Late Effects of the Reproductive System
Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors. The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy.
- Orchiectomy or oophorectomy performed for the management of pediatric germ cell tumors may reduce germ cell numbers.
- Alkylating agents and similar DNA interstrand cross-linking agents are the primary chemotherapeutic agents used in the treatment of pediatric cancers that are associated with a high risk of infertility. Factors influencing the risk of gonadal injury in children treated with alkylating agent chemotherapy include the following:
- Cumulative dose.
- The specific alkylating agent.
- The length of treatment.
- Age at treatment.
- The risk of radiation injury to the hypothalamic-pituitary axis or gonads is related to the treatment volume, total dose, fractionation schedule, and age at treatment.
In addition to anticancer therapy, age at treatment, and gender, it is likely that genetic factors influence the risk of permanent infertility. It should be noted that pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses are needed to estimate risks for gonadal dysfunction and infertility.
Cancer treatments that may impair testicular and reproductive function include the following:
- Surgery (orchiectomy, retroperitoneal lymph node dissection, extensive pelvic dissection).
- Radiation therapy (exposing the hypothalamic-pituitary axis or testes).
- Chemotherapy (alkylating agents and similar DNA interstrand cross-linking agents such as procarbazine).
- Hematopoietic stem cell transplantation (HSCT).
Surgery affecting testicular function
Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[1,2] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[3,4] and impotence may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.
Radiation affecting testicular function
Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells. A decrease in sperm counts can be seen 3 to 6 weeks after irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Irreversible germ cell failure may occur with fractionated irradiation doses of greater than 2 Gy to 4 Gy. Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both germ cell failure and Leydig cell dysfunction.
Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular radiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization. Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy.
Chemotherapy affecting testicular function
Cumulative alkylating agent (e.g., cyclophosphamide, mechlorethamine, dacarbazine) dose is an important factor in estimating the risk of testicular germ cell injury, but limited studies are available that correlate results of semen analyses in clinically well-characterized cohorts. In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m2 or more) and more than 3 months of combination alkylating agent therapy. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients.[10-13]
Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:
- Male survivors of non-Hodgkin lymphoma who received a cumulative cyclophosphamide dose of greater than 9.5 g/m2 and underwent pelvic radiation therapy were at increased risk for failure to recover spermatogenesis.
- In survivors of Ewing sarcoma and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose of greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.
- Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[16-18]
- A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial radiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.
- Treatment with a cyclophosphamide equivalent dose of less than 4 g/m2 results in infrequent azoospermia or oligospermia, with 88.6% of 31 men treated being normospermic.
- Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide before undergoing HSCT for aplastic anemia.
- The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported after treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).
- Alkylating agent plus procarbazine:
- Most studies suggest that combination chemotherapy with an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium that is irreversible at high cumulative doses.[10,23-26]
- Azoospermia occurred less frequently in adults after treatment with two, rather than six, cycles of MOPP.
- Elevation of the basal follicle-stimulating hormone (FSH) level, reflecting impaired spermatogenesis, was less frequent among patients receiving two courses of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) than among those who received two courses of OPPA in combination with two or more courses of cyclophosphamide, vincristine, procarbazine and prednisone (COPP).
Testicular function after HSCT
The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation (TBI), high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation may confer additional risks. Age at treatment also influences the risk of gonadal injury. Young boys and adolescents treated with high-dose cyclophosphamide (200 mg/kg) will generally maintain Leydig cell function and testosterone production, but germ cell failure is common. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure.
Recovery of gonadal function
Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with a median follow-up of 15.7 years (range, 3–37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7–11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal radiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level.
Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported. Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.
Cancer treatments that may impair ovarian function/reserve include the following:
- Surgery (oophorectomy).
- Radiation therapy (exposing the hypothalamic-pituitary axis or ovaries).
- Chemotherapy (alkylating agents, similar DNA interstrand cross-linking agents like procarbazine).
Surgery affecting ovarian function
Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments utilize fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk.
Radiation affecting ovarian function
In women treated for childhood cancer, the potential for primary gonadal injury exists if treatment fields involve the lumbosacral spine, abdomen, pelvis, or total body. The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. The ovaries of younger individuals are more resistant to radiation damage than are those of older women because of their greater complement of primordial follicles.
Whole-abdomen irradiation at doses of 20 Gy or greater is associated with the highest risk of ovarian dysfunction. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 20 Gy to 30 Gy. Other studies reported similar results in women treated with whole-abdomen irradiation  or craniospinal irradiation [35,36] during childhood.
