Congenital Tooth Agenesis and Risk of Early-Onset Cancer.

Importance: There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting. Objective: To examine the association between tooth agenesis and specific cancer types before 40 years of age. Design, Setting, and Participants: This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 years. Data were analyzed from January through June 2023. Exposure: Tooth agenesis as documented by the Danish Central Registry of Odontology (Danish municipal pediatric dental care) from January 1, 1988, to December 31, 2018, and from hospital encounters in the Danish National Patient Registry within the entire study period. Main Outcome and Measures: The primary outcome was first cancer diagnosis before 40 years of age obtained from the Danish Cancer Registry. Associations between tooth agenesis and specific cancers were estimated by Cox proportional hazards regression as hazard ratios (HRs) with 95% CIs. Analyses were split into age groups: younger than 1 year, 1 to younger than 3 years, 3 to younger than 10 years, 10 to younger than 20 years, 20 to younger than 30 years, and 30 to younger than 40 years. Associations with nonsyndromic tooth agenesis were evaluated after exclusion of individuals with known syndromes. Results: Among 2 501 715 included individuals (1 284 292 [51.3%] male), 70 288 (2.8%) had a diagnosis of tooth agenesis (mean [SD] age at diagnosis, 13.2 [4.1] years) and 26 308 (1.1%) had a diagnosis of early-onset cancer within the study period; 778 individuals had co-occurrence of tooth agenesis and cancer. Overall, tooth agenesis was positively associated with several cancer types, including neuroblastoma (age 1 to <3 years; HR, 4.20; 95% CI, 2.24-7.88), nephroblastoma (age 1 to <3 years; HR, 4.59; 95% CI, 2.37-8.91), hepatoblastoma (age 1 to <3 years; HR, 7.10; 95% CI, 2.70-18.68), osteosarcoma (age 10 to <20 years; HR, 2.19; 95% CI, 1.11-4.32), colorectal carcinomas (age 30 to <40 years; HR, 2.81; 95% CI, 1.38-5.71), and carcinomas of bladder (age 20 to <30 years; HR, 3.35; 95% CI, 1.35-8.30). Conclusions and Relevance: This cohort study found associations between congenital tooth agenesis and several cancer types, from childhood to early adulthood. Further evaluation of these associations is needed to assess possible clinical implications.

Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study.

INTRODUCTION: Glucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear. METHODS: We conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases. RESULTS: We found no effect on breast cancer risk in ever users (> 2 prescriptions) of any glucocorticoids (adjusted odds ratio (aOR) = 1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR = 1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR = 1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding two years) and former use (more than two years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (< 1, 1 to 5, 5+ years), was also not associated with breast cancer risk. CONCLUSIONS: Overall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.

Long-Term Risk of Hospitalization for Somatic Diseases Among Survivors of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) may be at increased long-term risk of hospitalization for somatic diseases. However, large population-based cohort studies with risk estimates for survivors successfully cured without experiencing a relapse or requiring hematopoietic stem cell transplantation (HSCT) are lacking. METHODS: Danish and Swedish patients diagnosed with ALL before age 20 years in 1982-2008 were identified in the national cancer registries. Five-year survivors and matched population comparisons without childhood cancer were followed for hospitalization for 120 somatic disease categories in the national hospital registries from 5 years postdiagnosis until 2017, and disease-specific hospitalization rate ratios (RR) were calculated. The mean cumulative count method was used to estimate the mean number of multiple and recurrent disease-specific hospitalizations per individual. RESULTS: A total of 2024 5-year survivors and 9797 population comparisons were included. The overall hospitalization rate was more than twice as high compared with comparisons (RR = 2.30, 95% confidence interval [CI] = 2.09 to 2.52). At 30 years postdiagnosis, the mean cumulative hospitalization count was 1.69 (95% CI = 1.47 to 1.90) per survivor and 0.80 (95% CI = 0.73 to 0.86) per comparison. In the subcohort without relapse or HSCT (n = 1709), the RR was 1.41 (95% CI = 1.27 to 1.58). CONCLUSIONS: Survivors of childhood ALL were at increased long-term risk for disease-specific hospitalizations; however, in survivors without relapse or HSCT, the rate was only modestly higher than in population comparisons without a childhood cancer. The absolute mean numbers of multiple and recurrent hospitalizations were generally low.

The epidemiology of herpes zoster in 226 children with acute lymphoblastic leukemia.

