Search

Background: To report our experience in planning and delivering total marrow irradiation (TMI) and total marrow and lymphatic irradiation (TMLI) in patients with hematologic malignancies., Methods: Twenty-seven patients undergoing bone marrow transplantation were treated with TMI/TMLI using Helical Tomotherapy (HT). All skeletal bones exclusion of the mandible comprised the treatment target volume and, for TMLI, lymph node chains, liver, spleen and/or brain were also included according to the clinical indication. Planned dose of 8Gy in 2 fractions was delivered over 1 day for TMI while 10Gy in 2 fractions BID was used for TMLI. Organs at risk (OAR) contoured included the brain, brainstem, lens, eyes, optic nerves, parotids, oral cavity, lungs, heart, liver, kidneys, stomach, small bowel, bladder and rectum. In particular, a simple method to avoid hot or cold doses in the overlapping region was implemented and the plan sum was adopted to evaluate dose inhomogeneity. Furthermore, setup errors from 54 treatments were summarized to gauge the effectiveness of immobilization., Results: During the TMI/TMLI treatment, no acute adverse effects occurred during the radiation treatment. Two patients suffered nausea or vomiting right after radiation course. For the 9 patients treated with TMI, the median dose reduction of major organs varied 30-65% of the prescribed dose, substantially lower than the traditional total body irradiation (TBI). Meanwhile, average biological equivalent doses to OARs with 8Gy/2F TMI approach were not different from the conventional 12Gy/6F TMI approach. In the dose junction region, the 93% of PTV was covered by the prescribed dose without obvious hotspots. For the 27 patients, the overall setup corrections were lower than 3 mm except those in the SI direction for abdomen-pelvis region, demonstrating excellent immobilization., Conclusion: The present study confirmed the technical feasibility of HT-based TMI/TMLI delivering 8-10Gy in 2 fractions over 1 day. For patients undergoing hematopoietic cell transplantation the proposed 8Gy/2F TMI (or 10Gy/2F TMLI) strategy may be a novel approach to improve delivery efficiency, increase effective radiation dose to target while maintaining low risk of severe organ toxicities.

Introduction: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Currently, there are no recommendations for an inclusion of the 'true' AILD in the clinical target volume (CTV) of definitive chemoradiation for anal cancer patients. To estimate the relevance of inguinal recurrence, we compared the incidental dose to the AILD in anal cancer (AC) patients who were treated either with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT) or conventional 3D-radiation technique., Methods: One VMAT-IMRT-plans and one 3D-plans were calculated on the same target volumes and identical dose prescription in ten patients. We defined the volume of the AILD on the planning CT-scans based on the information of new fluorescence methods. Furthermore, we defined several anatomical subvolumes of interest inside the AILD. We examined and compared absolute and relative dosimetric parameters of the AILD and different anatomical subunits., Results: The Dmean of the AILD was 40 Gy in the 3D-group and 38 Gy in the IMRT-group. Dmean and Dmedian as well as the V30Gy of the AILD and all subvolumes of the caudal AILD were significant higher using 3D-RT compared to IMRT. Even though the absolute differences were small, in the caudal aspect of the ano-inguinal lymphatic drainage the V30Gy could be more than 10% less with VMAT-IMRT., Conclusions: 3D-RT was slightly superior to IMRT in terms of dose coverage of the AILD. However, the absolute differences were very small. Some relevant caudal parts of the AILD received an insufficient dose for treating potential micrometastases. Particularly in high-risk situations, this may lead to inguinal recurrence and therefore the true deep AILD should be included into the target volume in high risk patients.

A new application of the photodynamic treatment (PDT) is presented for the opening of blood-brain barrier (BBB) and the brain clearing activation that is associated with it, including the use of gold nanoparticles as emerging photosensitizer carriers in PDT. The obtained results clearly demonstrate 2 pathways for the brain clearing: (1) using PDT-opening of BBB and intravenous injection of FITC-dextran we showed a clearance of this tracer via the meningeal lymphatic system in the subdural space; (2) using optical coherence tomography and intraparenchymal injection of gold nanorods, we observed their clearance through the exit gate of cerebral spinal fluid from the brain into the deep cervical lymph node, where the gold nanorods were accumulated. These data contribute to a better understanding of the cerebrovascular effects of PDT and shed light on mechanisms, underlying brain clearing after PDT-related opening of BBB, including clearance from nanoparticles as drug carriers., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Findings from fluorescence methods give us new information about anatomical conditions of the AILD. Current contouring guidelines do not advise the inclusion of the 'true' AILD into the clinical target volume (CTV). Aim of this work was the retrospective analysis of the incidental dose to the AILD in an anal cancer (AC) patient cohort who underwent definitive chemoradiation (CRT) therapy with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT)., Methods: VMAT-IMRT plans of 15 AC patients were analyzed. Based on findings from new fluorescence methods we created a new volume, the expected AILD. The examined dosimetric parameters were the minimal, maximal and mean dose and V10-V50 that were delivered to the AILD, respectively., Results: The median volume of AILD was 1047 cm³. Mean D min , D max and D mean were 7.5 Gy, 58.9 Gy and 40.8 Gy for AILD. The clinical relevant dose of 30.0 Gray covered in mean 76% of the volume of the AILD, respectively., Conclusions: Only 76% of the AILD-volume received at least an expected required treatment dose of 30 Gy incidentally. Concerning the low number of loco-regional relapses in AC patients after definitive CRT one has to balance increased side effects against a rigid oncological-anatomical interpretation of the local lymphatic drainage by including the AILD into the standard CTV.

