Breast carcinoma during pregnancy. International recommendations from an expert meeting.
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Breast Neoplasms↗
Biomedical subjects
Henk B Kal
Publications and source records attributed to Henk B Kal.
Renal dysfunction after total body irradiation: dose-effect relationship.
PURPOSE: Late complications related to total body irradiation (TBI) as part of the conditioning regimen for hematopoietic stem cell transplantation have been increasingly noted. We reviewed and compared the results of treatments with various TBI regimens and tried to derive a dose-effect relationship for the endpoint of late renal dysfunction. The aim was to find the tolerance dose for the kidney when TBI is performed. METHODS AND MATERIALS: A literature search was performed using PubMed for articles reporting late renal dysfunction. For intercomparison, the various TBI regimens were normalized using the linear-quadratic model, and biologically effective doses (BEDs) were calculated. RESULTS: Eleven reports were found describing the frequency of renal dysfunction after TBI. The frequency of renal dysfunction as a function of the BED was obtained. For BED>16 Gy an increase in the frequency of dysfunction was observed. CONCLUSIONS: The tolerance BED for kidney tissue undergoing TBI is about 16 Gy. This BED can be realized with highly fractionated TBI (e.g., 6x1.7 Gy or 9x1.2 Gy at dose rates>5 cGy/min). To prevent late renal dysfunction, the TBI regimens with BED values>16 Gy (almost all found in published reports) should be applied with appropriate shielding of the kidneys.
Hematopoietic Stem Cell Transplantation↗
Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation.
BACKGROUND AND PURPOSE: Total-body irradiation (TBI) is an important part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The results after treatment with various TBI regimens were compared, and dose-effect relationships for the endpoints relapse incidence, disease-free survival, treatment-related mortality, and overall survival were derived. The aim was to define requirements for an optimal treatment schedule with respect to leukemic cell kill and late normal-tissue morbidity. MATERIAL AND METHODS: A literature search was performed. Three randomized studies, four studies comparing results of two or three TBI regimens, and nine reports with results of one specific TBI regimen were identified. Biologically effective doses (BEDs) were calculated. The results of the randomized studies and the studies comparing results of two or three TBI regimens were pooled, and the pooled relative risk (RR) was calculated for the treatments with high BED values versus treatments with a low BED. BED-effect relationships were obtained. RESULTS: RRs for the high BED treatments were significantly lower for relapse incidence, not significantly different for disease- free survival and treatment-related mortality, and significantly higher for overall survival. BED-effect relationships indicate a decrease in relapse incidence and treatment-related mortality and an increase in disease-free and overall survival with higher BED values. CONCLUSION: "More dose is better", provided that a TBI setting is used limiting the BEDs of lungs, kidneys, and eye lenses.
Confidence Intervals↗
Why to start the concomitant boost in accelerated radiotherapy for advanced laryngeal cancer in week 3.