BACKGROUND: Herpes zoster (HZ) is rare in healthy children, but may occur frequently and take a complicated course in children receiving chemotherapy. We determined the morbidity related to HZ in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: Medical records of 226 children diagnosed with ALL were reviewed. Of these, 160 were seropositive at the time of diagnosis. HZ eruptions during primary chemotherapy, during therapy for relapse and following bone marrow transplantation (BMT) were registered. RESULTS: A total of 90 eruptions were recorded: 63 first-time attacks and 27 recurrent episodes among 14 children. All eruptions were treated with acyclovir (ACV) and in 60% it was given intravenously. Cutaneous dissemination occurred in 11 cases, post herpetic neuralgia in five, visceral dissemination in none. During primary chemotherapy 47 children (29%) had HZ. The eruption rate was significantly higher in children on high risk protocols compared to children on standard/intermediate risk protocols (0.36 vs. 0.07/0.09 per year) and was related to intensity of chemotherapy. During therapy for relapse 7 of 29 (24%) had a total of 13 eruptions. Following BMT 9 of 26 (35%) had a total of 10 eruptions. CONCLUSION: Almost one third of the seropositive children had HZ during primary chemotherapy. Of those treated on high risk protocols more than half had one or more eruptions during the course of treatment. The risk of complicated HZ is small, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions. Attempts to improve immunity by vaccination after attaining remission seem warranted.

Long-Term Risk of Hospitalization Among Five-Year Survivors of Childhood Leukemia in the Nordic Countries.

BACKGROUND: Adverse effects from childhood leukemia treatment may persist or present years after cure from cancer. We provide a comprehensive evaluation of subsequent hospitalization in five-year survivors of childhood acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). METHODS: In the Adult Life after Childhood Cancer in Scandinavia Study, we identified 4003 five-year survivors diagnosed with childhood leukemia 1970-2008 in Denmark, Sweden, Iceland, and Finland. Survivors and 129 828 population comparisons were followed for first-time nonpsychiatric hospitalizations for 120 disease categories in the hospital registries. Standardized hospitalization rate ratios and absolute excess rates were calculated. All statistical tests were two-sided. RESULTS: Survivors of ALL (n = 3391), AML (n = 389), and CML (n = 92) had an increased overall hospitalization rate compared with population comparisons. The rate ratio for any hospitalization was 1.95 (95% confidence interval [CI] = 1.83 to 2.07) in ALL, 3.09 (95% CI = 2.53 to 3.65) in AML, and 4.51 (95% CI = 3.03 to 6.00) in CML survivors and remained increased even 20 years from leukemia diagnosis. Corresponding absolute excess rates per 1000 person-years were 28.48 (95% CI = 24.96 to 32.00), 62.75 (95% CI = 46.00 to 79.50), and 105.31 (95% CI = 60.90 to 149.72). CONCLUSION: Leukemia survivors have an increased rate of hospitalization for medical conditions. We provide novel insight into the relative and absolute rate of hospitalization for 120 disease categories in survivors of ALL, AML, and CML, which are likely to be informative for both survivors and healthcare providers.

Anaphylaxis to Paracetamol in a Twelve-Year-Old Girl.

Paracetamol (acetaminophen) is widely used and considered safe, since adverse reactions to this drug in therapeutic doses are rare, especially in children.1,2 Only a few cases worldwide of anaphylaxis to paracetamol in children have previously been described.2-11 Anaphylaxis is defined as a life-threatening reaction resulting from mast cell derived mediator release.12 This report illustrates a case of anaphylaxis to oral paracetamol confirmed by an oral provocation test and an increase in serum tryptase level.

Use of ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study.

PURPOSE: To estimate associations between use of ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. PATIENTS AND METHODS: We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. ß-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. RESULTS: Compared with never users, users of any ß-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual ß-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). CONCLUSION: Our data do not support the hypothesis that ß-blockers attenuate breast cancer recurrence risk.

Risk of cancer in patients with inflammatory bowel disease and venous thromboembolism: a nationwide cohort study.

BACKGROUND: Venous thromboembolism (VTE) may be a harbinger of cancer. Inflammatory bowel disease (IBD) is known to increase the risk of VTE, but it is unclear whether VTE in IBD patients is also a marker for occult cancer. We assessed the risk of cancer after VTE in IBD patients. METHODS: We conducted a population-based cohort study by linking Danish medical registries during 1978-2008. We calculated standardized incidence ratios (SIRs) by comparing observed cancer incidence after VTE in IBD patients with that expected based on national cancer incidence in the Danish population. RESULTS: A total of 895 IBD patients with VTE were followed for a total of 5290 person-years. During the first year of follow-up, 28 (3.1%) patients were diagnosed with cancer, corresponding to an SIR of 3.2 (95% confidence interval [CI]: 2.2, 4.7). Patients with ulcerative colitis or Crohn's disease had similar relative risks (SIR = 3.1 [95% CI: 1.9, 4.9] and SIR = 3.5 [95% CI: 1.7, 6.3], respectively). In IBD patients <55 years the SIR was 5.7 (95% CI: 2.3, 11.8) and in patients ≥55 years the SIR was 2.8 (95% CI: 1.8, 4.3). During the second and subsequent years of follow-up 61 cancers were diagnosed (SIR = 1.2 [95% CI: 0.92, 1.6]). CONCLUSIONS: In patients with IBD a VTE event is not only a consequence of their disease, but might also be a marker of occult cancer. We suggest that IBD patients with VTE should follow the same diagnostic work-up guidelines as non-IBD VTE patients.

