotherapy, radiotherapy is another important therapeutic option used in the curative and palliative management of various abdominal malignancies. However, both these treatments affect the tumor as well as the normal tissues, leading to significant toxicity. These side effects range from mild to life threatening, and may involve multiple organs. Imaging plays an important role in the early identification of such complications, which may allow more effective patient management. The aim of this article is to discuss and illustrate the wide spectrum of chemotherapy and radiotherapy induced complications in the abdomen and pelvis.

[Five-year results of IMRT for prostate cancer - toxicity]. / Petileté výsledky IMRT karcinomu prostaty - toxicita.

BACKGROUND: Intensity modulated radiotherapy (IMRT) plays a crucial role in the treatment of prostate cancer thanks to its capacity for healthy tissue sparing. This work reports on the acute and late toxicity rates among 233 patients treated with high-dose IMRT. MATERIAL AND METHODS: From June 2003 to December 2007, 233 men with clinically localized prostate cancer underwent radical radiotherapy. One hundred sixty patients were treated with IMRT to the prostate and the base of seminal vesicles to 78 Gy in 39 fractions, 73 patients underwent simultaneous integrated boost. Prescribed doses were 82 Gy and 73,8 Gy in 41 fractions to the prostate and seminal vesicles, respectively. Late toxicity was evaluated prospectively using a RTOG/FC-LENT score. RESULTS: Thirty patients (12.8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. No acute Grade 3 or 4 GI toxicity developed. Forty two patients (18.1%) experienced acute Grade 2 genitourinary toxicity and 23 patients (9.9%) had Grade 3 GU toxicity. Grade 4 Genitourinary toxicity was observed in nine (3.8%) patients, due to a need of short-term urinary catheterization. With a median follow-up of 49.2 months, the estimated 5-year cumulative incidence of Grade 2 gastrointestinal toxicity was 22.4%. The estimated 5-year cumulative incidence of Grade 2 genitourinary toxicity was 17.7%. CONCLUSION: Intensity modulated radiotherapy enables dose escalation to 78-82 Gy with an acceptable toxicity.

Internal Dose Assessment after 131I-Iodide Misadministration in a Patient With Incompletely Blocked Thyroid Uptake: Personalized Internal Dose Assessment by Estimating Individual-Specific Biokinetics.

In July 2017, a medical accident occurred in South Korea, in which I-iodide solution was misadministered to the wrong patient. Although the International Commission on Radiological Protection provided internal dose coefficients for iodine for blocked thyroid, they were not reliable enough for determining the dose to the patient (whose thyroid uptake was incompletely blocked) due to a discrepancy in biokinetics. Therefore, a personalized dose assessment was performed to derive the individual-specific dose coefficients for the patient. Initially, the thyroid biokinetics of the patient were statistically clarified by fitting bioassay monitoring results and the corresponding predicted bioassay values, which were calculated repeatedly for varying iodine transfer rates in an iodine biokinetic model. After determining the transfer rate for the patient, the individual-specific dose coefficients were then calculated in accordance with latest recommendations of the International Commission on Radiological Protection. According to the individual-specific biokinetics, the 24 h thyroid uptake fraction of iodine was estimated as 0.52%. The thyroid absorbed dose of the patient was evaluated as 21.2 Gy, which differed greatly (by about 9 Gy) from the dose evaluated simply using the reference data for blocked thyroid uptake. The personalized dose assessment carried out for the patient not only reduced considerable uncertainties in the internal dose calculation, but also improved the reliability of the calculated internal dose by adopting the latest dosimetric data, including specific absorbed fraction values based on voxel phantoms. Through the dose assessment of the patient, the methodology of personalized dose assessment considering individual-specific biokinetics was developed.

The Influence of Aerosol Density and Shape Factor on the Assessment of Internal Exposure to 239Pu.

