Depressed left ventricular fractional shortening and left ventricular dilatation were uncommon years after treatment of childhood leukemia when cumulative anthracycline doses were < or = 300 mg/m2.

Our purpose was to assess the risk of developing a second malignant neoplasm (SMN) after cancer in childhood and adolescence associated with different treatment modalities. Our investigation was performed as a nested case‐control study within a Nordic cohort of 25,120 patients younger than 20 years old at first malignant neoplasm (FMN) diagnosed in 1960 through 1987. SMNs were diagnosed in 1960 through 1991. For each case of SMN, 3 controls were sampled, matched by sex, age, calendar year of diagnosis and length of follow‐up. For the final analysis, there were 234 cases and 678 controls. Relative risks (RRs) of various exposures were estimated by means of conditional logistic regression, with non‐exposed as the reference. The RR of developing SMN in the radiated volume was 4.3 (95% confidence interval 3.0–6.2). The risk was highest in children diagnosed before the age of 5 years; it increased with the dose of radiation and with increasing follow‐up time after FMN. Chemotherapy alone was not associated with an increased RR, but it significantly potentiated the effect of radiotherapy. RRs were unchanged between the periods 1960–1973 and 1974–1987, and since the use of chemotherapy increased in the latter period, the number of SMNs may increase. Hereditary factors were important for the occurrence of SMN independently of therapy. We conclude that radiation was the most important treatment‐related risk factor for the development of SMN. Chemotherapy appeared to play only an accessory role during the study period, potentiating the carcinogenic effect of radiotherapy. Int. J. Cancer 88:672–678, 2000. © 2000 Wiley‐Liss, Inc.

Patients who survive Hodgkin's disease at a young age are at very high relative risk of subsequent malignant neoplasms throughout their lives. In particular, the high relative risk of breast cancer following Hodgkin's disease in the teenage years calls for enhanced activity for early diagnosis.

Summary:Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to ؊2.6 standard deviation scores (SDS) (؊6.3 to ؊0.6), P ‫؍‬ 0.002, and ؊2.6 SDS (؊4.8 to ؊0.5), P ‫؍‬ 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated. Keywords: BMT; TBI; childhood; uterus; ovary; uterine blood flow During the past two decades allogeneic bone marrow transplantation (BMT) has been used in the treatment of children with relapsed or very high risk leukaemia and lymphoma. Since many of these children become long-term survivors, the late effects of treatment are of major concern. Preparative regimens for BMT, high-dose chemotherapy alone or in combination with total body irradiation (TBI), may cause various endocrine abnormalities, 1-10 and ovarian failure Correspondence: K Holm, Department of Growth and Reproduction, Section 5064, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark Received 26 March 1998; accepted 5 September 1998 resulting in life-long need for sex steroid replacement therapy (HRT) and infertility is common. Recovery of ovarian function occurs especially when preparative regimens do not include TBI, 5-11 and cases of pregnancies resulting in successful deliveries have been reported even when preparative regimens have included TBI. [12][13][14][15][16][17][18][19][20] The progress of assisted reproduction and the availability of oocyte donation has made pregnancy a possibility in women without ovarian function, provided there is normal function of the uterus. However, once pregnancy has been achieved, other problems may occur. In patients treated for solid tumours abdominal irradiation with 20-30 Gy have caused irreversible damage to uterine musculature and blood flow 21 and a high risk of adverse pregnancy outcome, eg low birth weight and increased perinat...

Encouraging patients to reduce or stop smoking is an important aspect of care. Smoking habits were recorded in 76% of patients, which compares well with the 44% found in an audit in 12 Oxfordshire practices in 1986.24 Results-247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3-6 (95% confidence interval 3-1 to 4.1). The risk changed significantly from 2*6 in people first diagnosed during the 1940s and 1950s to 6-9 among cohort members included in the late 1970s and 1980s. Increases were observed for most types of cancer. Highest levels of the relative risk were seen during the 10 years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years offollow up.Conclusion-The estimated risks for a second malignant neoplasm were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part ofthe European population.

The data of this study suggest that the majority of long-term survivors of brain tumours develop GH deficiency following radiotherapy in childhood and that the adverse effects of radiotherapy may be directly related to the biologically effective dose. With longer follow-up fewer patients might respond normally to GH stimulation tests.

Homeobox genes generally encode transcription factors involved in regulating developmental processes. In the pineal gland, a brain structure devoted to nocturnal melatonin synthesis, a number of homeobox genes are also expressed postnatally; among these is the LIM homeobox 4 gene (Lhx4). We here report that Lhx4 is specifically expressed in the postnatal pineal gland of rats and humans. Circadian analyses revealed a fourfold rhythm in Lhx4 expression in the rat pineal gland, with rhythmic expression detectable from postnatal day 10. Pineal Lhx4 expression was confirmed to be positively driven by adrenergic signaling, as evidenced by in vivo modulation of Lhx4 expression by pharmacological (isoprenaline injection) and surgical (superior cervical ganglionectomy) interventions. In cultured pinealocytes, Lhx4 expression was upregulated by cyclic AMP, a second messenger of norepinephrine. By use of RNAscope technology, Lhx4 transcripts were found to be exclusively localized in melatonin-synthesizing pinealocytes. This prompted us to investigate the possible role of Lhx4 in regulation of melatonin-producing enzymes. By use of siRNA technology, we knocked down Lhx4 by 95% in cultured pinealocytes; this caused a reduction in transcripts encoding the melatonin-producing enzyme arylalkylamine N-acetyl transferase (Aanat). Screening the transcriptome of siRNA-treated pinealocytes by RNAseq revealed a significant impact of Lhx4 on the phototransduction pathway and on transcripts involved in development of the nervous system and photoreceptors. These data suggest that rhythmic expression of Lhx4 in the pineal gland is controlled via an adrenergic-cyclic AMP mechanism and that Lhx4 acts to promote nocturnal melatonin synthesis. K E Y W O R D Shomeobox, melatonin, pineal gland, RNA sequencing, RNAscope, siRNA 2 of 12 | HERTZ ET al.

Among a cohort of 981 children who were followed up 4.3-26.5 years after cessation of antileukemic therapy, eight patients in remission of acute lymphoblastic leukemia (ALL) developed a distinctively new malignant disease. The second malignant neoplasms (SMN) included brain tumors, basal cell carcinomas, thyroid cancer, leiomyosarcoma and finally rhabdomyosarcoma in a patient who also had suffered from Hodgkin's disease while still on antileukemic treatment. Cranial radiation had been given to 58.4% of the patients in the study group, which consisted of 895 ALL patients who had completed various chemotherapy protocols. With one exception, the SMN appeared after 7.5-16.5 years at a location previously exposed to radiotherapy (RT). The estimated cumulative risk of SMN appearing within 20 years after diagnosis was 2.9%, and the corresponding risk for cases with RT was 8.1% compared to 0.3% for those without (p = 0.05). In a Cox regression analysis, the incidence rate ratio of SMN between patients with and without RT was 6.7 (95% CI = 0.8, 57.7). Based on age-, year- and sex-specific cancer incidence figures for Norway, the overall standardized incidence rate ratio (SIR) of SMN after treatment for ALL was 5.9 (95% CI = 2.2, 12.9). The number of brain tumors among patients who had received cranial radiation was nearly 27 times greater than expected, whereas no such tumors were seen after chemotherapy. Individuals treated for childhood ALL are at increased risk of a new malignancy, and this seems mainly to be associated with previous irradiation.