Survival of women with breast cancer in central and northern Denmark, 1998-2009.

OBJECTIVE: Breast cancer is the most common cancer among women worldwide. The Nordic countries have relatively high survival, but Denmark has a lower survival than neighboring countries. A breast cancer screening program was introduced in 2007 and 2008 in the northern and central regions of Denmark respectively. We aimed to examine possible changes in survival of Danish breast cancer patients in central and northern Denmark in the period 1998-2009. MATERIALS AND METHODS: From the northern and central Denmark regions, we included all women (n = 13,756) with an incident diagnosis of breast cancer, as recorded in the Danish National Registry of Patients during the period January 1, 1998 through December 31, 2009. We calculated age-stratified survival and used Cox proportional hazard regression to estimate mortality rate ratios (MRRs) for all breast cancer patients. RESULTS: Median age was 62 years (21-102 years). The overall 1-year survival improved steadily over the period from 90.9% in 1998-2000 to 94.4% in 2007-2009, corresponding to a 1-year age adjusted MRR of 0.68 in 2007-2009 compared with the reference period 1998-2000. We estimated the 5-year survival to improve from 70.0% in 1998-2000 to 74.7% in 2007-2009, corresponding to a 5-year age adjusted MRR of 0.82 in 2007-2009 compared with the reference period 1998-2000. For middle-aged women (50-74 years) 1-year survival increased from 92.8% in 1998-2000 to 96.6% in 2008-2009, and 5-year survival was expected to increase from 73.9% in 1998-2000 to 80.2% in 2007-2009. Among younger women (15-49 years) and elderly women (>75 years), 1-year survival and 5-year predicted survival did not change over the two time periods. CONCLUSION: Survival of breast cancer patients has improved in Denmark over the period 1998-2009, and this change was most distinct in women aged 50-74 years. Survival improved even before the implementation of a formal breast cancer screening program.

[Herpes zoster-associated morbidity in children undergoing chemotherapy for acute lymphoblastic leukaemia]. / Herpes zoster-associeret morbiditet hos børn i kemoterapi for akut lymfoblastaer leukaemi.

INTRODUCTION: Herpes zoster rarely occurs in healthy children, but may occur frequently and may take a complicated course in children receiving chemotherapy. We aimed to assess morbidity from herpes zoster in children with acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: Reviewing records, treatment and course of zoster eruptions were registered in a cohort of 67 children with newly diagnosed ALL. Of these, 45 had had varicella at the time of diagnosis and 15 contracted varicella or were vaccinated during the course of therapy. RESULTS: Eleven children had a total of 17 eruptions while receiving chemotherapy. All eruptions were treated with acyclovir, in eight cases intravenously, and in six cases chemotherapy was interrupted. Cutaneous dissemination occurred in two cases, visceral dissemination in none. One child had postherpetic trigeminal neuralgia for two months. The eruption rate was higher among small children than among school-aged children (0.22 vs. 0.13 per year of chemotherapy) and was related to the intensity of chemotherapy (0.30 per year of consolidation treatment vs. 0.13 for maintenance therapy). Three children on prolonged intensive chemotherapy had recurrent zoster episodes. CONCLUSION: Chemotherapy causes zoster eruptions in approximately one quarter of children with ALL, and with intensive protocols recurrent zoster can cause significant morbidity. Attempts to improve immunity by vaccine boosting after attaining remission seems warranted.

[Varicella-associated morbidity in children undergoing chemotherapy for acute lymphoblastic leukaemia]. / Varicel-associeret morbiditet hos børn i kemoterapi for akut lymfoblastaer leukaemi.

INTRODUCTION: In children with cancer, varicella can be complicated by visceral dissemination with a risk of fatal outcome, especially in children with acute lymphoblastic leukaemia (ALL). Immunoprophylaxis and antiviral therapy have reduced the mortality, but the morbidity remains significant and is explored here in a cohort of children with ALL. MATERIAL AND METHODS: Among 67 children diagnosed with ALL during 1992-2007, 22 were seronegative for varicella-zoster virus (VZV) at the time of diagnosis. Patient records were reviewed to describe varicella exposures, eruptions and vaccinations during chemotherapy (24-30 months) and the following six months of immune recovery. RESULTS: Fifteen exposures were recognised in eight children and were managed with oral acyclovir prophylaxis; three resulted in clinical infection. Adoption of brief prophylaxis in the second week of incubation has not - so far - increased the infection rate (one in six versus two in nine). A further six varicella cases occurred without recognised exposure. All nine eruptions (in eight children) were uncomplicated but entailed hospitalisation days for intravenous therapy with acyclovir and loss of chemotherapy days. Seven children were VZV-vaccinated during maintenance chemotherapy; none developed varicella or zoster later in the course. CONCLUSION: Despite protective isolation and prophylactic treatment, seronegative children with ALL have a high risk of varicella during or shortly after chemotherapy. We recommend that susceptible siblings should be vaccinated at the time of diagnosis and the child should receive vaccination once oral maintenance chemotherapy has been initiated.