PURPOSE: We analyzed toxicity and the local control rates for advanced laryngeal cancer, treated with two accelerated fractionation schedules. The main difference between the schedules was the onset of the concomitant boost, in Week 3 or Week 4. Overall treatment time and total dose were equivalent. METHODS AND MATERIALS: In a prospective, nonrandomized study of T3, T4, and advanced T2 laryngeal cancer, concomitant boost schedules were used in 100 patients. Thirty patients received a schedule of twice daily 1.2 Gy in Weeks 1-3, followed by twice daily 1.7 Gy in Weeks 4 and 5; total dose was 70 Gy (the hyperfractionated accelerated schedule [HAS] regimen). Seventy patients were treated with 5 times 2 Gy in Weeks 1 and 2, followed by daily 1.8 Gy and 1.5 Gy (boost) in Weeks 3-5; total dose 69.5 Gy (the accelerated schedule only [ASO] regimen). Distribution of T stage was 47%, 40%, and 12% for T2, T3, and T4, respectively. In 24% of the patients, lymph nodes were positive. Pretreatment tracheotomy or stridor or both occurred in 8 patients. The distribution of prognostic factors was not significantly different between the two fractionation schedules. Acute and late toxicity was assessed. Results were estimated by the use of actuarial methods. For late toxicity and local control univariate and multivariate analyses were performed. Tumor control probability analysis was used to model cure rate differences. RESULTS: Overall acute mucositis score was equal for both schedules. Acute mucositis started and decreased significantly earlier in the HAS regimen. In all patients acute mucositis healed completely. The treatment was completed within 38 days in all patients. The regional control rate was 100% for clinical N0, and 75% for the clinical N+ patients. The 3-year local control rate was 59% and 78% for the HAS and ASO regimens, respectively (p = 0.05); the ultimate local control was 80% and 94%, respectively. In multivariate analysis, besides the fractionation schedule (relative risk [RR], 2.6 for HAS vs. ASO), pretreatment tracheotomy/stridor (RR 4.3, yes vs. no), and local tumor response 3-6 weeks after radiotherapy (RR 5.1, no vs. yes) were independent factors for local control. Tumor control probability analysis indicated that the onset of repopulation may be about 4-6 days earlier for the HAS regimen. The onset of repopulation in the HAS regimen is probably at the end of the second week or at the beginning of the third week. Severe late toxicity was observed in the HAS group and ASO group in, respectively, 11% and 16%. In multivariate analysis this toxicity related significantly to the field size and pretreatment tracheotomy/stridor. CONCLUSIONS: In our study the timing of the boost in accelerated radiotherapy for advanced laryngeal cancer was an independent factor for local control, favoring the use of a concomitant boost in Week 3. This finding may indicate that accelerated repopulation of tumor cells starts early in the treatment phase.
Adult↗
Biologically effective doses of postoperative radiotherapy in the prevention of keloids. Dose-effect relationship.
PURPOSE: To review the recurrence rates of keloids after surgical excision followed by radiotherapy, and to answer the question whether after normalization of the dose, a dose-effect relationship could be derived. MATERIAL AND METHODS: A literature search was performed to identify studies dealing with the efficacy of various irradiation regimens for the prevention of keloids after surgery. Biologically effective doses (BEDs) of the various irradiation regimens were calculated using the linear-quadratic concept. A distinction between recurrence rates of keloids in the face and neck region and those in other parts of the body was made. RESULTS: 31 reports were identified with PubMed with the search terms keloids, surgery, radiation therapy, radiotherapy. 13 reports were excluded, because no link could be found between recurrence rate and dose, or if less than ten patients per dose group. The recurrence rate for surgery only was 50-80%. For BED values > 10 Gy the recurrence rate decreased as a function of BED. For BED values > 30 Gy the recurrence rate was < 10%. For a given dose, the recurrence rates of keloids in the sites with high stretch tension were not significantly higher than in sites without stretch tension. CONCLUSION: The results of this study indicate that for effectively treating keloids postoperatively, a relatively high dose must be applied in a short overall treatment time. The optimal treatment probably is an irradiation scheme resulting in a BED value of at least 30 Gy. A BED value of 30 Gy can be obtained with, for instance, a single acute dose of 13 Gy, two fractions of 8 Gy or three fractions of 6 Gy, or a single dose of 27 Gy at low dose rate. The radiation treatment should be administered within 2 days after surgery.
Brachytherapy↗
Radiotherapy during pregnancy: fact and fiction.
Radiotherapy during pregnancy might cause harm to the developing fetus. Generally, pregnant women with malignant diseases are advised to delay radiotherapy until after delivery. However, this advice is not based on knowledge of the risks of radiation to the unborn child. In general, the expected radiation effects, such as mental retardation and organ malformations probably only arise above a threshold dose of 0.1-0.2 Gy. This threshold dose is not generally reached with curative radiotherapy during pregnancy, provided that tumours are located sufficiently far from the fetus and that precautions have been taken to protect the unborn child against leakage radiation and collimator scatter of the teletherapy machine; such precautions also reduce the risk of radiation-induced childhood cancer and leukaemia in the unborn child.
Abortion, Induced↗
Prevention of pterygium recurrence by postoperative single-dose beta-irradiation: a prospective randomized clinical double-blind trial.
