Chronic fatigue in childhood cancer survivors is associated with lifestyle and psychosocial factors; a DCCSS LATER study.

BACKGROUND: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS). PATIENTS AND METHODS: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS (≥5 years after diagnosis) and siblings as controls. Fatigue severity was assessed with the 'fatigue severity subscale' of the Checklist Individual Strength ('CIS-fatigue'). CF was defined as scoring ≥35 on the 'CIS-fatigue' and having fatigue symptoms for ≥6 months. Twenty-four parameters were assessed, categorized into assumed fatigue triggering, maintaining and moderating factors. Multivariable logistic regression analyses were carried out to investigate the association of these factors with CF. RESULTS: A total of 1927 CCS participated in the study (40.7% of invited cohort), of whom 23.6% reported CF (compared with 15.6% in sibling controls, P < 0.001). The following factors were associated with CF: obesity [versus healthy weight, odds ratio (OR) 1.93; 95% confidence interval (CI) 1.30-2.87], moderate physical inactivity (versus physical active, OR 2.36; 95% CI 1.67-3.34), poor sleep (yes versus no, OR 2.03; 95% CI 1.54-2.68), (sub)clinical anxiety (yes versus no, OR 1.55; 95% CI 1.10-2.19), (sub)clinical depression (yes versus no, OR 2.07; 95% CI 1.20-3.59), pain (continuous, OR 1.49; 95% CI 1.33-1.66), self-esteem (continuous, OR 0.95; 95% CI 0.92-0.98), helplessness (continuous, OR 1.13; 95% CI 1.08-1.19), social functioning (continuous, OR 0.98; 95% CI 0.97-0.99) and female sex (versus male sex, OR 1.79; 95% CI 1.36-2.37). CONCLUSION: CF is a prevalent symptom in CCS that is associated with several assumed maintaining factors, with lifestyle and psychosocial factors being the most prominent. These are modifiable factors and may therefore be beneficial to prevent or reduce CF in CCS.

Perspectives on follow-up care and research for childhood cancer survivors: results from an international SIOP meet-the-expert questionnaire in Kyoto, 2018.

INTRODUCTION: Survival of childhood cancer has increased over the past decades. This has led to the development of strategies aiming to enhance follow-up care and research, for which priorities may vary globally. We explored perspectives of an international healthcare workers panel. METHODS: Attendants of a meet-the-expert session on childhood cancer survivorship at the 2018 SIOP conference completed a survey about their view on important follow-up care and research aspects for survivors below and over 18 years. We analysed overarching categories and subtopics, and compared Asian versus European and North American healthcare workers. RESULTS: A total of 58 participants from different medical specialties (67.2% paediatric oncologists) and continents (48.3% Asia, 39.7% Europe/North America) responded. Follow-up care priorities for survivors below and over 18 years included physical care (39.3% ≤18 years, 35.9% >18 years) and healthcare structure (29.4%, 26.0%). Physical care was also the most important research aspect for both age groups (52.5%, 50.7%). Psychological support was the most frequently reported subtopic. Asian clinicians (n = 22) primarily prioritized physical care aspects of follow-up care, whereas European/North American (n = 19) clinicians underscored the importance of healthcare structure. CONCLUSION: Physical care is the most important aspect of survivorship care and research according to clinicians from several continents. Asian and European/North American respondents shared most priorities, however, healthcare structure was a more important category for European/North American clinicians. The most common subtopic was psychological support, underlining also the need to involve psychologists in follow-up.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning.