Internal exposure due to inhalation of aerosols depends on the ratio of aerodynamic shape factor (χ) to aerosol mass density (ρ). Inhaled aerosol parameters may differ from the default ρ and χ values provided by the International Commission on Radiological Protection, which are adopted for the assessment of internal exposures. This paper focuses on the influences of χ/ρ on the assessment of internal exposure to Pu for reference workers. Regional deposition fractions are found to decrease with increasing χ/ρ, and larger decreases are observed with smaller activity median aerodynamic diameter aerosols, while the slow clearance fractions (fs) in the tracheobronchial region are more sensitive for larger activity median aerodynamic diameter aerosols. Results from biokinetics calculations reveal that both the time-dependent content (excretion) and cumulative activities are determined mainly for particles initially deposited in the alveolar-interstitial region, while fs affects the local cumulative activities in the tracheobronchial region. χ/ρ is proven to have different influences for aerosols with different activity median aerodynamic diameters. The default χ/ρ values can be used when activity median aerodynamic diameters are greater than 1 µm, while one should pay attention to the value of χ/ρ when activity median aerodynamic diameters are less than 1 µm, where significant influence may be anticipated.

STATE OF COGNITIVE FUNCTIONS IN CHILDREN WITH PATHOLOGY OF DIGESTIVE ORGANS, WHO LIVE AT RADIOACTIVE CONTAMINATED TERRITORIES OF UKRAINE. / STAN KOGNITYVNYKh FUNKTsIY̆ U DITEY̆ Z PATOLOGIIeIu ORGANIV TRAVLENNIa, IaKI PROZhYVAIuT' NA RADIOAKTYVNO ZABRUDNENYKh TERYTORIIaKh UKRAÏNY.

OBJECTIVE: to study the state of cognitive functions in children who were born and permanently live at radioactive contaminated territories (RCT) with pathology of the upper digestive tract, using pathopsychological testing; to increase the effectiveness of treatment and prophylactic measures aimed at preserving and restoring the health of RCT residents. DESIGN, PATIENTS AND METHODS: A randomized blind controlled clinical trial was conducted. There were examined, a total of 90 persons aged 6 to 17 years (35 boys and 55 girls) who were divided into two groups: the control group (I) included 30 persons of the conventional «clean¼ territories, and the main group (II) - 60 patients with patho- logy of the digestive organs who were born and live at the RCT. The study program included: the collection of anam- nesis, complaints; clinical and instrumental examinations. The following tests were applied by us: «What things are hidden in the drawings¼, Toulouse-Pieron, Raven, and Luria testing. For detecting the anxiety level, and the subjec- tive signs of autonomic dysfunctions were used the Spilberg-Hanin self-diagnosis and the Wein questionnaire, respectively. RESULTS: It was shown that in children aged 6-11 years, according to the results of the Toulouse-Pieron test, speed of cognitive information-processing was significantly decreased by 7.17 conventional units, while on the back- ground of the etiopathogenetic treatment of the digestive tract - by 10.24 conventional units relative to the va- lues of the control group. The long-term memory was statistically significantly decreased in the examined children of senior school age (from 12 to 17 years). A significant increase in reactive anxiety and a reverse correlation between the personal anxiety (PA) and speed of cognitive information-processing (r = -0.331) were recorded in patients aged 6-11 years. In older patients, PA was increased.Сonclusions. The obtained results indicate that the state of cognitive functions was characterized by a decrease in speed of cognitive information-processing, long-term memory and a high level of anxiety in children aged from 6 to 17 years residents of RСT with pathology of digestive organs, according to the used testing.

Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07).

PURPOSE: Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. METHODS AND MATERIALS: BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). RESULTS: Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly. CONCLUSIONS: The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.

A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2.

Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-kappaB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-kappaB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti-mucotoxic-targeted therapies.

