Risk of second malignancies in long-term survivors of childhood cancer.

INTRODUCTION: Childhood cancer survivors are known to be at increased risk for second malignancies. PATIENTS AND METHODS: The risk of second malignancies was assessed in 1368 5-year survivors of childhood cancer treated in the Emma Children's Hospital AMC in Amsterdam. The median follow-up time was 16.8 years. RESULTS: Sixty two malignancies were observed against 5.4 expected, yielding a standardised incidence ratio (SIR) of 11.2 (95% confidence interval: 8.53-14.4; absolute excess risk: 3.2 per 1000 person-years). New observations were the strongly increased risks of meningiomas (SIR=40) and basal cell carcinomas (SIR=9). Patients whose treatment involved radiotherapy had a 2-fold increased second cancer risk compared to patients with chemotherapy alone. DISCUSSION: The relative risk of second malignancies does not decrease till at least 30 years of follow-up. With aging of the survivor cohort this results in a strong increase of the AER, due to the rising background risk of cancer with age.

Development of a national protocol to screen Dutch cancer survivors on late cancer treatment effects.

PURPOSES: The development of a national protocol to formalize the screening of Dutch cancer survivors on potential late cancer treatment effects and the medical terminology used in describing the patient follow up procedures. METHODS: A combined evidence-based and qualitative approach, the Glaser's State of the Art Strategy, was used to reach consensus on how to screen Dutch cancer survivors on late cancer treatment effects. A core working group set up a first proposal of a screening protocol and a handbook of medical term definitions by incorporating available research evidence (1980-2003), clinical expertise and definitions from Dutch medical dictionaries and textbooks. External experts reviewed this proposal in a cycle of two postal and two discussion rounds. The follow-up procedures and medical term definitions described in the draft screening protocol were to be accepted if consensus among external experts was > or =50%. RESULTS: A protocol for screening cancer survivors on late cancer treatment effects was developed describing the follow-up procedures for cancer survivors according to previous therapeutic exposures. Four hundred and twenty one medical terms were used in describing these follow-up procedures. One hundred and fifteen of these terms were classified as multi-interpretable and 101 of these terms were defined. No definitions could be found for the remaining 14 medical terms. CONCLUSIONS: We succeeded in reaching consensus throughout The Netherlands on a protocol to screen cancer survivors on late cancer treatment effects. This protocol is now in use by all Dutch outpatient clinics and warrants that the screening of cancer survivors is consistent across The Netherlands. The screening protocol specifies in detail how screening of cancer survivors should take place and can therefore be used by clinicians who were not involved in the consensus study.

Identification of the divergent calmodulin binding motif in yeast Ssb1/Hsp75 protein and in other HSP70 family members.

Yeast soluble proteins were fractionated by calmodulin-agarose affinity chromatography and the Ca2+/calmodulin-binding proteins were analyzed by SDS-PAGE. One prominent protein of 66 kDa was excised from the gel, digested with trypsin and the masses of the resultant fragments were determined by MALDI/MS. Twenty-one of 38 monoisotopic peptide masses obtained after tryptic digestion were matched to the heat shock protein Ssb1/Hsp75, covering 37% of its sequence. Computational analysis of the primary structure of Ssb1/Hsp75 identified a unique potential amphipathic alpha-helix in its N-terminal ATPase domain with features of target regions for Ca2+/calmodulin binding. This region, which shares 89% similarity to the experimentally determined calmodulin-binding domain from mouse, Hsc70, is conserved in near half of the 113 members of the HSP70 family investigated, from yeast to plant and animals. Based on the sequence of this region, phylogenetic analysis grouped the HSP70s in three distinct branches. Two of them comprise the non-calmodulin binding Hsp70s BIP/GR78, a subfamily of eukaryotic HSP70 localized in the endoplasmic reticulum, and DnaK, a subfamily of prokaryotic HSP70. A third heterogeneous group is formed by eukaryotic cytosolic HSP70s containing the new calmodulin-binding motif and other cytosolic HSP70s whose sequences do not conform to those conserved motif, indicating that not all eukaryotic cytosolic Hsp70s are target for calmodulin regulation. Furthermore, the calmodulin-binding domain found in eukaryotic HSP70s is also the target for binding of Bag-1 - an enhancer of ADP/ATP exchange activity of Hsp70s. A model in which calmodulin displaces Bag-1 and modulates Ssb1/Hsp75 chaperone activity is discussed.

