Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator-mandated cohort postauthorization safety study in Denmark, Norway, and Sweden.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. METHODS: This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS: There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS: This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY: Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)-death of a jawbone-is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid-treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.

Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010.

BACKGROUND: Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites. MATERIALS AND METHODS: Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high. RESULTS: We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%). CONCLUSION: The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness.

Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events.

OBJECTIVE: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. METHODS: As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA(®) clinical trials program. CONCLUSION: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies.

Colorectal cancer and the methylenetetrahydrofolate reductase 677C -> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort.

Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of colorectal cancer. We evaluated the relation between the polymorphisms 677C --> T of the methylenetetrahydrofolate reductase (MTHFR) and 2756A --> G of the methionine synthase (MTR) genes and risk of colorectal cancer. From the Norwegian JANUS cohort of 309,000 subjects, 2,179 cases were identified and a similar number of controls were selected. The controls were matched for age, gender, time, and place of serum donation. Genotypes were obtained from 2,168 case-control pairs by real-time PCR of serum samples. Risk of colorectal cancer was estimated with conditional and unconditional logistic regression. Median age at diagnosis was 60 years and mean follow-up 13 years. The odds ratio for MTHFR TT versus CC was 0.73 [95% confidence interval (95% CI), 0.58-0.92] and for MTR GG versus AA was 0.65 (95% CI, 0.47-0.90). No interaction between the polymorphisms was found. Relative risk estimates were similar for men and women, and for young and old age at diagnosis. For the MTR GG genotype, risk reduction was observed at the two most distal sites (sigmoideum and rectum) only (P = 0.003). The folate marker, serum total homocysteine (tHcy), was measured in 1,837 subjects. Odds ratio for the upper versus the lower tertile of tHcy was 1.32 (95% CI, 1.04-1.68). No significant effect modification by tHcy levels was detected for either polymorphism. In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected.

Height and body mass index and risk of lymphohematopoietic malignancies in two million Norwegian men and women.

Reports on the association between obesity and lymphohematopoietic malignancies (LHMs) have been inconsistent. The present study aimed at exploring this association for specific disease lymphohematopoietic entities in a large Norwegian cohort. Height and weight were measured in two million Norwegian men and women aged 20-74 years during 1963-2001. During follow-up, 24,500 cases of LHMs were observed. Relative risks of disease were estimated by Cox proportional hazards regression. The risk of LHMs overall increased moderately by increasing body mass index and height in both sexes. The relative risk of LHMs per five-unit increase in body mass index was 1.11 (95% confidence interval (CI): 1.08, 1.14) in men and 1.08 (95% CI: 1.05, 1.11) in women. For each 10-cm increase in height, the relative risk was 1.19 (95% CI: 1.16, 1.22) in men and 1.16 (95% CI: 1.12, 1.20) in women. Separate analyses for different lymphohematopoietic malignancies did not reveal any group's being particularly strongly associated with body mass index. A modest increase in the risk of LHMs combined was observed with increasing height. The moderate associations between height and body mass index and LHMs found in the present study indicate that the observed increase in overweight/obesity plays only a minor role in explaining the increase in the incidence of LHMs.

Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status.

BACKGROUND: Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear. AIM: To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach. METHODS: Nested case-control study. To each of 129 non-cardia and 44 cardia cancers, three controls were matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin. RESULTS: Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and gastric atrophy (pepsinogen I:II <2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32 to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1). CONCLUSION: These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer.

Is there an association between SV40 contaminated polio vaccine and lymphoproliferative disorders? An age-period-cohort analysis on Norwegian data from 1953 to 1997.

Between 1955 and 1963, an estimated number of 150 million people in various parts of the world, including Norway, received poliomyelitis vaccine possibly contaminated with infectious simian virus 40 (SV40). Human studies have investigated the hypothesised association between SV40 and various cancers, but the results have so far been contradicting. The aim of the present study was to examine Norwegian cancer incidence data to assess a possible association between birth cohorts assumed to have been subjected to the vaccine and the incidence rate of lymphoproliferative disorders (excluding Hodgkin's lymphoma), further subdivided into non-Hodgkin's lymphoma (NHL), lymphocytic leukemia and plasma cell neoplasms. Between 1953 and 1997, the incidence rate of lymphoproliferative diseases combined increased about 3-fold in both males and females. Subgroup analysis showed that this increase was largely attributable to NHL. Age-period-cohort modelling of the subgroups, as well as of all groups combined, showed that the cohort effect was more prominent than the period effect. However, the variations in incidence patterns across the birth cohorts did not fit with the trends that would be expected if a SV40 contaminated vaccine did play a causative role. Thus, our data do not support the hypothesis of an association between the vaccine and any subgroup of lymphoproliferative diseases.

Determination of hereditary mutations in the BRCA1 gene using archived serum samples and capillary electrophoresis.

Analysis of DNA variation in biological samples most frequently utilizes the polymerase chain reaction (PCR) performed on extracted genomic DNA, followed by visualization of alleles using various methodologies. Few reports have demonstrated that amplification of DNA from plasma and serum samples is possible. We have performed DNA amplification on a large set of serum samples (n = 2955). Here, we report that known hereditary mutations in the BRCA gene can efficiently be analyzed in serum samples collected and stored over several decades. Fragments were PCR-amplified following a short initial denaturation of the serum sample in a standard microwave oven. Fragment analysis was subsequently performed using a DNA capillary-sequencing instrument. The PCR success rates were fragment- and size-dependent ranging from 83.2% to 97.9%. Of the 11,820 polymerase chain reactions performed, the overall PCR success rate was 91.3% (10,796/11,820), which is comparable to PCR performed on genomic DNA. The advantage of the method described herein is its ability to utilize archival material stored in serum biobanks for long periods of time.