Space flight causes a number of alterations in physiological systems, changes in the immunological status of subjects, and altered interactions of the host to environmental stimuli. We studied the effect of space flight on the lymphatic system of the gastrointestinal tract which is responsible for lipid transport and immune surveillance which includes the host interaction with the gut microbiome. We found that there were signs of tissue damage present in the space flown animals that was lacking in ground controls (epithelial damage, crypt morphological changes, etc.). Additionally, morphology of the lymphatic vessels in the tissue suggested a collapsed state at time of harvest and there was a profound change in the retention of lipid in the villi of the ileum. Contrary to our assumptions there was a reduction in tissue fluid volume likely associated with other fluid shifts described. The reduction of tissue fluid volume in the colon and ileum is a likely contributing factor to the state of the lymphatic vessels and lipid transport issues observed. There were also associated changes in the number of MHC-II + immune cells in the colon tissue, which along with reduced lymphatic competence would favor immune dysfunction in the tissue. These findings help expand our understanding of the effects of space flight on various organ systems. It also points out potential issues that have not been closely examined and have to potential for the need of countermeasure development., (Copyright © 2018 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Microvascular damage is an important component of late radiation-induced morbidity. In our pre-clinical models, we demonstrated that repair of vessel injury is dependent on proper endoglin-mediated transforming growth factor-beta (TGF-β) signalling and that it can be affected by infiltrating macrophages. We now wanted to extend these findings in irradiated patients, using skin as a model system, and assess whether bisphosphonates could modulate the response., Materials and Methods: Paired skin biopsies from irradiated and non-irradiated sites were obtained from 48 breast cancer patients. In 8 patients, biopsies were repeated after 4months of bisphosphonate treatment. Immunohistochemistry was used to assess vascular alterations and leucocyte infiltration. Western Blot and qPCR were used to assess expression of growth factors and their receptors., Results: Decreased blood vessel numbers at early time points were followed by increased endoglin expression and restoration of vessel number. Loss of small lymphatic vessels was associated with increased TGF-β levels, whereas dilation of lymphatic vessels correlated with increased macrophage infiltration. Bisphosphonate treatment reduced leucocyte infiltration, but also prevented restoration of blood vessel numbers after irradiation., Conclusion: Radiation injury of the microvasculature is mediated through TGF-β, whereas repair is modulated by the co-receptor endoglin and promoted by macrophages., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Long-term results of randomised trials have confirmed the safety and efficacy of hypofractionated radiotherapy using approximately 2.6 Gy per fraction to lower total doses of 40-42.6 Gy delivered over 3 weeks, for postoperative treatment of early breast cancer. In these trials, hypofractionated radiotherapy was predominantly used for breast only treatment, while there are fewer trials that specifically examined hypofractionated radiotherapy to the breast plus regional nodes. Hypofractionated locoregional radiation is considered a standard of care in the United Kingdom and in some parts of Canada. We aim to review the radiobiology and normal tissue effects of hypofractionated locoregional radiation and to summarize available published clinical experiences using this treatment strategy as adjuvant therapy after breast conserving surgery or mastectomy for women with early breast cancer., (Copyright © 2015. Published by Elsevier SAS.)

Background: 5-fluorouracil (5-FU) is employed to enhance radiotherapy (RT) effect. Here, we evaluated the influence of whole-pelvic irradiation on the pharmacokinetics (PK) of 5-FU in plasma and lymphatic system of rats as the experimental model., Methods: RT with 2 Gy was delivered to the whole pelvis of Sprague-Dawley rats. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. The pharmacokinetics of 5-FU in plasma and lymphatic system were calculated., Results: RT at 2 Gy reduced the area under the plasma concentration vs. time curve and mean residence time of 5-FU by 21.5% and 31.5%, respectively compared with those of non-RT controls. By contrast, RT at 2 Gy increased drug clearances of 5-FU by 28.2% when compared with those of non-RT controls. There was no significant difference in T1/2, Cmax and Vss in plasma between both groups. Intriguingly, 5-Fu could be detected in the lymphatic system. In addition, the AUC in 5-FU without and with RT was 3.3-fold and 4.9-fold greater for lymph than for plasma, respectively. Compared with the non-RT group, the RT group showed increase in distribution of 5-FU in the lymphatic system (p = 0.001)., Conclusions: The local whole pelvic RT at 2 Gy could modulate systemic PK of 5-FU in plasma of rats and intravenous 5-FU passing into the lymphatic system was proved. The metabolism of 5-FU might be modulated by RT but the distribution of 5-FU from blood circulation to the lymphatic system might not be changed. The RT-PK phenomena in plasma provide references for adjustment of drug administration. Chemotherapy drugs entering the lymphatic system is worthy of further investigation.