Screening for late effects in survivors of childhood cancer: growth hormone deficiency from a pediatric oncologist's point of view.

At the Emma Kinderziekenhuis/Academic Medical Center in Amsterdam, survivors of childhood cancer are screened annually or biennially for the occurrence of late treatment effects. The screening procedures are based on previously used treatment modalities. The data gathered at the outpatient clinic are registered in the database PLEKsys. Evaluation of the data concerning over 1000 cancer survivors screened since the start of the clinic once more illustrated the relation between cranial irradiation and the development of central endocrine abnormalities. Surprisingly, at least a proportion of the growth hormone (GH)-deficient cancer survivors were registered as not being on a replacement therapy regimen. The reasons for survivors not to be on replacement therapy are currently being evaluated. The late-effects outpatient clinic and the PLEKsys database provide a platform for additional research in fields including endocrinology, which should be aimed at improving the care for and the health status of the survivors of childhood cancer.

The EKZ/AMC childhood cancer survivor cohort: methodology, clinical characteristics, and data availability.

PURPOSE: Childhood cancer survivors are at high risk of late adverse effects of cancer treatment, but there are still many gaps in evidence about these late effects. We described the methodology, clinical characteristics, data availability, and outcomes of our cohort study of childhood cancer survivors. METHODS: The Emma Children's Hospital/Academic Medical Center (EKZ/AMC) childhood cancer survivor cohort is an ongoing single-center cohort study of ≥5-year childhood cancer survivors, which started in 1996 simultaneously with regular structured medical outcome assessments at our outpatient clinic. RESULTS: From 1966 to 2003, 3,183 eligible children received primary cancer treatment in the EKZ/AMC, of which 1,822 (57.2 %) survived ≥5 years since diagnosis. Follow-up time ranged from 5.0 to 42.5 years (median, 17.7). Baseline primary cancer treatment characteristics were complete for 1,781 (97.7 %) survivors, and 1,452 (79.7 %) survivors visited our outpatient clinic. Baseline characteristics of survivors who visited the clinic did not differ from those without follow-up. Within our cohort, 54 studies have been conducted studying a wide range of late treatment-related effects. CONCLUSIONS: The EKZ/AMC childhood cancer survivor cohort provides a strong structure for ongoing research on the late effects of childhood cancer treatment and will continuously contribute in reducing evidence gaps concerning risks and risk groups within this vulnerable population. IMPLICATIONS FOR CANCER SURVIVORS: Our large cohort study of childhood cancer survivors with complete baseline characteristics and unique, long-term medical follow-up decreases gaps in evidence about specific risks of late effects and high-risk groups, with the ultimate goal of improving the quality of care for childhood cancer survivors.

Hypertension in long-term survivors of childhood cancer: a nested case-control study.

AIM OF THE STUDY: To examine risk factors for developing hypertension in childhood cancer survivors (CCS). METHODS: We conducted a nested case-control study of risk for hypertension within a cohort of 1362 childhood cancer survivors treated between 1966 and 1996 in the Emma's Children's Hospital/Academic Medical Center in the Netherlands. Detailed information on treatment and several lifestyle factors was collected for 44 cases with hypertension and 123 matched controls. Odds ratios (ORs) for hypertension were calculated by conditional logistic regression analysis. RESULTS: Body Mass Index (BMI) was the only significant risk factor associated with the occurrence of hypertension (OR 3.95; 95% confidence interval (CI) 1.7-9.1 for BMI25kg/m(2) compared to BMI<25kg/m(2)). However, cisplatin, cyclophosphamide and radiotherapy (RT) to the abdominal region were all associated with non-significant risk increases (ORs of 4.3, 2.1, and 1.8, respectively). CONCLUSION: Our results show that BMI is the most important risk factor for hypertension following treatment of childhood cancer, emphasising the need for CCS to maintain a normal weight.