Proton therapy for hepatocellular carcinoma: Current knowledges and future perspectives.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, as few patients can be treated with currently available curative local modalities. In patients with HCC where curative modalities are not feasible, radiation therapy (RT) has emerged as an alternative or combination therapy. With the development of various technologies, RT has been increasingly used for the management of HCC. Among these advances, proton beam therapy (PBT) has several unique physical properties that give it a finite range in a distal direction, and thus no exit dose along the beam path. Therefore, PBT has dosimetric advantages compared with X-ray therapy for the treatment of HCC. Indeed, various reports in the literature have described the favorable clinical outcomes and improved safety of PBT for HCC patients compared with X-ray therapy. However, there are some technical issues regarding the use of PBT in HCC, including uncertainty of organ motion and inaccuracy during calculation of tissue density and beam range, all of which may reduce the robustness of a PBT treatment plan. In this review, we discuss the physical properties, current clinical data, technical issues, and future perspectives on PBT for the treatment of HCC.

Alimentary hyperlipemia of rabbits is affected by exposure to low-intensity pulsed magnetic fields.

An experimental study was carried out in rabbits to investigate the effects of exposing rabbits to low-intensity pulsed magnetic fields (PMFs) on alimentary hyperlipemia. Thirty female white big ear rabbits were randomly divided into three groups. The normal group was fed with a standard chow diet and the other two groups (hyperlipid and magnetic) were fed with the chow diet supplemented with cholesterol, yolk powder and lard. The magnetic group was exposed to 15 Hz pulsed magnetic fields. After 8 weeks, levels of blood lipid and indices of hemorheology were examined. In addition, histomorphologic changes of hepatic and myocardial tissues were compared across the groups respectively. Compared with the hyperlipid group, hemorheology indices of the magnetic group reduced significantly from 12.80% to 38.05% (P < 0.01) indicating lower blood viscosity. Similarly, compared with the hyperlipid group, the levels of total cholesterol and triglycerides in the magnetic group decreased 40.52% and 52.42% (P < 0.01). On the contrary, high density lipoprotein (HDL) value obviously increased 66.67% (P < 0.01). Furthermore, compared with the control group, the values of triglycerides and HDL of the magnetic group did not show statistical differences (P > 0.05). The deposit of fatty material on the inner lining of thoracic aorta wall of the magnetic group was significantly lighter than that of the hyperlipid group. Numerous aggregation of lipoids emerged among myocardial myofibrils in the hyperlipid group, while no notable change was found in both the magnetic and control group. The results indicate that low-intensity PMFs could be helpful for the treatment of alimentary hyperlipemia.

Inclusion of thin target and source regions in alimentary and respiratory tract systems of mesh-type ICRP adult reference phantoms.

It is not feasible to define very small or complex organs and tissues in the current voxel-type adult reference computational phantoms of the International Commission on Radiological Protection (ICRP), which limit dose coefficients for weakly penetrating radiations. To address the problem, the ICRP is converting the voxel-type reference phantoms into mesh-type phantoms. In the present study, as a part of the conversion project, the micrometer-thick target and source regions in the alimentary and respiratory tract systems as described in ICRP Publications 100 and 66 were included in the mesh-type ICRP reference adult male and female phantoms. In addition, realistic lung airway models were simulated to represent the bronchial (BB) and bronchiolar (bb) regions. The electron specific absorbed fraction (SAF) values for the alimentary and respiratory tract systems were then calculated and compared with the values calculated with the stylized models of ICRP Publications 100 and 66. The comparisons show generally good agreement for the oral cavity, oesophagus, and BB, whereas for the stomach, small intestine, large intestine, extrathoracic region, and bb, there are some differences (e.g. up to ~9 times in the large intestine). The difference is mainly due to anatomical difference in these organs between the realistic mesh-type phantoms and the simplified stylized models. The new alimentary and respiratory tract models in the mesh-type ICRP reference phantoms preserve the topology and dimensions of the voxel-type ICRP phantoms and provide more reliable SAF values than the simplified models adopted in previous ICRP Publications.

The atlas of complication incidence: a proposal for a new standard for reporting the results of radiotherapy protocols.