Secondary lymphedema is a common complication after lymph node excision and radiotherapy in cancer therapy. Therapies are limited to symptomatic treatment. Adequate animal models to test potential surgical therapies are needed. The aim of this study was to induce a tissue environment in the hind leg of the rat similar to the one found in operated and irradiated patients. Quantification of edematous swelling was performed by an automatic 3D-contour segmentation (ITK- Snap ©) on MR- images. Swelling was induced by excision of superficial inguinal and popliteal lymph nodes and adjacent lymphatic vessels, followed by radiotherapy of the right groin with a single dose of 15 Gy. Four weeks after irradiation, the animals were examined with MRI of both hind legs. Fluid volumes around the joint line of the knee were calculated on T2-weighted images. We documented a significant higher volume of fluid in the legs following excision of lymph nodes and lymphatic vessels, combined with radiotherapy than in control legs.

Aim: Imaging of the lymphatic system is critical in preoperative planning of resections of complex lymphatic malformations. However, safe, effective imaging methods with sufficient resolution to identify the lymphatics have been lacking. In this study, we demonstrate the use of gadolinium-labeled dendrimers to image the lymphatics in small and large animal models during magnetic resonance lymphangiography., Methods: Polyamidoamine G6-Gd_1B4M_N-hydroxysuccinimide was synthesized and administered intradermally in the extremities of normal mice and pigs at several doses., Results: The lymphatics were well demonstrated in both animal models and there was rapid uptake in the deep lymphatic system, including the thoracic duct. A significant dose reduction was achieved (1 µmol Gd/kg) in the 35-kg pig compared with mice, while still producing excellent results. No toxicity was observed and only minor inflammatory changes were observed at the injection site 30 days later., Conclusion: We demonstrate that a low dose of a macromolecular magnetic resonance contrast agent can provide rapid imaging of the deep lymphatic system in both small and large animals. This data provides a basis to consider a similar agent in clinical trials.

Background: Immunological unresponsiveness of T cells to alloantigen can be induced by intrathymic injection of donor-specific antigen in small-animal models. Intrathymic tolerance to vascularized grafts in large animals has not previously been reported., Methods: Thirty-two dogs were allocated into dog leukocyte antigen DP locus allele (class II)-matched donor-recipient pairs. Female recipients were paired with male donors. Tissue typing was based on restriction fragment length polymorphism. Recipients were given 18 Gy total lymphoid irradiation in 16 fractions (1.125 Gy each) over 4 weeks. Thoracotomy after the 6th fraction permitted perithymic (n=4) or intrathymic (n=4) injection of donor bone marrow (BM) or intrathymic injection of saline (n=5). Another group received intravenous peripheral BM infusion (n=3). Fifty days postthoracotomy recipients underwent bilateral nephrectomy and donor-specific kidney transplantation. Acute rejection, suspected when serum creatinine was more than 600 mumol/L or urea was more than 40 mmol/L, was confirmed histologically. Full-thickness skin grafts followed more than 100 days posttransplantation. Tissue samples were taken for Y-chromosome polymerase chain reaction., Results: One intrathymic (25%) and three perithymic (75%) BM recipients developed tolerance to renal allografts. Three intrathymic BM recipients rejected after 27, 32, and 54 days and one perithymic BM recipient rejected after 42 days. All recipients given peripheral BM or saline had rejected by 29 and 38 days, respectively. All recipients surviving more than 100 days posttransplantation, accepted donor specific and rejected dog leukocyte antigen-DP locus allele (class II) identical third-party skin grafts. Polymerase chain reaction detected intrathymic but not hematopoietic chimerism in sex-mismatched pairs., Conclusions: Fractionated total lymphoid irradiation and perithymic or intrathymic donor-specific BM induced tolerance to renal and skin allografts without inducing hematopoietic chimerism.

Purpose: Sentinel lymph node biopsy (SNB) has been a standard technique in early breast cancer. However, it is not clear that the SNB procedure can be applied to second breast cancer or recurrence occurring in the previously treated breast. The purpose of this study was to clarify the feasibility of the SNB procedure in breast cancer occurring in the previously treated breast, and to investigate the factors related to altered lymphatic flow., Patients and Methods: Between April 2004 and December 2006, 1490 patients underwent the breast SNB procedure. Among them, 31 patients had a history of previous treatments in the same breast. Recent excision biopsy cases were not included in this group. All patients had previous breast-conserving surgery in the same breast. Sixteen patients had axillary dissection, 3 had SNB, and 12 had no axillary treatment. Ten patients had received radiation therapy to the breast and axilla. Visualization of axillary nodes, internal mammary nodes and contralateral axillary nodes was evaluated and compared with pathological results., Results: Axillary nodes were visualized in 23 patients, internal mammary nodes in 7 patients, and contralateral axillary nodes in 7 patients. The patients with previous axillary dissection exhibited altered lymph node distribution, but did not show involvement of contralateral axillary nodes. Visualization of contralateral axillary nodes occurred in 7 of the 10 patients with previous irradiation to breast irrespective of axillary dissection. Twenty-eight patients underwent SNB, 4 of whom showed cancer-positive nodes. Three patients were cancer-positive in non-ipsilateral axillary nodes (one patient showed positive opposite axillary node and two patients showed positive internal mammary nodes)., Conclusion: Previous axillary dissection or irradiation to the breast greatly influences lymphatic flow. Irradiation to the breast may be a strong factor for the visualization of contralateral axillary nodes. Despite the frequent alteration of lymphatic flow, SNB seems to be feasible in secondary or recurrent breast cancer patients.