BACKGROUND: Functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate (sgACC) may serve as a biomarker for transcranial magnetic stimulation (rTMS) treatment response. The first aim was to establish whether this finding is veridical or artifactually induced by the pre-processing method. Furthermore, alternative biomarkers were identified and the clinical utility for personalized medicine was examined. METHODS: Resting-state fMRI data were collected in medication-refractory depressed patients (n = 70, 16 males) before undergoing neuronavigated left DLPFC rTMS. Seed-based analyses were performed with and without global signal regression pre-processing to identify biomarkers of short-term and long-term treatment response. Receiver Operating Characteristic curve and supervised machine learning analyses were applied to assess the clinical utility of these biomarkers for the classification of categorical rTMS response. RESULTS: Regardless of the pre-processing method, DLPFC-sgACC connectivity was not associated with treatment outcome. Instead, poorer connectivity between the sgACC and three clusters (peak locations: frontal pole, superior parietal lobule, occipital cortex) and DLPFC-central opercular cortex were observed in long-term nonresponders. The identified connections could serve as acceptable to excellent markers. Combining the features using supervised machine learning reached accuracy rates of 95.35% (CI=82.94-100.00) and 88.89% (CI=63.96-100.00) in the cross-validation and test dataset, respectively. LIMITATIONS: The sample size was moderate, and features for machine learning were based on group differences. CONCLUSIONS: Long-term nonresponders showed greater disrupted connectivity in regions involving the central executive network. Our findings may aid the development of personalized medicine for medication-refractory depression.

Metabolic syndrome detection with biomarkers in childhood cancer survivors.

PURPOSE: Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography. METHODS: The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations. RESULTS: After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (ß = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value. CONCLUSIONS: Long-term childhood nephro- and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA - adiponectin, LDL, apoB, and uric acid - may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value.

Discordant biological parameters of remission in acromegaly do not increase the risk of hypertension or diabetes: a study with the Liege Acromegaly Survey database.

PURPOSE: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease; however, a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of diabetes mellitus (DM) and hypertension (HT) in acromegalic patients with congruent GH and/or IGF-1 levels vs. discordant biochemical parameters. METHODS: Retrospective analysis of the data of 3173 patients from the Liege Acromegaly Survey (LAS) allowed us to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning DM and HT both at diagnosis and at the last follow-up (LFU). We recorded the number of anti-HT and anti-DM drugs used at the first evaluation and at LFU for every patient. RESULTS: Ninety-nine patients belonged to the REM group (concordant parameters), 65 patients were considered as GHdis (high random GH/controlled IGF-1), and 26 patients were considered as IGF-1dis (high IGF-1/controlled random GH). At diagnosis, 72 patients (37.8%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of the number of anti-HT and anti-DM drugs at diagnosis versus LFU (mean duration: 7.3 ± 4.5 years) between all three groups. CONCLUSION: The long-term outcome of DM and HT in acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study.

PURPOSE: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). METHODS: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). RESULTS: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA. CONCLUSION: Although most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.

Metabolic syndrome as cardiovascular risk factor in childhood cancer survivors.

Over the past decades, survival rates of childhood cancer have increased considerably from 5 to 30% in the early seventies to current rates exceeding 80%. This is due to the development of effective chemotherapy, surgery, radiotherapy and stem cell transplantation, combined with an optimized stratification of therapy and better supportive care regimens. As a consequence, active surveillance strategies of late sequelae have been developed to improve the quality of survival. Several epidemiological studies have reported an increased incidence of (components of) metabolic syndrome (MetS) and cardiovascular disease in childhood cancer survivors (CCS). Growth hormone deficiency (GHD) after cranial radiotherapy (CRT) has been previously described as an important cause of MetS. New insights suggest a role for abdominal radiotherapy as a determinant for MetS as well. The role of other risk factors, such as specific chemotherapeutic agents, steroids, gonadal impairment, thyroid morbidity and genetics, warrants further investigation. This knowledge is important to define subgroups of CCS that are at risk to develop (subclinical) MetS features. These survivors might benefit from standard surveillance and early interventions, for example lifestyle and diet advice and medical treatment, thereby preventing the development of cardiovascular disease.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency.

INTRODUCTION AND BACKGROUND: Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al. OBJECTIVE: To investigate whether normative data of the VARIETE cohort lead to differences in Z-scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al. DESIGN: We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH-deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al. RESULT: Before GH treatment, Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al: -2.40 (-4.52 to +1.31) (mean [range]) vs. -1.41 (-3.14 to +1.76); P < .001). After 12 months of GH treatment, again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al: -0.65 (-4.32 to +2.79) vs 0.21 (-3.00 to +3.28); P < .001). CONCLUSION: IGF-I Z-scores in 102 GH-deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice, this would most likely have led to different clinical interpretations and GH dose adjustments.

