The NEOLETRIB trial: neoadjuvant treatment with Letrozole and Ribociclib in ER-positive, HER2-negative breast cancer.

Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.Trial registration number: NCT05163106 (ClinicalTrials.gov).

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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.

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.

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.

Influence of narrowband UVB phototherapy on vitamin D and folate status.

BACKGROUND: A variety of studies have shown beneficial effects of different types of phototherapy in skin disorders. Such therapy leads to enhanced cutaneous vitamin D synthesis, which may be one of the mechanisms of action. Furthermore, another nutrient, folate, can probably also be influenced by UV radiation. OBJECTIVE: The aim of our study was to investigate the influence of low-dose narrowband UVB (nUVB) phototherapy of patients with psoriasis, atopic eczema and other skin disorders on serum levels of 25(OH) vitamin D (the serum marker for vitamin D status) and on serum and erythrocyte-folate. METHODS: 25(OH) vitamin D (25(OH)D), serum and erythrocyte-folate levels were measured before and after low-dose nUVB (TL-01 tubes) phototherapy of these patients. The spectrum of the TL-01 tube was compared with the solar spectrum, and the efficiency spectra of vitamin D photosynthesis were calculated. RESULTS: For patients with a high initial 25(OH)D serum level (> 80 nmol/l), no significant (P = 0.36) increase in 25(OH)D levels was seen, in contrast to patients with a low initial level (< 80 nmol/l) where a significant increase (P < 0.001) was observed. The increase was 30-60%, depending on the UVB dose (2.35-13.4 J/cm(2)). No significant nUVB-effect was found on the erythrocyte and serum-folate level. CONCLUSION: Low-dose nUVB treatment gives a significant increase (P < 0.001) of the vitamin D status in persons with low initial levels of 25(OH)D, but no effect on the folate level.

Sunbeds as vitamin D sources.

The objectives of this work were: (1) To determine whether repeated exposures to small doses from a commercial sun bed (Wolff Solarium Super Plus 100 W) over 5 weeks gave less vitamin D than repeated exposures to twice as large, but still nonerythemogenic, doses. (2) To investigate whether the contribution to the vitamin D status from such sessions of exposures was dependent on the baseline status before the start of the sessions. (3) To determine the decay rate of the induced increment of vitamin D. The sun bed sessions raised the 25-hydroxyvitamin D levels from typical winter values to typical summer values. The mean value after exposure being 80 nm (+/-14) and the increase being 15 nm on average. Persons with the lowest initial levels got the largest increase. The level in this group was back to the pre-exposure level after 2-4 weeks. To maintain a summer level through the winter, when no vitamin D is produced by the sun in northern countries, one should consider increasing the recommended intake of vitamin D intake significantly, or encouraging the population to get moderate, nonerythemal sun bed exposures.

Sun and sun beds: inducers of vitamin D and skin cancer.

Solar radiation is both the main cause of all types of skin cancer, including cutaneous malignant melanoma (CMM), and the main source of vitamin D accompanied by its beneficial effects. The dilemma lies in that increased sun exposure could lead to an increase in skin cancers and yet is necessary for the better prognosis of internal cancers. Solar radiation varies in intensity and spectral composition with geographic location and time. Of central interest in the present context is that the UVA/UVB ratio can vary. Thus, the UVA/UVB ratio increases with decreasing solar elevation. The ratio is also larger for most sun beds than that in the midday sun, but similar to that in the afternoon sun. This may have large health implications, since vitamin D is exclusively generated by UVB, while UVA and UVB likely play a role in the onset of CMM. Sun and sun beds act similarly: one quantum of radiation at a given wavelength has the same biological effect, irrespective of the source from which it comes. The winter levels of vitamin D are 10 to 100% lower than the summer levels in most populations, but can be brought up to summer levels by moderate sun bed exposure. Doses of 200 IU of vitamin D per day are not sufficiently large to maintain a summer vitamin D status in winter. At high latitudes (>40 degrees) the sun provides no vitamin D in winter. A number of epidemiological studies, interventional studies, animal studies and cell experiments show that vitamin D reduces the risk and/or prognosis of internal cancers. Populations living at high latitudes would probably benefit from moderately increasing their exposure to UVB to provide a good vitamin D status.

Solar radiation, vitamin D and cancer incidence and mortality in Norway.

Solar radiation is of fundamental importance for human development and health: On the one hand, too much of it can lead to skin ageing and skin cancer, whilst on the other, too little of it can result in vitamin D deficiency, and, thereby lead to high incidence and poor prognosis of internal cancer as well as a number of other diseases. The following data, mostly from Norway, will be reviewed: Variation of ambient solar ultraviolet radiation (UV) and vitamin D status with season and latitude, variation of incidence rates and prognosis of skin cancer and variation of prognosis of internal cancer with latitude and season. In short, the following issues are discussed: 1) Vitamin D level varies with season, but probably not with latitude in Norway, because of an increased intake of vitamin D in the north; 2) Skin cancer incidence rates increase from north to south, as do annual fluence rates of UV radiation, while there seems to be a slight improvement in prognosis from north to south; 3) Prognosis of internal cancer is best for cases diagnosed in the seasons with the best vitamin D status, i.e. in summer and autumn; 4) Incidence rates of cutaneous melanomas have increased from 1960 to 1990, but have decreased slightly thereafter for young people; 5) Changes in sun exposure habits have taken place; 6) An increase in body mass index (BMI) of the population has occurred, which may have led to a worsening of the vitamin D status.

The dependency of vitamin D status on body mass index, gender, age and season.

BACKGROUND: Obesity is a rapidly growing health problem in most developed countries. Excess body weight is a risk factor for many somatic and even psychological disorders, including cardiovascular disease, type 2 diabetes mellitus, osteoarthritis and several cancer types. Recently, overweight and obesity have been shown to be related to low vitamin D status. MATERIALS AND METHODS: The 25(OH)D3 status was analyzed in a population of 2,126 patients registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. Seasonal variation and prevalence of vitamin D deficiency were assessed in different body mass index (BMI), sex and age categories. RESULTS: For both sexes and both age groups (<50 years and > or = 50 years) there was a significant decrease of serum 25(OH)D3 levels with increasing BMI. Surprisingly, not only were the 25(OH)D3 levels negatively correlated with BMI, but the serum 1,25(OH)2D3 levels were also. The seasonal variation of serum 25(OH)D3 was highest in young (<50 years) non-obese men. The prevalence of vitamin D deficiency was highest in individuals with BMI > or = 40, being as high as 32% among women and 46% among men. CONCLUSION: The 25(OH)D3 level, as well as its seasonal variation and the prevalence of vitamin D deficiency, are all dependent on BMI, and age separately. The results of the study suggest that 1 in 3 women and 1 in 2 men with BMI > or = 40 are vitamin D deficient.

Seasonal variation of 1,25-dihydroxyvitamin D and its association with body mass index and age.

Under most normal conditions the serum level of 1,25-dihydroxyvitamin D is constant throughout the year, due to tight biochemical regulation. In contrast to this, the level of 25-hydroxyvitamin D is variable through the year, being largest in late summer, due to photosynthesis in the skin. The vitamin D status is usually assessed by measuring the level of the latter vitamin D derivative, rather than that of the presumably most active derivative 1,25(OH)2 vitamin D.We here show that for persons with a high body mass index (BMI) there is a significant seasonal variation, not only of 25(OH) vitamin D, but also of 1,25(OH)2 vitamin D. The variation seems to be largest for those with the poorest vitamin D status. Furthermore, there seems to be a correlation between the levels of the two vitamin D metabolites, indicating that the regulation of 1,25(OH)2 vitamin D is not always tight, notably in persons with high BMI.

Sun beds and cod liver oil as vitamin D sources.

The objective of this study was to (1) to determine the contribution of moderate sun bed exposure to serum 25(OH)D(3) levels; (2) to estimate the decay time of a high 25(OH)D(3) level obtained by sun bed exposure; and (3) to evaluate if the recommended ingestion of vitamin D is sufficient to maintain the 25(OH)D(3) concentration obtained by sun bed exposure. Ten volunteers (20-35 y.o.), skin type I and II, living in Olso, Norway were whole body exposed twice per week to the radiation of a commercial and approved sun bed (Life Sun S 100 W, Wolff System), starting with 0.5 MED (minimal erythema dose) and escalating to up to 1 MED per exposure for 4 weeks. After that, half of the volunteers were given a daily supplement of 200 IU vitamin D in the form of cod liver oil capsules, while the other half of the persons received no supplements. Erythema did not occur at any time and a slight pigmentation was seen in most of the volunteers after the sun bed exposures. Serum level of 25(OH)D(3) increased by about 40% on the average. The initial serum 25(OH)D(3) level was different among the volunteers (40-100 nmol/L). Within eight weeks after the last exposure the 25(OH)D(3) level decreased to the initial value in all volunteers irrespective of vitamin D supplementation or not.

Sun exposure and cancer survival in Norway: changes in the risk of death with season of diagnosis and latitude.

Epidemiological and experimental studies suggest that derivatives of vitamin D may improve prognosis of a number of cancer types. Sun is our most important source of vitamin D. Seasonal variations and latitudinal gradients of calcidiol (the marker of vitamin D status) have been reported. We wanted to investigate if season and latitude play any role for survival from seven different cancer types in Norway. Seasonal and geographical variations of vitamin D were estimated by calculations and were compared with clinical data. For the survival analyses, 249373 cancer patients were followed for three years after diagnosis and the risk of death was analyzed separately for summer- and winter diagnosis, as well as for two geographical regions with different UV exposures. We found a 15-25% better survival for patients diagnosed during summer and a slight beneficial effect for residents of the high UV region for some of the cancer forms investigated. Based on our results we suggest that calcidiol concentration at the time of cancer diagnosis is related to survival and discuss briefly ways to improve the vitamin D levels in the general population.