Objective: To determine the effects of very weak, extremely low frequency (50 Hz) electromagnetic field (ELF-EMF) on the relative spleen weight, lymphoid organ histology, peripheral blood leukocyte and alpha-naphthyl acetate esterase positive (ANAE- positive) lymphocyte percentages of the mouse., Methods: The study was carried out in Scientific Research and Application Center of Selcuk University, Konya, Turkey in 2005. A total of 120 Swiss albino mice were divided into 6 groups (20 in each group). The experimental animals were exposed to 1, 2, 3, 4 and 5 microT flux intensities (rms) of EMF at 50 Hz for 40 days., Results: In the exposure groups with 20 animals, the body weight (BW) increased gradually in higher field intensities and reached at peak level in the 4 microT, and then slightly decreased. The relative spleen weight (% of the BW) was not affected. The ELF-EMF treatment did not cause any significant change in lymphocyte, monocyte and ANAE-positive lymphocyte ratios, whereas percentages of neutrophils and basophiles changed non-linearly. Any change in the lymphoid organ histology, which is attributable to the field effect, was not observed in the exposure groups., Conclusion: Extremely low frequency-EMF exposure with the flux intensities between 1-5 microT for 40 days did not cause any effect on the relative spleen weight, lymphoid organ histology, leukocyte and ANAE-positive lymphocyte percentages of the mouse.

Retrospective dosimetry for radiologic and nuclear medicine examinations has been a challenge both for individual patients and in epidemiologic studies. Methodological problems include the large range of patient exposures from radiologic examinations, which spans over three orders of magnitude, the considerable dose reduction over time for most types of examinations due to technical advancements, and the increasing concern for radiation protection and quality issues in radiologic practice. A three-step model for retrospective dosimetry for patient exposure is presented that allows determination of organ doses to the red bone marrow and the lymphatic tissue, respectively, for typical examinations over the time period 1946-1995. The model starts from a set of doses assuming ideal technical equipment and radiologic practice. Step II considers the advancement of technical equipment over the different decades since the introduction of medical radiology in the early 1940's. Step III refers to quality in radiologic routine and allows for adjustment for less-than-ideal standards of radiologic practice. Model parameters are derived from contemporary literature and a multitude of historical sources. Tables with reference data are provided that allow a straightforward application of the model in the context of analytic epidemiologic studies. Wherever possible, reference doses are based on dose area product to allow for easy adjustment to different settings and inclusion of prospective data. The model and the results can be readily extended to different countries with different technical advancement and standard of radiologic practice.

The aim of this study was to investigate the breast lymph circulation and skin blood circulation after radiotherapy and breast conservation. In 23 patients who had undergone lumpectomy for breast cancer (mean age 58 years, range 44-75) and 12 patients with lumpectomy for benign lesions (mean age 51 years, range 33-72), lymph circulation in the breast was measured by 99mTc-nanocolloid clearance and skin circulation by Laser Doppler Fluxmetry (LDF). Measurements were made 2-5 years after radiotherapy (50 Gy) in the former group and at a corresponding time in the latter. The lymph circulation was measured 2 cm above and medial or lateral to the areolar border in the quadrant not operated on for carcinoma. Skin circulation was measured at corresponding sites. The lymph circulation expressed as the ratio of 99mTc-nanocolloid clearance in the operated irradiated to that in the non-operated (radiation 2-4 Gy) breast was 2.33 (2.66) (median, interquartile range) (p value 0.01) and the skin circulation ratio over the corresponding area was 0.92 (0.21). Corresponding ratios in the non-radiotherapy group were 2.07 (1.96) (p value 0.03) and 1.04 (0.18) respectively. Compared with the control breast (i.e., the non-operated non-irradiated breast), there was a 4-fold increase in lymph flow in the operated, irradiated breast, a 2.5-fold increase in the contralateral non-operated (2-4 Gy) breast and a 1.5-fold increase in the operated non-irradiated breast. Radiotherapy after breast conservation surgery leads to increased long-term changes in basal lymph circulation and smaller increases in lymph flow in the contralateral breast receiving 2-4 Gy and after surgery. If maximal lymph transport capacity is unchanged, edema may be more likely in this circumstance of reduced lymphatic transport reserve.