PURPOSE: To affirm the effectiveness and complication rate of postoperative single-dose beta-irradiation (RT) with (90)Sr in the case of primary pterygium in a clinical trial. Pterygium is a benign disease of the supporting orbital tissue that can cause impairment of visual function. Depending on the technique used for surgery, recurrence is described in up to 70% of cases-a reason to combine the initial treatment with radiotherapy or chemotherapy. METHODS AND MATERIALS: This trial was designed as a prospective, randomized, multicenter, double-blind study. Surgery was performed in all cases according to the bare sclera technique. Ninety-one patients with 96 pterygia were postoperatively randomized to either beta-RT or sham RT. In the case of beta-RT, a (90)Sr eye applicator was used to deliver 2500 cGy to the sclera surface at a dose rate of between 200 and 250 cGy/min. Sham RT was given using the same type of applicator without the (90)Sr layer. After treatment, both an ophthalmologist and a radiation oncologist performed the follow-up examinations. The accumulated data were analyzed using a group sequential test. RESULTS: Between February 1998 and September 2002, 96 eyes with primary pterygium were operated on according to the trial protocol. Additional treatment was performed within 24 hours postoperatively. Ten patients were lost to follow-up, resulting in 86 patients who could be analyzed. In the 44 eyes randomized to receive beta-RT, 3 relapses occurred compared with 28 recurrences in the 42 eyes that received sham RT, for a crude control rate of 93.2% vs. 33.3%, respectively. At a mean follow-up of 18 months, major treatment complications had not been observed. CONCLUSION: Single-dose beta-RT after bare sclera surgery is a simple, effective, and safe treatment that reduces the risk of primary pterygium recurrence.
Adult↗
Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA.
AIM: To determine whether radiation combined with Trans-4-AminoMethyl Cyclohexane carboxylic Acid (AMCA, or tranexamic acid, Cyklokapron) results in a better tumor response than radiation alone. MATERIALS AND METHODS: We evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. RESULTS: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. CONCLUSION: The enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types.
Angiogenesis Inhibitors↗
Ataxia telangiectasia mutated expression and activation in the testis.
Ionizing radiation (IR) and consequent induction of DNA double-strand breaks (DSBs) causes activation of the protein ataxia telangiectasia mutated (ATM). Normally, ATM is present as inactive dimers; however, in response to DSBs, the ATM dimer partners cross-phosphorylate each other on serine 1981, and kinase active ATM monomers are subsequently released. We have studied the presence of both nonphosphorylated as well as active serine 1981 phosphorylated ATM (pS1981-ATM) in the mouse testis. In the nonirradiated testis, ATM was present in spermatogonia and spermatocytes until stage VII of the cycle of the seminiferous epithelium, whereas pS1981-ATM was found only to be present in the sex body of pachytene spermatocytes. In response to IR, ATM became activated by pS1981 cross-phosphorylation in spermatogonia and Sertoli cells. Despite the occurrence of endogenous programmed DSBs during the first meiotic prophase and the presence of ATM in both spermatogonia and spermatocytes, pS1981 phosphorylated ATM did not appear in spermatocytes after treatment with IR. These results show that spermatogonial ATM and ATM in the spermatocytes are differentially regulated. In the mitotically dividing spermatogonia, ATM is activated by cross-phosphorylation, whereas during meiosis nonphosphorylated ATM or differently phosphorylated ATM is already active. ATM has been shown to be present at the synapsed axes of the meiotic chromosomes, and in the ATM knock-out mice spermatogenesis stops at pachytene stage IV of the seminiferous epithelium, indicating that indeed nonphosphorylated ATM is functional during meiosis. Additionally, ATM is constitutively phosphorylated in the sex body where its continued presence remains an enigma.
Animals↗
How low is the alpha/beta ratio for prostate cancer?