We present a new method of reporting the results of radiotherapy protocols. The dose-volume atlas of complication incidence is a comprehensive and unbiased summary of the dose-volume exposures and complications occurring in patients after treatment. This new tool provides clear and systematic information about the safety of regions of dose-volume exposure previously treated that can be used when considering new treatments. Actuarial and model-dependent versions of the atlas are described. By using the raw data in the appropriate forms of the atlas, logistic regression, Kaplan-Meier, and Cox proportional hazards analysis can be performed, allowing for the independent calculation of dose-volume response. The data required are simple enough that provided compatible definitions of dose, volume, and complications are used, atlases from different protocols are potentially additive, facilitating the meta-analysis of inter-interinstitutional data. If this method were adopted as a standard for reporting the outcome of treatment protocols, a potentially synergistic increase in the utility of each protocol could result.

The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice.

Three h after whole-body irradiation (8 Gy) of C57BL x DBA/2 F1 mice, p53 protein was expressed strongly in the stem cell compartment of the small intestine but at lower levels in the colon. At this time, apoptotic cells were also observed in the stem cell position of the small intestine, with fewer in the colon. In mice without copies of the p53 gene (nulls), the levels of spontaneous apoptosis, in both the small intestine and the colon, were not different from wild-type. Irradiation of the nulls with 8 Gy of gamma-rays failed to induce any further apoptosis: the loss of p53 essentially rendered the epithelial cells, from both the small intestine and the colon, radioresistant. The response of the epithelial stem cells of the small intestine suggests that p53 may play a role in the deletion of damaged cells with carcinogenic potential, whereas this process is limited in the colon.

Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice.

Ionizing radiation (IR) induces p53-dependent apoptosis in radiosensitive tissues, suggesting that p53 is a determinant of radiation syndromes. In fact, p53-deficient mice survive doses of IR that cause lethal hematopoietic syndrome in wild-type animals. Surprisingly, p53 deficiency results in sensitization of mice to higher doses of IR, causing lethal gastro-intestinal (GI) syndrome. While cells in the crypts of p53-wild-type epithelium undergo prolonged growth arrest after irradiation, continuous cell proliferation ongoing in p53-deficient epithelium correlates with accelerated death of damaged cells followed by rapid destruction of villi and accelerated lethality. p21-deficient mice are also characterized by increased sensitivity to GI syndrome-inducing doses of IR. We conclude that p53/p21-mediated growth arrest plays a protective role in the epithelium of small intestine after severe doses of IR. Pharmacological inhibition of p53 by a small molecule that can rescue from lethal hematopoietic syndrome has no effect on the lethality from gastro-intestinal syndrome, presumably because of a temporary and reversible nature of its action.

Loss of interstitial cells of Cajal after pulsating electromagnetic field (PEMF) in gastrointestinal tract of the rats.

Exposure to the magnetic field has remarkably increased lately due to fast urbanization and widely available magnetic field in diagnosis and treatment. However, biological effects of the magnetic field are not well recognized. The myoelectric activity recorded from the gastrointestinal and urinary systems is generated by specialized electrically active cells called interstitial cells of Cajal (ICCs). Thus it seems rational that ICC have significant vulnerability to physical factors like an electromagnetic field. The aim of this study was to evaluate the influence of pulsating electromagnetic field (PEMF) (frequency 10 kHz, 30ms, 300 muT burst, with frequency 1Hz) on ICCs density in the rat gastrointestinal tract. Rats were divided into two groups (n=32). The first group was exposed to PEMF continuously for 1, 2, 3, and 4 weeks (n = 16), and the second group (n=16) served as a control. Tissue samples of the rat stomach, duodenum and proximal colon were fixed and paraffin embedded. The tangential sections of 5 microm thickness were stained immunohistochemically with anti-c-Kit (sc-168) antibody and visualized finally by DAB as chromogen (brown end product). C-Kit positive branched ICC-like cells were detected under the light microscope, distinguished from the c-kit-negative non-branched smooth muscle cells and from the c-kit positive but non-branched mast cells and quantitatively analyzed by MultiScan computer program. Apoptosis detection was performed with rabbit anti-Bax polyclonal antibody (Calbiochem, Germany) and LSAB 2 visualization system. The surface of c-Kit immunopositive cells decreased after exposure to PEMF in each part of the gastrointestinal tract. Reduced density of ICCs was related to exposure time. The most sensitive to PEMF were ICCs in the fundus of the stomach and in the duodenum, less sensitive were ICCs in the colon and pacemaker areas of the stomach. No marked changes in ICC density in the pyloric part of the stomach were observed. We demonstrate that the PEMF induced apoptosis dependent decrease in ICC expression.