Background: We evaluated the role of total lymphoid irradiation (TLI) in the management of refractory rejection among pediatric heart transplant patients., Methods: Eleven of 298 patients underwent TLI at 6 to 195 months of age and were divided into subgroups: those who survived (group A, n = 7) and those who did not survive beyond 1 year after TLI (group D, n = 4). Non-TLI recipient data were considered as the controls., Results: Six out of 11 patients died eventually (54%). TLI was initiated 3 to 107 months after transplantation with a dosage of 600 to 840 cGy. The pre-TLI rejection rate (0.62 +/- 0.40 per month) was higher (p < 0.0001); however, the post-TLI rejection rate (0.24 +/- 0.65 per month) showed no significant difference from the control rejection rate. The Cox proportional hazard model found significance for TLI as a risk factor for development of posttransplant coronary artery disease (relative risk, 4.8; 95% CI, 1.1 to 21.3) and posttransplant lymphoproliferative disease (relative risk, 47.9; 95% CI, 1.6 to 1,475.3), respectively. Although the rejection rate decreased after TLI in both groups (group A pre/post, 0.51 +/- 0.31/0.06 +/- 0.08 per month; group D pre/post, 0.82 +/- 0.49/0.57 +/- 1.09 per month), significance was obtained only in group A (p = 0.018)., Conclusions: TLI was an effective adjunct for reversal of refractory rejection in pediatric heart transplantation by reducing the rejection rate. Great care must be taken for the risk of development of coronary artery disease or lymphoproliferative disease.

Background: An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern., Methods: Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days; postoperative irradiation consisted mostly of 15 x 2 Gy (range, 20-40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature., Results: Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter p(a) was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate p(a) remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same (p(a)=10-14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively)., Discussion: Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae., Conclusions: There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

Background: In the literature there is some evidence that the incidence of metastases may increase after radiation treatment., Methods: In order to investigate whether radiation-induced changes in the lymphatic drainage may alter the rate of lymph node metastasis, the center part of the left hind foot of rats was irradiated with a dose of 1 x 55 Gy before inoculation of tumor cells into the irradiated part of the footpad at different time intervals. Cells of 2 different tumor lines were employed. A rarely metastasising rhabdomyosarcoma, R-1, to look for a possible enhancement of lymphatic metastases, and a readily metastasising mammary carcinoma, Cl-2, in case of a possible decrease in the rate of lymphatic metastasis from tumors growing in pre-irradiated footpads., Results: The incidence of regional lymph node metastasis decreased for R-1 tumors growing in pre-irradiated footpads, but not for Cl-2 tumors. Furthermore, the average time required for lymph node metastasis to attain a reference volume of 100 mm3 is not significantly influenced by pre-irradiation of the footpad. No difference was observed in average times for doubling in volume of lymph node metastases originating from primary tumors in pre-irradiated footpads. Abscopal effects after footpad irradiation may cause a 50-fold increase in size of regional lymph nodes and, therefore, histological examination is essential for verification of lymph node metastases., Conclusions: Damage to the lymphatic system to be expected in the irradiated footpad did not enhance the incidence of regional metastasis of R-1 tumors. A reduced rate of lymphatic metastasis contradicts earlier findings of enhanced lymphatic metastasis development of R-1 tumors, growing in pre-irradiated gastrocnemius muscles. The influence of irradiation on regional metastasis formation seems to be "tumor bed" dependent for R-1 tumors.

Ultraviolet (UV) irradiation of the skin induces complex local and systemic immunomodulatory reactions. The biological effects of UV irradiation on human skin derived afferent lymph however are unknown. The aim of this study was to examine the effects of a single combined UV-A and UV-B irradiation with 1 minimal erythema dose (MED) on human skin derived lymph in vivo. After cannulation of a superficial lymph vessel on the lower leg, lymph flow and cell output per hour were determined before and for 6 days after UV irradiation of the lymph draining skin area in 5 volunteers. Furthermore, expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells and cytokine levels (IL-1alpha, IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-13, TNF-alpha and IFN-gamma) in the afferent lymph were analyzed by cytofluorometry and ELISA. After UV irradiation a small initial enhancement in the daily lymph flow per hour was noticed in correlation with the slight erythematous skin reaction. Following resolution of the skin reaction, a delayed increase in cell output in correlation with an additional peak in the lymph flow was found between the 4th and 6th day after UV irradiation. However, no changes in the expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells were detectable. Interestingly, in parallel to the increased lymph flow and cell output, only elevated IL-8 protein levels were reproducibly detected in the afferent lymph after UV irradiation. Furthermore, using immunohistochemistry positive staining for IL-8 was found on migrating mononuclear lymph cells. In conclusion, our data demonstrate that a single UV irradiation of the skin with 1 minimal erythema dose leads to a delayed enhancement of lymph flow, number of migrating lymph cells and cytokine levels of IL-8. Moreover, we provide evidence that migrating lymph cells, besides resident epidermal and dermal cells, may contribute to the detected levels of IL-8 in the afferent lymph.