PURPOSE: Recently, low alpha/beta values of 1.2 and 1.5 Gy for prostate tumors have been derived from clinical results of external beam radiotherapy and of permanent implants of (125)I and (103)Pd. In the analyses the contributions of tumor repopulation, and edema as a result of inserting radioactive seeds in the prostate, have been ignored. In this paper we reanalyzed the clinical data and introduced the contribution of repopulation and edema. METHODS AND MATERIALS: The linear quadratic-biologically effective dose model was used for reanalysis. In this model, the influence of repopulation and edema has been taken into account. The biologically effective dose was calculated as a function of alpha/beta for 2 brachytherapy regimens with (125)I and (103)Pd and 2 fractionated treatments, and for different half-times for repair of sublethal damage for the brachytherapy regimens. RESULTS: We have found a plausible alpha/beta value of 3.1 to 3.9 Gy, an alpha value of 0.1 to 0.15 Gy(-1), and a half-time of repair of about 0.5 h. CONCLUSIONS: It seems now that the alpha/beta value is low, 3.1-3.9 Gy, but not as low as the 1.2 and 1.5 Gy reported earlier.
Brachytherapy↗
Response to motexafin gadolinium and ionizing radiation of experimental rat prostate and lung tumors.
PURPOSE: To investigate the responses of two experimental rat tumors to single and fractionated X-ray doses whether or not combined with Motexafin gadolinium (MGd), and the distribution of MGd in R3327-MATLyLu (MLL) tumors using MRI. METHODS: L44 lung tumor in BN rats and MLL prostate tumor in Copenhagen rats were grown subcutaneously. MGd at concentrations of 8.7 to 25.1 micro mol/kg was administered 2 h before or just before treatments with single and fractionated X-ray doses. Tumor volume growth delay was the endpoint used. The two-dimensional distribution of the MGd concentration in time was analyzed simultaneously in slices through the center of MLL tumors using MRI. Directly after the MRI experiments, tumor sections were stained for cytoplasm, nuclei, and microvessel endothelium. RESULTS: MGd at different concentrations administered a few minutes or 2 h before X-ray doses produced no radiation enhancement in the two tumor models. The MGd concentration as determined by MRI was maximal 5 min after injection and decreased slowly thereafter. In a representative section at the center of the MLL tumor, the microvessel density is nearly homogeneous and correlates with a nearly homogeneous MGd distribution. Hardly any MGd is taken up in underlying muscle tissue. CONCLUSION: No radiosensitization was observed for the different irradiation regimens. The distribution of MGd is nearly homogeneous in the MLL tumor and hardly any MGd is taken up in underlying muscles. Our negative results on radiosensitivity in our two tumor models raise questions about the efficacy of MGd as a general radiosensitizing agent.
Animals↗
Single fraction radiotherapy is as effective as multiple fractions for palliating painful bone metastases.
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Journal Article↗
DNA double-strand breaks and gamma-H2AX signaling in the testis.
Within minutes of the induction of DNA double-strand breaks in somatic cells, histone H2AX becomes phosphorylated at serine 139 and forms gamma-H2AX foci at the sites of damage. These foci then play a role in recruiting DNA repair and damage-response factors and changing chromatin structure to accurately repair the damaged DNA. These gamma-H2AX foci appear in response to irradiation and genotoxic stress and during V(D)J recombination and meiotic recombination. Independent of irradiation, gamma-H2AX occurs in all intermediate and B spermatogonia and in preleptotene to zygotene spermatocytes. Type A spermatogonia and round spermatids do not exhibit gamma-H2AX foci but show homogeneous nuclear gamma-H2AX staining, whereas in pachytene spermatocytes gamma-H2AX is only present in the sex vesicle. In response to ionizing radiation, gamma-H2AX foci are generated in spermatogonia, spermatocytes, and round spermatids. In irradiated spermatogonia, gamma-H2AX interacts with p53, which induces spermatogonial apoptosis. These events are independent of the DNA-dependent protein kinase (DNA-PK). Irradiation-independent nuclear gamma-H2AX staining in leptotene spermatocytes demonstrates a function for gamma-H2AX during meiosis. gamma-H2AX staining in intermediate and B spermatogonia, preleptotene spermatocytes, and sex vesicles and round spermatids, however, indicates that the function of H2AX phosphorylation during spermatogenesis is not restricted to the formation of gamma-H2AX foci at DNA double-strand breaks.