Long-term cause-specific mortality among five-year survivors of childhood cancer.

BACKGROUND: The purpose of our study was to assess long-term cause-specific mortality of 5-year childhood cancer survivors. PROCEDURE: The study population consisted of 1,378 patients who had been treated for childhood cancer in The Netherlands between 1966 and 1996 and survived at least 5 years; follow-up was complete for 99% of survivors. Cause-specific mortality was compared with general population rates to assess relative and absolute excess risks of death (standardized mortality ratio (SMR) and AER). RESULTS: After a median follow-up of 16.1 years, 120 patients had died. The overall SMR was 17-fold (95% CI: 14.3-20.6) increased compared to the general population. Our cohort experienced an excess of 7 deaths per 1,000 person-years. Patients who received combined modality treatment and were treated for at least one recurrence experienced the highest risk of death (SMR = 92.3; AER = 37.0 per 1,000 person-years). The SMR appeared to stabilize at an about 4 to 5-fold increased risk of death after 20 years of follow-up. Only after more than 20 years of follow-up excess mortality due to other causes than the primary cancer exceeded mortality from the primary childhood cancer (2.3 vs. 0.3/1,000 patients/year). The SMR for all causes other than primary cancer was 5.4 in 25-year survivors. The overall risks of death strongly decreased with increasing attained age, with an SMR of 1.6 (n.s.) and an AER of 0.3 per 1,000 person-years for survivors of 30 years or older. CONCLUSIONS: The first primary cancer contributes most to the absolute excess risk of death in 5-year survivors of childhood cancer, but after 25 years childhood cancer mortality is negligible. Relative risk of death due to other causes is still significantly increased after 25 years of follow-up.

Identification of the divergent calmodulin binding motif in yeast Ssb1/Hsp75 protein and in other HSP70 family members

Yeast soluble proteins were fractionated by calmodulin-agarose affinity chromatography and the Ca2+/calmodulin-binding proteins were analyzed by SDS-PAGE. One prominent protein of 66 kDa was excised from the gel, digested with trypsin and the masses of the resultant fragments were determined by MALDI/MS. Twenty-one of 38 monoisotopic peptide masses obtained after tryptic digestion were matched to the heat shock protein Ssb1/Hsp75, covering 37 percent of its sequence. Computational analysis of the primary structure of Ssb1/Hsp75 identified a unique potential amphipathic alpha-helix in its N-terminal ATPase domain with features of target regions for Ca2+/calmodulin binding. This region, which shares 89 percent similarity to the experimentally determined calmodulin-binding domain from mouse, Hsc70, is conserved in near half of the 113 members of the HSP70 family investigated, from yeast to plant and animals. Based on the sequence of this region, phylogenetic analysis grouped the HSP70s in three distinct branches. Two of them comprise the non-calmodulin binding Hsp70s BIP/GR78, a subfamily of eukaryotic HSP70 localized in the endoplasmic reticulum, and DnaK, a subfamily of prokaryotic HSP70. A third heterogeneous group is formed by eukaryotic cytosolic HSP70s containing the new calmodulin-binding motif and other cytosolic HSP70s whose sequences do not conform to those conserved motif, indicating that not all eukaryotic cytosolic Hsp70s are target for calmodulin regulation. Furthermore, the calmodulin-binding domain found in eukaryotic HSP70s is also the target for binding of Bag-1 - an enhancer of ADP/ATP exchange activity of Hsp70s. A model in which calmodulin displaces Bag-1 and modulates Ssb1/Hsp75 chaperone activity is discussed.