This study was conducted to evaluate the influence of subchronic exposure to pure, linearly polarized 60-Hz magnetic fields (MF) on the host immune response in mice. The experimental design was as follows: three groups were exposed continuously (18.5 hr/day) to MF at field strengths of 0.02, 2, or 10 gauss (G), one group was exposed intermittently (1 hr on/1 hr off) to MF at a field strength of 10 G, and one group served as a sham control. Experimental endpoints included spleen and thymus weights and cellularity, antibody-forming cell (AFC) response, delayed-type hypersensitivity (DTH) response, splenic lymphocyte subset analysis, susceptibility to infection with Listeria monocytogenes, and natural killer (NK) cell activity. No differences in body weight, lymphoid organ weight, or lymphoid organ cellularity were observed in any MF-exposed group in comparison to sham controls. Likewise, no statistically significant differences were found in comparisons of AFC responses. Isolated statistically significant differences from control were observed in MF-exposed mice in the DTH assay, although no clear dose-related pattern of altered activity was seen. Splenic lymphocyte subset parameters examined were within normal limits in all groups, and no differences between control and MF-exposed mice were found. Host resistance to bacterial infection was not altered at any MF exposure examined in this study. Finally, although apparently dose-related, statistically significant alterations were observed in an initial study of NK cell function, repeat studies failed to demonstrate a consistent pattern of alteration.

Three successive generations of CFW mice were exposed to a 25-mT (250,000 mG), 60-Hz electromagnetic field for prolonged periods. At the end of the exposure period, animals from both the exposed and control groups were sacrificed for tests. A complete autopsy was performed and tissue sections were taken from the main organs for histopathological examination. The results from the pathological findings in the various animals were classified under the following categories: (1) normal; (2) lymphoid hyperplasia; (3) premalignant changes; (4) early lymphoma; (5) advanced lymphoma. The three first-generation animals developed generalized lymphoid hyperplasia. In the second-generation animals, 5% developed premalignant changes, and 15.8% had lymphoid hyperplasia. In addition, 4 female mice left in the field for 418 days developed malignant lymphoma. In the third-generation animals, 58% developed premalignant changes or malignant lymphoma. An additional 30% had lymphoid hyperplasia. Statistical analysis of the data using the Mantel-Haenszel test for the difference in the prevalence of lymphoma between the exposed and control groups shows a very significant difference for the male groups (P < 0.001), the female groups (P < 0.001), and all animals combined (P < 0.001). The results suggest a cause-effect relationship between chronic exposure to very strong 60-Hz magnetic field for prolonged period and the development of malignant lymphoma in CFW mice.

Radiotherapy is a useful tool in the treatment of head and neck cancer either in an adjuvant or in a palliative setting. The tolerance doses of many tissues are near or even lower than the necessary therapeutic doses. Therefore some side effects of radiotherapy are unavoidable, others can be reduced if special technics are applied. Lymphedema of the head and neck is more often caused by radical surgery than by radiotherapy. If a combined modality treatment is used with surgery and radiotherapy, it results in an increased risk of lymphedema. If lymphedema results from radiotherapy it is caused by the late reaction of blood vessels and connective tissue within the irradiation field. Direct irradiation effects on lymphatic vessels are less important. Finally we stated four rules for the practical management of patients with visible lymphedema or the risk of developing an edema.

The efficacy of transmission block technique with contiguous photon irradiation of inguinal as well as pelvic and perineal structures has been reported in literature. In this paper, a simple and accurate method for the proper fabrication of transmission block has been described and also demonstrated to be effective and useful. The procedures for a precise geometrical alignment and dose verification are also detailed.

In order to assess the effects of irradiation on lymphatic function, the contraction frequency and maximum and minimum diameters of guinea pig mesenteric collecting lymphatic vessels were measured in vivo 4 hours after 1000 rads of abdominal irradiation. The mean contraction frequency for lymphatics from irradiated guinea pigs (7.6 +/- 0.7) was significantly higher than for normals (non-irradiated) (4.7 +/- 0.7) during an initial control observation period, but there was no difference in maximum or minimum diameter between the two groups during this period. Topical application of 10(-4) M noradrenaline (NA) significantly increased contraction frequency in both groups; lymph vessel diameter significantly decreased after NA in irradiated, but not in normal guinea pigs. Intravenous infusion of calcium dobesilate (200 mg/kg) caused a significant increase in the contraction frequency of lymphatic vessels in both normal (to 9.4 +/- 1.5) and irradiated (to 9.8 +/- 1.2) animals, but diameter was not significantly altered. Thus, lymphatic vessels from irradiated guinea pigs were still responsive to exogenous stimuli 4 hours post-irradiation and were initially pumping more actively than those from normal guinea pigs, presumably in response to radiation-induced edema. They also exhibited a supersensitivity to the vasoconstrictive effects of NA, perhaps due to an alteration of the pacemaker or smooth muscle cells by irradiation.

Three-day rat pups were X-irradiated (5 Gy) and killed on days 3-4, 6-7, and 10-11. Using the microscopic, histological and morphometric methods it was found that the microcirculation channel was damaged to a greater extent than the hemocirculation one. This was followed up during the radiation sickness. The pathological changes were more pronounced in all structures of the derma papillary layer than in those of the reticular layer. Oedema and reduced cellularity were noted in the connective frame.

Albino female rats were exposed to X radiation (5 Gy, 180 kV, 10 mA, filter 0.5 mm Cu) on days 10-15 of pregnancy. After 3 and 7 days they were sacrificed (under ether anesthesia) and fetuses were extracted. The status of the lympho- and hemomicrocirculatory beds (LMCB and HMCB) of the fetus back skin was studied by the macro- and microscopic methods. As early as day 3 of radiation sickness the diameter of LMCB vessels increased by 1.4-1.9 times, whereas changes in GMCB were less pronounced. On day 7, there was a progressive increase in dilatation of LMCB vessels, alongside with the narrowing of large units (arteries and veins). The development of the connective framework of the fetus skin was retarded.