Animals↗
Function of DNA-protein kinase catalytic subunit during the early meiotic prophase without Ku70 and Ku86.
All components of the double-stranded DNA break (DSB) repair complex DNA-dependent protein kinase (DNA-PK), including Ku70, Ku86, and DNA-PK catalytic subunit (DNA-PKcs), were found in the radiosensitive spermatogonia. Although p53 induction was unaffected, spermatogonial apoptosis occurred faster in the irradiated DNA-PKcs-deficient scid testis. This finding suggests that spermatogonial DNA-PK functions in DNA damage repair rather than p53 induction. Despite the fact that early spermatocytes lack the Ku proteins, spontaneous apoptosis of these cells occurred in the scid testis. The majority of these apoptotic spermatocytes were found at stage IV of the cycle of the seminiferous epithelium where a meiotic checkpoint has been suggested to exist. Meiotic synapsis and recombination during the early meiotic prophase induce DSBs, which are apparently less accurately repaired in scid spermatocytes that then fail to pass the meiotic checkpoint. The role for DNA-PKcs during the meiotic prophase differs from that in mitotic cells; it is not influenced by ionizing radiation and is independent of the Ku heterodimer.
Animals↗
Intercellular bridges and apoptosis in clones of male germ cells.
When an As spermatogonium divides to form a pair of Apr spermatogonia the two daughter cells stay interconnected by an intercellular bridge. These cytoplasmic bridges form after every subsequent division leading to large clones of interconnected germ cells. Cohorts of spermatogonia maintain synchronous development throughout spermatogenesis, which has been attributed to the presence of these intercellular bridges. To examine whether apoptotic signals are transduced through the intercellular bridges we studied germ cell apoptosis in whole mounts of seminiferous tubules from non-irradiated and irradiated mouse testes, using whole mount seminiferous tubules and confocal microscopy. This allowed us to use TUNEL staining of apoptotic germ cells and at the same time to study these apoptotic germ cells in their topographical context. Our results show that in response to ionizing radiation single spermatogonia within a clone can undergo apoptosis without affecting their neighboring cells. Additionally, also early spermatocytes were shown to undergo apoptosis individually. Both radiation-induced spermatogonial apoptosis and spontaneous apoptosis of spermatocytes are caused by DNA damage of individual cells. Degeneration of healthy spermatogonia because of regulatory signals, however, follows other death inducing mechanisms, which lead to apoptosis of chains of interconnected spermatogonia.
Animals↗
Biologically effective dose for permanent prostate brachytherapy taking into account postimplant edema.
PURPOSE: To study the influence of radiobiologic and physical parameters and parameters related to edema on the biologically effective dose (BED) for permanent prostate implants and to determine the optimal timing of seed reconstruction for BED calculation. METHODS AND MATERIALS: On the basis of the linear-quadratic model, an expression for the BED was derived, including the edema parameters. A set of parameter values was defined, and these parameter values were varied one at a time to examine the effect on the BED and the theoretically effective treatment time (t(eff)). A ratio epsilon was defined to investigate the optimal timing of seed reconstruction. RESULTS: The maximal BED decreases when the extent of lethal damage is smaller, the potential tumor doubling time is smaller, the half-life time of the seeds is shorter, and the magnitude of prostate volume increase is larger. For 125I, the optimal timing of seed reconstruction is 25 days after implantation. Seed reconstruction 1 day after the implantation results in an underestimation of the BED of at most 43%, depending on the magnitude and half-life of edema. An overestimation of the BED of at most 22% is calculated when seed reconstruction took place at the effective treatment time. CONCLUSION: The maximal BED depends strongly on the value of alpha, the potential tumor doubling time, and the choice of isotope. If prostate volume increase due to edema is not taken into account, the BED will be underestimated shortly after the implantation and overestimated if the calculations are based on images taken several months after implantation. The optimal timing of BED evaluation for 125I seed implants and typical prostate edema values is 25 days after implantation.