[Non-invasive brain stimulation in schizophrenia: hallucinations and negative symptoms]. / Non-invasieve hersenstimulatie bij schizofrenie, gericht op hallucinaties en negatieve symptomen.

BACKGROUND: New approaches are needed in the treatment of characteristic symptoms of schizophrenia such as hallucinations and negative symptoms. Non-invasive brain stimulation can make a useful contribution.
AIM: To discuss the published evidence regarding efficacy and safety of repetitive transcranial magnetic stimulation (rtms) and transcranial direct current stimulation (tdcs) when used in the treatment of auditory verbal hallucinations and negative symptoms.
METHOD: We review and discuss recent meta-analyses and we analyse relevant factors.
RESULTS: On average, when compared to sham-stimulation, rtms was found to have a significant effect on hallucinations and negative symptoms. Nevertheless, the results of some studies were variable and some studies did not report any improvement. There are indications that some factors such as age and distance between scalp and cortex may influence efficiency. There were only a few studies relating to the use of tdcs and none of these reported a clear effect.
CONCLUSION: There is reasonable evidence that rtms is an efficient treatment for hallucinations and negative symptoms, although some variable results have been reported. There is insufficient evidence for conclusions to be drawn about the efficacy of tdcs for the treatment of hallucinations and negative symptoms. However, both simulation methods are safe and largely without side-effects.

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.

BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.

Longitudinal follow-up in female Childhood Cancer Survivors: no signs of accelerated ovarian function loss.

STUDY QUESTION: Is the long-term decline of ovarian function, as reflected by a decrease in serum anti-Müllerian hormone (AMH) concentration, accelerated over time in female childhood cancer survivors (CCS) as compared to healthy women of the same age? SUMMARY ANSWER: The median decline of AMH levels in long-term female CCS is not accelerated and similar to that observed in healthy controls. WHAT IS KNOWN ALREADY: Gonadal function is compromised in female CCS treated with chemotherapy and/or radiation therapy. Ovarian function is most compromised in survivors treated with total body irradiation, abdominal or pelvic irradiation, stem cell transplantation or high doses of alkylating agents. STUDY DESIGN SIZE, DURATION: Longitudinal single-centre cohort study in 192 CCS in Rotterdam, The Netherlands, between 2001 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH levels of 192 adult female CCS were assessed, at least five years after cessation of treatment and at a follow-up visit with a median of 3.2 years (range: 2.1-6.0) later and were compared to the age-based P50 of AMH in healthy controls. MAIN RESULTS AND THE ROLE OF CHANCE: Median AMH levels were below the P50 at both visit 1 (-0.59 µg/L) and at visit 2 (-0.22 µg/L). In women with a sustained ovarian function (AMH > 1.0 µg/L), the decline in AMH is similar to that in the normal population (difference in decline per year: -0.07 µg/L (range: -2.86 to 4.92), P  = 0.75). None of the treatment modalities was correlated with a significant acceleration of decline of AMH per year. LIMITATIONS REASONS FOR CAUTION: We selected CCS that visited our late effect outpatient clinic and who had two AMH levels available. It is conceivable that women without any apparent late effects of treatment as well as women with extreme late effects, which might be the ones with the largest impact on ovarian function, could be more likely to be lost to follow-up. However, general characteristics did not differ between the included and excluded patients. WIDER IMPLICATIONS OF THE FINDINGS: While prospective longitudinal research is required to strengthen our findings, they may help physicians to counsel female CCS about their expected reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: A.L.F.v.d.K., M.M.v.d.H.-E. and S.M.F.P. are supported by FP7-PanCare LIFE. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. The other authors have no conflicts of interest to declare.

Efficacy and safety of bariatric surgery for craniopharyngioma-related hypothalamic obesity: a matched case-control study with 2 years of follow-up.