The most important results of the morphological research of the lymphatic system of the larynx with surrounding tissues were presented. Based on section specimens of larynx the topography of the lymphatic system was described. We also described changes in the lymphatic system after radiation and after manifestation of squamous cell carcinoma in this region. We concluded that the main causes of our clinical adversities in treatment of larynx cancer were lymphatic stasis, cancer embolism of small nodes between mucosa and deep lymph nodes of the neck. We also studied over the methods of intravital examinations of the neck's lymphatic system.

The early and late effects of X rays on lymphatic microcirculatory function have been investigated in pig skin. Paired estimates of lymph clearance were performed in irradiated and unirradiated sites on the flank skin of anaesthetized Large White pigs at 3, 6, 9, 12, 26, 39, 52, 64 and 78 weeks after a single dose of 18 Gy of X rays. The dermal clearance of 99Tcm-colloid was used to assess lymph flow. The results demonstrated two waves of impaired lymphatic clearance which correlated well with the gross morphological changes observed. The first wave occurred between 6 and 12 weeks after irradiation and corresponded to a period of ischaemia and oedema. The second wave, at 52 weeks, corresponded with dermal thinning and subcutaneous atrophy. X irradiation resulted in an impairment of lymph drainage both within and outside the field of irradiation. Impaired lymphatic drainage probably contributes to the gross and histological changes observed in the skin after X irradiation.

Morphofunctional state of the lymphatic bed of the conjunctiva has been studied under effect of ultraviolet radiation. A comparative characteristics of development of the clinical picture and morphological criteria of the harmful effect of the ultraviolet radiation is presented. When all clinical symptoms disappear, there is no complete restoration of the capacitance function of the lymphatic vessels and intracellular regeneration of ultra-microscopical structures of endotheliocytes.

After 60Co irradiation of rat spleen, the most severe damage was found initially in the lymph follicles (LFs); lymphocytes were decreased in number in the periarteriolar lymphoid sheath (PALS), and almost completely depleted in the marginal zone (MZ). Recovery was observed first in the PALS, followed by the LFs, and finally the MZ. From the results of immunohistochemistry, the process of recovery was assumed to involve migration of T and B lymphocytes along the arterioles from the area surrounding the terminal arteriole at the end of the PALS into the central part of the PALS and into the LF. Peripheral blood IgM+, IgD- B lymphocytes, known to be MZ precursor cells, flowed from the follicular artery to settle in the MZ. Furthermore, recovery of the PALS prior to the LFs was suggested to be essential for lymphocyte migration to the LFs.

Of the various forms of radiation injury resulting from irradiation several reactions are important in lymphology since they respond well to manual lymphatic drainage according to Vodder-Asdonk, to surgery or to fibrosis stretching. In acute and sub-acute radiation injury there is usually transient inflammatory swelling, e.g. in the extremities, and radiogenic oedema of the breast which reacts favourably to manual lymphatic drainage. Late sequelae such as ulcerating radiodermatitis and lymphatic oedema may be improved by manual lymphatic drainage or surgery as well as radiogenic fibrosis which is treated with intensive but careful stretching which may, in part, prevent further plexus injury.

The article deals with the results of ultrasonic examination (USE) of 39 patients with secondary edema of the lower extremities. The authors developed a USE method which yields objective data characterizing changes of the structure, thickness, boundaries, and firmness of the soft tissues in lymphedema of the lower extremities of various severity. It was established that lymphostasis produced a characteristic ultrasonic pattern, which, as claimed by the author, may be used in differential diagnosis of lymphatic and venous edema of the extremities.

The use of allogeneic thymus transplantation as a means of inducing tolerance across MHC barriers was investigated in thymectomized, total lymphoid irradiated BALB/c mice. In 90% of the animals long term outgrowth of histologically normal C57BL thymus grafts was observed. None of the latter animals was chimeric. All thymus graft-bearing mice showed specific nonresponsiveness for C57BL MHC Ag in mixed lymphocyte reaction and cell-mediated lympholysis. Spleen cells of the C57BL thymus-bearing mice were unable to induce lethal graft-vs-host disease in neonatal (BALB/c X C57BL) F1 mice but provoked a vigorous graft-vs-host disease reaction in (BALB/c x C3H) F1 neonates. Tolerant mice permanently accepted C57BL heart and pancreas grafts, but all rejected C3H grafts. Induction of tolerance of BALB/c pre-T cells through allogeneic thymus graft and/or specific suppressor cells seems to be involved. The present model offers new opportunities to study thymocyte maturation in a fully allogeneic environment and may yield applications for clinical organ transplantation.