Algorithms↗
Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment.
PURPOSE: To assess the degree of visual impairment as a result of cataract formation after total body irradiation (TBI) for bone marrow transplantation. METHODS AND MATERIALS: The data from 93 patients who received TBI in 1 or 2 fractions as a part of their conditioning regimen for bone marrow transplantation were analyzed with respect to the degree of visual impairment as a result of cataract formation. The probability to develop severe visual impairment (SVI) was determined for all patients, and the degree of visual impairment was assessed for 56 patients with stabilized cataract, using three categories: no, mild, or severe. RESULTS: For all 93 patients, the probability of developing a cataract causing SVI was 0.44. For allogeneic patients, it was 0.33 without and 0.71 with steroid treatment (p <0.001). All SVI-free probability curves reached a plateau distinct from the cataract-free curves. Apparently, cataracts developing late in the follow-up period rarely cause SVI. Of the patients with stabilized cataract, 32% had no visual impairment, 16% had mild, and 52% severe impairment. No or mild visual impairment was present in 61% of all patients with stable cataract and no steroid treatment compared with only 13% of the patients treated with steroids (p = 0.035). CONCLUSION: SVI occurs in only some of the patients (52%) with stable cataract after TBI for bone marrow transplantation in 1 or 2 fractions. Steroid treatment markedly increases the probability of developing visual problems as result of a cataract after TBI.
Acute Disease↗
Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia.
PURPOSE: To determine a dose-effect relationship for cataract induction, the tissue-specific parameter, alpha/beta, and the rate of repair of sublethal damage, mu value, in the linear-quadratic formula have to be known. To obtain these parameters for the human eye lens, a large series of patients treated with different doses and dose rates is required. The data of patients with acute leukemia treated with single-dose total body irradiation (STBI) and bone marrow transplantation (BMT) collected by the European Group for Blood and Marrow Transplantation were analyzed. METHODS AND MATERIALS: The data of 495 patients who underwent BMT for acute leukemia, who had STBI as part of their conditioning regimen, were analyzed using the linear-quadratic concept. The end point was the incidence of cataract formation after BMT. Of the analyzed patients, 175 were registered as having cataracts. Biologic effective doses (BEDs) for different sets of values for alpha/beta and mu were calculated for each patient. With Cox regression analysis, using the overall chi-square test as the parameter evaluating the goodness of fit, alpha/beta and mu values were found. Risk factors for cataract induction were the BED of the applied TBI regimen, allogeneic BMT, steroid therapy for >14 weeks, and heparin administration. To avoid the influence of steroid therapy and heparin on cataract induction, patients who received steroid or heparin treatment were excluded, leaving only the BED as a risk factor. Next, the most likely set of alpha/beta and mu values was obtained. With this set, the cataract-free survival rates were calculated for specific BED intervals, according to the Kaplan-Meier method. From these calculations, cataract incidences were obtained as function of the BED at 120 months after STBI. RESULTS: The use of BED instead of the TBI dose enabled the incidence of cataract formation to be predicted in a reasonably consistent way. With Cox regression analysis for all STBI data, a maximal chi-square value was obtained for alpha/beta = 1.75 Gy and mu = 0.75 h(-1). When Cox regression analysis was applied for patients who had no steroid treatment after BMT, a maximal chi-square value was obtained for alpha/beta = 1 Gy and mu = 0.6 h(-1). Cox regression analysis was repeated using the data of patients who had not received posttransplant steroid treatment and also no heparin administration; we found alpha/beta = 0.75 Gy and mu= 0.65 h(-1). An increased cataract incidence was observed after steroid treatment of >14 weeks and heparin administration. CONCLUSION: The alpha/beta value of 0.75 Gy and mu value of 0.65 h(-1) found for the eye lens are characteristic for late-responding tissues. The incidence of cataract formation can now be quantified, taking into account the values calculated for alpha/beta and mu, TBI dose, and dose rate. Also, the reduction in cataract incidence as a result of lens dose reduction by eye shielding can be estimated.
Acute Disease↗