Chemotherapy affecting ovarian function
Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine. In general, girls maintain gonadal function at higher cumulative alkylating agent doses than do boys. Most female childhood cancer survivors who are treated with risk-adapted combination chemotherapy retain or recover ovarian function. However, the risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation or dose-intensive alkylating agents for myeloablative conditioning before HSCT.[37-40]
Premature ovarian failure
Premature ovarian failure is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal radiation.[37,41,42] Studies have associated the following factors with an increased rate of premature ovarian failure (acute ovarian failure and premature menopause):
- Age at the time of treatment and attained age.
- Increasing doses of abdominal-pelvic radiation therapy.
- Exposure to alkylating agents and/or procarbazine.
The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred. Studies of acute ovarian failure and premature menopause have observed the following:
- Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure (defined as never having menses or ceased having menses within 5 years of diagnosis). Survivors with acute ovarian failure were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than were survivors without acute ovarian failure. Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic radiation. Radiation doses to the ovary of at least 20 Gy were associated with the highest rate of acute ovarian failure, with over 70% of such patients developing acute ovarian failure. In a multivariable logistic regression model, increasing doses of ovarian radiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.
- A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause, defined as cessation of menses before 40 years. The cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8% vs. 0.8%; relative risk [RR], 13.21; 95% confidence interval [CI], 3.26–53.51; P < .001). A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose score, and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominal-pelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.
- A French cohort study of 1,109 female survivors of childhood solid cancer identified the following as risk factors for nonsurgical menopause:
- Exposure to and dose of alkylating agents, especially during adolescence.
- Radiation dose to the ovaries.
Women treated with alkylating agents after the onset of puberty, either alone (RR, 9; 95% CI, 2.7–28; P = .0003) or associated with even a low dose of radiation to the ovaries (RR, 29; 95% CI, 8–108; P < .0001), had the highest risk ratio for nonsurgical menopause. Unilateral oophorectomy was associated with a 7-year-earlier age at menopause. The overall rate of nonsurgical menopause by age 40 years was only 2.1% and substantially lower than the CCSS and European Organization for Research and Treatment of Cancer cohort studies that include survivors of hematological malignancies.
- In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure. In 460 women, premature ovarian failure was mainly influenced by alkylating chemotherapy use with a linear dose relationship between alkylating chemotherapy and premature ovarian failure occurrence. Premature ovarian failure risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy before age 32 years and at age 32 years or older, cumulative premature ovarian failure risks were 3% and 9%, respectively. If menstruation returned after treatment, cumulative premature ovarian failure risk was independent of age at treatment. Among women who ultimately developed premature ovarian failure, 22% had one or more children after treatment, compared with 41% of women without premature ovarian failure who had one or more children after treatment. This report indicates that women with proven fertility after treatment can still face infertility problems at a later stage.
Ovarian function after HSCT
The preservation of ovarian function among women treated with HSCT is related to age at treatment, receipt of pretransplant alkylating agent chemotherapy and abdominal-pelvic radiation, and transplant conditioning regimen. Studies of ovarian function among women treated with HSCT have observed the following:
- Girls and young women conditioned with TBI or busulfan-based regimens appear to be at equally high risk of declining ovarian function and premature menopause compared with patients conditioned with cyclophosphamide only. All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before HSCT for aplastic anemia developed amenorrhea after transplantation. In one series, 36 of 43 women with aplastic anemia conditioned with cyclophosphamide (200 mg/kg) had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of HSCT.
- TBI is especially damaging when given in a single fraction. Most postpubertal women who receive TBI before HSCT develop amenorrhea. In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at radiation in patients younger than 25 years.
- Among women with leukemia, cranial radiation before transplantation further decreased the possibility of retaining ovarian function.
Infertility remains one of the most common life-altering treatment effects experienced by long-term childhood survivors. Pediatric cancer cohort studies demonstrate the impact of cytotoxic therapy on reproductive outcomes. CCSS investigations have elucidated factors contributing to subfertility among childhood cancer survivors. Fertility was evaluated among the 6,224 male CCSS participants aged 15 to 44 years who were not surgically sterile. They were less likely to sire a pregnancy than siblings (hazard ratio [HR] 0.56; 95% CI, 0.49–0.63).
Treatment factors associated with significantly lower rates of siring a pregnancy include the following:
- Radiation dose greater than 0.75 Gy to the testes (HR, 0.12; 95% CI, 0.02–0.61).