BACKGROUND: Hypothalamic obesity is a devastating consequence of craniopharyngioma. Bariatric surgery could be a promising therapeutic option. However, its efficacy and safety in patients with craniopharyngioma-related hypothalamic obesity remain largely unknown. OBJECTIVES: We investigated the efficacy of bariatric surgery for inducing weight loss in patients with craniopharyngioma-related hypothalamic obesity. In addition, we studied the safety of bariatric surgery regarding its effects on hormone replacement therapy for pituitary insufficiency. METHODS: In this retrospective matched case-control study, we compared weight loss after bariatric surgery (that is, Roux-en-Y gastric bypass and sleeve gastrectomy) between eight patients with craniopharyngioma-related hypothalamic obesity and 75 controls with 'common' obesity during 2 years of follow-up. We validated our results at 1 year of follow-up in a meta-analysis. In addition, we studied alterations in hormone replacement therapy after bariatric surgery in patients with craniopharyngioma. RESULTS: Mean weight loss after bariatric surgery was 19% vs 25% (difference -6%, 95% confidence of interval (CI) -14.1 to 4.6; P=0.091) at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity compared with control subjects with 'common' obesity. Mean weight loss was 25% vs 29% (difference -4%, 95% CI -11.6 to 8.1; P=0.419) after Roux-en-Y gastric bypass and 10% vs 20% (difference -10%, 95% CI -14.1 to -6.2; P=0.003) after sleeve gastrectomy at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity vs control subjects with 'common' obesity. Our meta-analysis demonstrated significant weight loss 1 year after Roux-en-Y gastric bypass, but not after sleeve gastrectomy. Seven patients with craniopharyngioma suffered from pituitary insufficiency; three of them required minor adjustments in hormone replacement therapy after bariatric surgery. CONCLUSIONS: Weight loss after Roux-en-Y gastric bypass, but not sleeve gastrectomy, was comparable between patients with craniopharyngioma-related hypothalamic obesity and control subjects with 'common' obesity at 2 years of follow-up. Bariatric surgery seems safe regarding its effects on hormone replacement therapy.

Risk factors for subsequent endocrine-related cancer in childhood cancer survivors.

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen-progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen-progestin replacement therapy on radiation-induced breast cancer require further study.

The effect of hypopituitarism on fatigue after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) survivors often complain of fatigue, which is disabling. Fatigue is also a common symptom of pituitary dysfunction (PD), in particular in patients with growth hormone deficiency (GHD). A possible association between fatigue after SAH and long-term pituitary deficiency in SAH survivors has not yet been established. METHODS: A single center observational study was conducted amongst 84 aneurysmal SAH survivors to study the relationship between PD and fatigue over time after SAH, using mixed model analysis. Fatigue was measured with the Fatigue Severity Scale and its relationships with other clinical variables were studied. RESULTS: Three-quarters of respondents (76%) have pathological fatigue directly after SAH and almost two-thirds (60%) of patients still have pathological levels of fatigue after 14 months. The severity of SAH measured with a World Federation of Neurosurgical Societies (WFNS) score higher than 1 (P = 0.008) was associated with long-term fatigue. There is no statistically significant effect of PD (P = 0.8) or GHD (P = 0.23) on fatigue in SAH survivors over time. CONCLUSIONS: Fatigue is a common symptom amongst SAH survivors. WFNS is a usable clinical determinant of fatigue in SAH survivors. Neither PD nor GHD has a significant effect on long-term fatigue after SAH.

What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

CONTEXT: Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients' comfort, but the efficacy is unknown. OBJECTIVE: To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. DESIGN: Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. SUBJECTS AND METHODS: The study included 15 subjects (eight males), with a median age of 58 years (range 35-80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. RESULTS: After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30-0.84) to 0.83 × ULN (0.30-1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30-80) mg to 80 (50-120) mg. CONCLUSION: Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.

Combined treatment of somatostatin analogues with pegvisomant in acromegaly.

Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV.

Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review.

BACKGROUND: Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients. METHODS: Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE. RESULTS: In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity. CONCLUSION: Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC.