Long-term follow-up of complex oncoplastic breast-conserving surgery, standard breast conservation and skin-sparing mastectomy in DCIS - a register-based study.

BACKGROUND: Few studies evaluate oncological safety in complex oncoplastic breast-conserving surgery(C-OBCS) for DCIS. It still needs to be defined whether it is equivalent to standard breast conservation(S-BCS) or an alternative to skin-sparing mastectomy(SSM). This study compares local recurrence rates(LR), disease-free survival(DFS) and overall survival (OS) between the three surgical techniques. METHODS: We conducted a retrospective register-based study on LR, DFS and OS of patients operated with S-BCS(n=1388), C-OBCS (n=106) or skin-sparing mastectomy (n=218) for DCIS diagnosed 2007-2020. Data was extracted from the Norwegian Breast Cancer Registry. RESULTS: In the S-BCS, C-OBCS and SSM groups, median age was 60, 58 and 51 years (p<0.001), median size 15, 25, and 40 mm (p<0.001) and median follow-up 55, 48 and 76 months. At ten years, the overall LR was 12.7%, 14.3% for S-BCS, 11.2% for C-OBCS and 6.8% for SSM. Overall DFS at ten years was 82.3%, 80.5% for S-BCS, 82.4% for C-OBCS and 90.4% for SSM. At ten years, the OS was 93.8%, 93.0% in S-BCS, 93.3% in C-OBCS and 96.6% in the SSM group. Weighted Kaplan Meier plots showed that SSM had a significantly higher DFS than S-BCS (p=0.003) and C-OBCS (p=0.029). DFS in C-OBCS versus S-BCS and the difference in OS was not significant (p=0.264). CONCLUSION: SSM had a significantly higher DFS than S-BCS and C-OBCS. The difference in DFS between S-BCS and C-OBCS, and OS between the three groups was not statistically significant. Our study suggests that C-OBCS is a safe alternative to S-BCS and SSM.

Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

Oncological outcomes after simple and skin-sparing mastectomy of ductal carcinoma in situ: A register-based cohort study of 576 Norwegian women.

BACKGROUND: For Ductal Carcinoma in Situ (DCIS), recurrence is shown to be higher after skin-sparing (SSM) versus simple (SM) mastectomy. This study aimed to compare the two groups recurrence rates, disease-free survival (DFS), and overall (OS) survival. METHODS: We conducted a retrospective register-based cohort study of women operated with SSM (n = 338) or SM (n = 238) for DCIS between 2007 and 2017. Data from the Norwegian Breast Cancer Registry was used to estimate recurrences rates, DFS and OS. RESULTS: Mean age was 51 and 61 years in the SSM and SM groups, respectively. Median follow-up time was 77 months for SSM (range: 21-152 months) vs 84 months for SM (range: 7-171 months). After five years of follow-up, the overall recurrence rate (OR) was 2.1%; 3.9% for SSM and 0.9% for SM. After ten years, the rates were 3.0%, 6.2% for SSM and still 0.9% for SM. DFS was after ten years 92.2%; 91.8% for SSM, and 92.4% for SM. OS was 95.0%; 97.5% for SSM and 93.3% for SM at ten years. For SSM, involved margins represented a significant risk for recurrence. CONCLUSION: The recurrence rate was higher in the SSM versus the SM group. Whether the difference is due to the operating procedures or underlying risk factors remains unknown. When stratifying for the difference in age, there was no statistical difference in DFS or OS. Involved margins in the SSM group were associated with an increased risk of recurrence.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Fatal Cholestatic Liver Injury during Treatment with PD1 Immune Checkpoint Inhibitor for Malignant Melanoma: A Case Report.

The use of immune checkpoint inhibitors has dramatically improved the chance of surviving malignant melanomas; however, the effect comes at the cost of toxicities that are difficult to predict. Immune-mediated hepatitis is the most common form of liver toxicity, but fatal outcome is uncommon. We report the case of a 70-year-old female with metastatic malignant melanoma who developed severe liver toxicity characterized by bile duct injury and cholestasis. The condition progressed despite potent immunosuppressive treatment, plasmapheresis, and intensive supportive care; and the patient died while still having tumor response.

High level of circulating vitamin D during neoadjuvant therapy may lower risk of metastatic progression in high-risk rectal cancer.

BACKGROUND: Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patients' circulating 25-hydroxyvitamin D [25(OH)D] levels were associated with outcome. METHODS: Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samples collected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation before surgery, and analyzed with respect to season, disease presentation, and treatment effects. RESULTS: In the cohort of patients residing at latitude 58-62°N, baseline 25(OH)D differed significantly over the seasons, with highest measures (mean of 71.2 ± 5.6 nmol/L) in summer and lowest (48.7 ± 4.5 nmol/L) in spring, and changed over the three-month neoadjuvant period till response evaluation solely owing to season. The patient subgroup with slightly reduced performance status, anemia, and T4 disease that did not respond to the neoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D (below 50 nmol/L) than T4 cases with response (ypT0-3) and T2-3 cases (above 60 nmol/L). Compared to the T4 patients with levels above 50 nmol/L, regarded as sufficient for a healthy bone status, those presenting levels below had significantly heightened risk of disease progression (mainly metastasis) and death, with hazard ratio of 3 and 17, respectively, on adjustment for age, sex, body mass index, and season. CONCLUSION: Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levels were insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse than patients with T2-3 disease when 25(OH)D was sufficient. TRIAL REGISTRATION: ClinicalTrials.gov NCT00278694 ; registration date: 16 January 2006, retrospective to enrollment of the first 10 patients of the current report.

Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females.

AIMS: Ultraviolet (UV) radiation is a major source for vitamin D production. Furthermore, UV destroys cobalamins (also called vitamin B12) in solution. However, data from humans are scarce. The aim of the present study was to clarify if UV exposure has any effect on serum cobalamins, as compared to vitamin D levels, in healthy volunteers. METHODS: This single-center, open observational study was conducted in a research institute: 23 non-pregnant, non-lactating, healthy, fair-skinned female subjects had their serum cobalamin and 25-hydroxyvitamin D (25(OH)D, the marker for vitamin D status) levels measured before and after exposure to UV. RESULTS: UV exposure increased serum 25(OH)D levels from 61.6 nmol/L to 88.5 nmol/L (44%; p < 0.001). A statistically insignificant decay in serum cobalamin levels from 300 pmol/L to 260 pmol/L (13%; p = 0.142) was observed in the volunteers after the first UV exposure; however, no additional decline of statistical significance was seen after subsequent exposures. CONCLUSIONS: Multiple exposure to UV radiation give a significant increase in 25(OH)D levels, but has no detrimental effect on cobalamin concentrations.

Vitamin D levels and dietary intake among patients with benign soft tissue tumors and sarcomas.

BACKGROUND: Calcitriol [1,25(OH)2D] is hypothesized to lower the risk of cancer via binding to the vitamin D receptor (VDR). VDRs are also found in benign and malignant cells of mesenchymal origin. To our knowledge, vitamin D levels and dietary intake have not been previously evaluated in patients newly diagnosed with benign and malignant mesenchymal tumors. PATIENTS AND METHODS: Forty-eight patients with benign soft tissue tumors and 25 patients with sarcoma had their serum 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D and parathyroid hormone levels measured, vitamin D intake scored and body mass index [BMI] calculated. RESULTS: Vitamin D deficiency [25(OH)D level<50 nmol/l] was observed in 19% and 28% of patients with benign tumor and sarcoma, respectively. CONCLUSION: Serum 25(OH)D, 1,25(OH)2D and parathyroid hormone concentrations, BMI and daily vitamin D intake did not differ significantly between the two groups of patients. Higher vitamin D intake or UV exposure is needed to ensure that all patients achieve sufficient vitamin D levels.

Ultraviolet radiation and cutaneous malignant melanoma.

Essential features of the epidemiology and photobiology of cutaneous malignant melanoma (CMM) in Norway were studied in comparison with data from countries at lower latitudes. Arguments for and against a relationship between ultraviolet radiation (UV) from sun and artificial light and CMM are discussed. Our data indicate that UV is a carcinogen for CMM and that intermittent exposures are notably melanomagenic. This hypothesis was supported both by latitude gradients, by time trends and by changing patterns of tumor density on different body localizations. However, even though UV radiation generates CMM, it may also have a protective action and/or an action that improves prognosis. There appears to be no, or even an inverse latitude gradient for CMM arising on non-UV exposed body localizations (uveal melanoma, CMMs arising in the vulva, perianal/anorectal regions, etc.). Furthermore, CMM prognosis was gradually improved over all years of increasing incidence (up to 1990), but during the past 20 years, incidence rates stabilized and prognosis was not improved significantly. Comparisons of skin cancer data from Norway, Australia and New Zealand indicate that squamous cell carcinoma and basal cell carcinoma are mainly related to annual solar UVB fluences, while UVA fluences play a larger role of CMM.

Vitamin D status in healthy Romanian caregivers and risk of respiratory infections.

OBJECTIVES: To investigate the vitamin D status during winter of a healthy population of hospital employees and to assess the correlation between vitamin D status and risk of infections in the upper respiratory tract. DESIGN: One hundred and ten healthy volunteers answered a questionnaire on their solar exposure habits and vitamin D intake and delivered one blood sample for quantification of vitamin D level (serum 25-hydroxyvitamin D (25(OH)D) concentration) during December 2007-January 2008. At the end of the winter we screened for the occurrence of respiratory infections and sought associations with vitamin D status. SETTING: Bucharest, Romania, 45°N. SUBJECTS: One hundred and ten healthy hospital employees. RESULTS: Eighty per cent of participants were vitamin D deficient (25(OH)D level below 50 nmol/l). The main determinant of serum 25(OH)D was sun exposure during the summer previous to the study (P = 0·02 in multivariate analysis). Intake of vitamin D, BMI and age played no significant role for the level of 25(OH)D. Overall we found a non-significant negative correlation between 25(OH)D level and new cases of infection (Spearman correlation coefficient of -0·12, P = 0·2). CONCLUSIONS: Vitamin D status is alarmingly poor in active, relatively young women residing in Romania. If our results are reproduced by other investigations, action to improve vitamin D status at the population level is necessary. We were not able to show a statistically significant relationship between vitamin D status and infection risk in our material.

UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden.

Latitudinal dependencies of UVA and UVB were studied together with relevant epidemiological data for squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM) in Norway and Sweden. Our data support the hypothesis that solar UVA radiation may play a role for CMM induction. The etiologies of SCC and CMM are different according to a latitudinal dependency and differences in age curves. Sun exposure patterns, age-related decay rates of repair of UV damage and sex hormones may play different roles for the two skin cancers. Also, UVB induction of vitamin D may be involved. CMM incidence rates among young people have decreased or been constant since about 1990 in Norway and Sweden. All reasons for UVA contributing to CMM will be discussed.

Vitamin D, sun, sunbeds and health.

OBJECTIVE: To review the health effects of solar radiation, sunbeds and vitamin D. DESIGN: The literature was searched in the electronic database MEDLINE to indentify published data between 1981 and 2011. Studies were included if they reported relative risk for cutaneous malignant melanoma (CMM) associated with sunbed use, vitamin D and UV effects on human health. SETTING: Data from different time periods for populations at different latitudes. SUBJECTS: Persons of different ages and ethnic groups. RESULTS: UV from sun and sunbeds is the main vitamin D source. Young people with white or pigmented skin in northern Europe have a low vitamin D status. A number of health benefits from sufficient levels of vitamin D have been identified. However, UV exposure has been suspected of causing skin cancer, notably CMM, and authorities warn against it. CONCLUSIONS: The overall health benefit of an improved vitamin D status may be more important than the possibly increased CMM risk resulting from carefully increasing UV exposure. Important scientific facts behind this judgement are given.

Vitamin D status in Norwegian children and adolescents with excess body weight.

OBJECTIVES: The prevalence of childhood and adolescent obesity has increased during the past decades. A high body mass index (BMI) is associated with a low vitamin D status. The purpose of this study was to determine the prevalence of vitamin D deficiency and insufficiency in Norwegian children and adolescents with excess body weight. METHODS: Vitamin D status and seasonal variations of 25(OH)D and 1,25(OH)(2)D were analyzed in 102 children and adolescents (70 girls and 32 boys), 8-19 yr of age, with overweight and obesity. RESULTS: Overall, 50% of the children and adolescents included in the study had a low vitamin D status (25(OH)D <75 nmol/L) and 19% had vitamin D deficiency (25(OH)D <50 nmol/L). This was most prevalent in adolescents. Only 42% of teenagers had 25(OH)D levels ≥75 nmol/L vs. 72% of preteens. Both 25(OH)D and 1,25(OH)(2)D showed seasonal variations. A peak in serum 25(OH)D concentrations was observed during the summer while the lowest values were seen during the spring. In contrast, serum 1,25(OH)(2)D had a peak during the spring and the lowest concentrations during the winter. CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency is higher in obese and overweight adolescents than in overweight children. This might be related to low outdoor activities and low vitamin D intake in teenagers. Seasonal variations of both the vitamin D metabolites were observed.