We have investigated the efficacy of standard conditioning regimens for bone marrow transplantation in depleting functional T lymphocytes in vivo and have compared it with the efficacy of the monoclonal antibody Campath-1G. Using limiting dilution techniques the frequencies of proliferating T cell precursors (PTL), cytotoxic T cell precursors (CTL-p), helper T cell precursors (HTL-p), and mature helper T cells (HTL) were determined before and after treatment. Both total body irradiation and combination chemotherapy with busulfan/cyclophosphamide were highly efficient at depleting PTL, CTL-p, and HTL-p (0-4 days) but spared HTL to a variable extent (0-99.5%). In the majority of patients treated with Campath-1G a similar degree of PTL, CTL-p, and HTL-p depletion was achieved, and, in addition, HTL were effectively removed (greater than 95.5%). These results suggest that Campath-1G could be successfully employed in depleting radio- and chemotherapy-resistant host T lymphocytes prior to T-depleted bone marrow transplantation.

The addition of 3M KCl-extracted donor antigen (HAg) to immunosuppressive therapy with 16 Gy total lymphoid irradiation produces a significantly higher fraction of Wistar-Furth (WFu) recipients displaying indefinite survival of heterotopic buffalo (BUF) heart allografts, namely 80 versus 20%. The experiments presented herein analyzed the direct activity as well as estimated the potential precursor numbers at 1 and 3 months in treated recipients. At 1 month post-TLI/HAg therapy, recipients showed reduced proliferative responses in mixed lymphocyte reactions (MLR) in a specific pattern toward donor but not third-party stimulators. Both TLI/Graft and TLI/HAg/Graft groups showed a higher frequency of BUF antigen-directed T-cytotoxic cells (fTc) than TLI-treated, but nontransplanted, WFu hosts. In addition, the TLI/HAg group alone displayed alloantigen-specific suppressor cells that suppressed the MLR proliferative responses of normal spleen T cells against donor, but not third-party, alloantigens. At 3 months postirradition, both TLI/Graft and TLI/HAg/Graft groups displayed variable MLR proliferative responses toward donor and third-party alloantigens. Whereas nontransplanted, TLI-treated WFu rats recovered their fTc to normal levels at 3 months, the TLI and TLI/HAg treated recipients bearing functional heart allografts demonstrated significantly decreased splenic fTc. These results show that reduced numbers of cytotoxic cell precursors may afford more reliable indices of prolonged heart allograft survival than MLR responses. The observations suggest that TLI/HAg transplant hosts display both reduced cytotoxic precursors and activated suppressor elements.

The course and prognosis of radiation myelopathies are determined by 3 factors; the segmental (vertical) location of the lesion, the extent of the transverse syndrome (complete or incomplete) and the radiation dose. The median spinal dose in cervical radiation myelopathies with fatal outcome was higher than in survivals with an incomplete transverse syndrome. In thoracic radiation myelopathies a dose difference between complete and incomplete transverse syndromes could be found as well. Incomplete transverse syndromes as submaximum radiation injuries are more suitable for the determination of the spinal tolerance dose than complete transverse syndromes. The lowest threshold could be stated for cases following high-volume irradiation of the lymphatic system.

The influence of single dose and fractionation on the immunosuppressive effect of a total lymphoid irradiation (TLI) was investigated by experimentation on animals and compared to literature. Lewis rats were irradiated with a constant temporal dose distribution. The weekly dose of 7,0 Gy was fractionated into 1 X 7,0 Gy, 2 X 3,5 Gy and 7 X 1,0 Gy, with rising total doses. The survival time of cutaneous allografts served as parameter for the immunosuppression; the toxicity of the treatment was related to the immunosuppressive effect. Immunosuppression as well as toxicity showed differences depending on fractionation. For both criteria, the fractionation of 2 X 3,5 Gy per week had better results. The validity of the Ellis formula for the immunosuppression induced by total lymphoid irradiation was restricted.

Neonatal cardiac allograft survival was examined in mice treated with anti-L3T4 antibody, posttransplantation total lymphoid irradiation (TLI) or a combination of both therapies. Independently, both posttransplantation TLI and short-course antibody treatment allowed minimal prolongation. However, synergistic prolongation in graft survival was observed with the combination (synergistic) therapy. Fluorescence-activated cell sorter analysis of peripheral blood lymphocytes from animals treated with combined anti-L3T4 and posttransplantation TLI additionally revealed "synergy" with respect to the degree of peripheral lymphocyte depletion.

Large lung sections of humans of advanced adult age revealed a markedly nonuniform retention pattern of dense anthracotic particle aggregates, with an impressive accumulation of this material along pulmonary lymphatics, i.e. the deep (peribronchial), septal (perivenous) and superficial (pleural) networks. Conversely, the alveolar parenchyme contained only occasional, small aggregates of macrophages heavily loaded with carbon, representing little more than 2% of this material in lung tissue. Although translocation kinetics of anthracotic particles cannot readily be compared to those of highly toxic alpha-emitting, poorly soluble radionuclides such as 239PuO2, lymphatic drainage of the latter over the years may also be expected to lead to a concentration of radioactive material along lymph vessels. Since human data on the effects of inhaled 239PuO2 are virtually lacking, the above distribution pattern is apt to help in identifying cells and other tissue components most heavily at risk. Findings are also relevant to the problem of "hot spot" formation in vivo and its possible sequelae. The latter are briefly discussed with regard to both stochastic and non-stochastic effects.