Acute graft-vs-host disease: pathobiology and management.

Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD.

[Towards an improvement of the quality of life after radiotherapy in children]. / Vers une amélioration de la qualité de vie après une radiothérapie réalisée dans l'enfance.

Pediatric radiotherapy did not differ technically from adult radiotherapy but its characteristics, its difficulties and challenges are specific. Thanks in part to this treatment, overall survival of French children with cancer is around 80%. It is therefore important to integrate in the elaboration of the treatment planning potential side long-term effects. Indeed, whatever the technique is, even the most sophisticated, it is usually inevitable that healthy nearby organs receive a dose of radiation. Dose limits on organs at risk come from adult data and are adapted for children. After the treatment, it is important to graduate the potential risks of side effects to propose a personalized monitoring protocol avoiding excessive medicalization. This article presents the medical thinking concerning radiotherapy in different anatomical areas (brain, head and neck, chest, abdomen) including concepts of dose level corresponding to side effects usually described. In parallel, we present follow-up recommendations with the aim to preserve an optimal quality of life for the adults cured of a childhood cancer, currently called survivors.

Mechanisms of radiation-induced conditioned taste aversion learning.

The literature on taste aversion learning is reviewed and discussed, with particular emphasis on those studies that have used exposure to ionizing radiation as an unconditioned stimulus to produce a conditioned taste aversion. The primary aim of the review is to attempt to define the mechanisms that lead to the initiation of the taste aversion response following exposure to ionizing radiation. Studies using drug treatments to produce a taste aversion have been included to the extent that they are relevant to understanding the mechanisms by which exposure to ionizing radiation can affect the behavior of the organism.

Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer.

Randomised studies in locally advanced cervical cancer patients showed that cisplatin should be given concurrently with radiotherapy, because of a better long-term survival compared to radiotherapy alone. This increases the relevance of treatment related toxicity. This review summarises the acute and long-term toxicity of radiotherapy given with or without chemotherapy for cervical cancer. Acute toxicity (all grades) of radiotherapy is reported in 61% of the patients in the rectosigmoid, in 27% as urological, in 27% as skin and in 20% as gynaecological toxicity. Moderate and severe morbidity consists of 5% to 7% gastrointestinal and 1% to 4% genitourinary toxicity. Adding chemotherapy to radiotherapy increases acute haematological toxicity to 5% to 37% of the patients and nausea and vomiting in 12% to 14%. Late effects of radiotherapy include gastrointestinal, urological, female reproductive tract, skeletal and vascular toxicity, secondary malignancies and quality of life issues. For at least 20 years after treatment, new side effects may develop. Gastrointestinal toxicity usually occurs in the first 2 years after treatment in about 10% of the patients. The incidence of moderate and severe urological toxicity can increase up to 10% and rises over time. Gynaecological toxicity usually occurs shortly after treatment while skeletal and vascular toxicity can occur years to decades later. Thus far, no increase in late toxicity has been observed after the addition of cisplatin to radiotherapy. Finally, methods to prevent or decrease late toxicity and therapeutical options are discussed. However, most randomised studies still have a limited follow-up period.

Biology of mucosal pain.

Pain is experienced when injury to mucosal tissues occurs. Although the neurobiology of mucosal pain has not been fully elucidated, research has demonstrated that the oral mucosa contains primary afferent nociceptors that respond to thermal, mechanical, and chemical stimuli. Inflammation occurs during the initial phase of mucosal injury caused by stomatotoxic chemotherapy or radiation therapy. This article reviews the mechanisms that underlie acute pain in inflamed cutaneous tissue and summarizes the major mediators that activate and sensitize primary afferent nociceptors. Recommendations for future research to elucidate the neurobiology of mucosal pain throughout the gastrointestinal tract are presented.