Serum 25-hydroxyvitamin D is a predictor of serum 1,25-dihydroxyvitamin D in overweight and obese patients.

Recent research suggests that 1,25-dihydroxyvitamin D [1,25(OH)(2)D], a steroid hormone that regulates calcium homeostasis, may also play a role in the development and progression of cancer, multiple sclerosis, cardiovascular, and other diseases. Decreased serum 1,25(OH)(2)D concentrations are often observed in overweight and obese patients. However, little is known about the factors that may influence 1,25(OH)(2)D renal synthesis, because it is generally accepted that serum 1,25(OH)(2)D concentration is strictly regulated by parathyroid hormone and serum concentrations of calcium and phosphorus. In this study, the associations among serum 1,25(OH)(2)D, serum 25-hydroxyvitamin D [25(OH)D], and body composition were analyzed in 1779 patients with excess body weight registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. According to our results, serum 25(OH)D, adiposity, age, season of blood sampling, and gender directly influence serum 1,25(OH)(2)D (r = 0.33; P < 0.001), with serum 25(OH)D being the strongest predictor for serum 1,25(OH)(2)D. The 1,25(OH)(2)D concentrations were 25.4 pmol/L (95% Cl: 19.3-31.5; P < 0.001) lower in the lowest 25(OH)D quartile to compared with highest quartile. A seasonal variation was observed for both vitamin D metabolites. Thus, our results suggest that in patients with excess body weight, serum 1,25(OH)(2)D concentrations were associated with 25(OH)D and varied during the year. Therefore, it may also be valuable to measure both serum 25(OH)D and 1,25(OH)(2)D for the evaluation of vitamin D status in overweight and obese persons.

Obesity and increased risk of cancer: does decrease of serum 25-hydroxyvitamin D level with increasing body mass index explain some of the association?

Low levels of vitamin D and excess body weight are both factors associated with increased risk of cancer. The increased risk seems to be proportional to the increase in BMI, and to decrease in serum 25-hydroxyvitamin D (25(OH)D) level. Our earlier investigations suggest that serum 25(OH)D levels decrease with increasing BMI. Although the connection between cancer risk, BMI and vitamin D status might be arbitrary, it has not been discussed in the literature so far. In this study, we analyze data published in current meta-analysis, prospective studies, and systematic reviews on cancer-specific risk attributed to high BMI and low vitamin D status. The contribution of low 25(OH)D levels associated with high BMI to increased cancer risk was calculated for 13 vitamin-D-sensitive cancers with a focus on colorectal and breast cancer as the most frequently studied vitamin-D-sensitive cancer types. Our study suggests that a low vitamin D status may explain at least 20% of the cancer risk attributable to high BMI. The contribution of low 25(OH)D to the increased cancer risk with increasing BMI may be different for different cancer types. Thus, we find 40% for breast cancer, and 26 and 75% for colorectal cancer in men and women, respectively.

Latitude gradient for melanoma incidence by anatomic site and gender in Norway 1966-2007.

Latitude gradients and time trends for cutaneous malignant melanoma (CMM) were analyzed using incident cases from the Norwegian Cancer Registry for the period 1966-2007. Sex and various anatomic regions of the body were taken into account, for better understanding of the role of ultraviolet radiation in CMM etiology. There is a latitude gradient for CMM on all body sites included in the present study, with 2-2.5 times higher incidence rates in the south. The latitude gradients seem to be largest for the trunk. Melanomas on sites intermittently exposed to the sun (like the trunk) dominate both in the north and in the south and this distribution has not changed over the years. A leveling off of the incidence rates are observed for both sexes and for all sites studied, after 1985-1995, slightly more in the south than in the north, except for the head and neck where the incidence rates have continued to increase slowly in the north as well as in the south. The leveling off of melanoma trend is probably associated with melanoma prevention campaigns and with increasing awareness, although vitamin D could play a role.