- Higher cyclophosphamide equivalent dose.
- ≥ 4 g/m2 to < 8 g/m2: HR, 0.72; 95% CI, 0.55–0.95.
- ≥ 8 g/m2 to < 12 g/m2: HR, 0.49; 95% CI, 0.36–0.68.
- ≥ 12 g/m2 to < 16 g/m2: HR, 0.37; 95% CI, 0.24–0.57.
- ≥ 16 g/m2 to < 20 g/m2: HR, 0.53; 95% CI, 0.34–0.8.
- ≥ 20 g/m2: HR, 0.17; 95% CI, 0.10–0.29.
Fertility was evaluated among the 5,149 female CCSS participants and 1,441 female siblings of CCSS participants, aged 15 to 44 years. The RR for ever being pregnant was 0.81 (95% CI, 0.73–0.90; P < .001), compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic-pituitary radiation dose of greater than 30 Gy (RR, 0.61; 95% CI, 0.44–0.83) or an ovarian/uterine radiation dose of greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5–10 Gy; 95% CI, 0.37–0.85; RR, 0.18 for >10 Gy; 95% CI, 0.13–0.26). A summed alkylating agent dose score of 3 (RR, 0.72; 95% CI, 0.58–0.90; P = .003) or 4 (RR, 0.65; 95% CI, 0.45–0.96; P = .03) was associated with lower observed risk of pregnancy, compared with those with no alkylating agent exposure. A follow-up study of the same cohort demonstrated impaired fertility in female survivors who received modest doses (22–27 Gy) of hypothalamic-pituitary radiation and no or very low doses (<0.1 Gy) of ovarian radiation, providing support for the contribution of the role of luteal phase deficiency to infertility in some women.
Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation. [3,4,47]
- Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection.[3,4]
- Uterine structure may be affected by abdominal irradiation. A study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole-abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.
For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[43,45,48-56]
- In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation. Risk of miscarriage was 3.6-fold higher in women treated with craniospinal radiation and 1.7-fold higher in those treated with pelvic radiation. Chemotherapy exposure alone did not increase risk of miscarriage. Survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low-birth-weight babies than were siblings.
- In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births. Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank radiation, in a dose-dependent manner.
- Another CCSS study evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared with partners of male siblings, there was a decreased incidence of live births (RR, 0.77), but no significant differences of pregnancy outcome by treatment.
- Results from a Danish study confirm the association of uterine radiation with spontaneous abortion, but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified. No significant differences were seen between survivors and comparison women in the proportions of live births, stillbirths, or all types of abortions combined. Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion. Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.
- In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies. Irradiation of the testes in men and pituitary gland in women and chemotherapy with alkylating drugs were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased the risk of stillbirth and neonatal death at doses higher than 10 Gy. For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1 Gy to 2.49 Gy significantly increased the risk of stillbirth or neonatal death.
- Most pregnancies reported by HSCT survivors and their partners result in live births. In female HSCT survivors who were exposed to TBI, there appears to be an increased risk of preterm delivery of low-birth-weight infants. Female HSCT survivors are at higher risk of needing Cesarean sections than are the normal population (42% vs. 16%). 
- Preservation of fertility and successful pregnancies may occur after HSCT, although the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. One study evaluated pregnancy outcomes in a group of females treated with HSCT. Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination. Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination. There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.
Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy. For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[60,61] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.
For females, the most successful assisted-reproductive techniques depend on harvesting and banking the postpubertal patient’s oocytes and cryopreserving unfertilized oocytes or embryos before gonadotoxic therapy. Options for prepubertal patients are limited to investigational ovarian tissue cryopreservation for later autotransplantation, which may be offered to girls with nonovarian, nonhematologic cancers.
Offspring of childhood cancer survivors
For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments, as supported by the following observations:
- A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS showed no significant associations between gonadal radiation or cumulative exposure to alkylating agents and congenital anomalies in offspring.
- In a report of 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring.
- Survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.
- In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer. Data from the five-center study also indicated no excess risk of single-gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings.
- Offspring of male and female HSCT recipients do not appear to be at increased risk for birth defects, developmental delay, or cancer.
(Refer to the PDQ summary on Sexuality and Reproductive Issues for more information about sexuality and reproductive issues and cancer patients.)
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for reproductive late effects information including risk factors, evaluation, and health counseling.
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