Postabsorptive and postprandial glucose and fat metabolism in postmenopausal women with breast cancer-Preliminary data after chemotherapy compared to healthy controls.

BACKGROUND: Breast cancer survivors are a growing population due to improved treatment. It is known that postmenopausal women treated for breast cancer may experience weight gain and increased insulin resistance, but detailed knowledge on how chemotherapy impact metabolic and endocrine mechanisms remain unknown. OBJECTIVES: We performed a thorough, preliminary study to elucidate the differing mechanisms of postprandial absorption and metabolism in postmenopausal early breast cancer (EBC) patients treated with adjuvant chemotherapy compared to healthy controls. We hypothesize that chemotherapy has a negative impact on metabolism in EBC patients. METHODS: We examined four postmenopausal women shortly after treatment with chemotherapy for EBC and four age-matched healthy women who served as controls using isotopic tracers during a mixed meal-test. Blood was sampled during the 240 min meal-test to examine postprandial absorption and endogenous synthesis of lipid and carbohydrate metabolites. RESULTS: We found that insulin concentrations were numerically higher before the meal-test in the EBC patients compared to controls (76.3 pmol/L vs 37.0 pmol/L; P = 0.06). Glucose kinetics was increased postprandial (most pronounced at 30 min, 9.46 mmol/L vs 7.33 mmol/L; P = 0.51), with no difference between the groups regarding liver glucose output. Fatty acid kinetics showed a numeric increase in oleic acid rate of appearance in BC patients, but only during the first hour after the mixed meal. There was no significant difference in VLDL-TAG synthesis between the two groups. CONCLUSIONS: This preliminary study is unique in using advanced tracer methods to investigate in vivo metabolism of EBC patients after chemotherapy although no statistical differences in glucose and fatty acid kinetics was seen compared to controls. However, during the first two postprandial hours, oral glucose and oleic acid appearance in the systematic circulation was elevated in the EBC patients. This could be due to changes in gastrointestinal uptake and further studies with altered set-up could provide valuable insights.

Treatment Effect of Zoledronic Acid in Chronic Non-bacterial Osteomyelitis of the Jaw: A Case Series.

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory, osteolytic bone disorder sometimes localized to a unifocal site in the jaw, causing long-term pain and reduced function. The aim of this study was to describe the patients with CNO of the jaw, focusing on treatment with zoledronic acid for pain relief. An analysis of medical records of 24 patients with CNO of the jaw, including treatment with zoledronic acid and effects on pain relief. Descriptive statistics and nonparametric tests were used to describe the population and compare treatment effects, respectively. The average treatment period was 33.4 months (median 23; Q1 11.5; Q3 42.0) with an average of 4.1 infusions (median 3; Q1 2; Q3 5) of zoledronic acid. The average pain VAS score (visual analogue scale) was significantly reduced from 7.7 (median 8; Q1 6.5; Q3 8.5) to 2.5 points (median 2; Q1 0.5; Q3 4.5) (p < 0.001). At final visit, 46% of patients reported no pain and 38% reported a reduction of pain. At least 67% of patients had at least one episode of pain recurrence, and most patients experienced the first recurrence within a year of initial treatment. Four patients (16%) had no pain relief from the treatment. In this group of patients with CNO of the jaw, there was a positive response to treatment with zoledronic acid on pain relief, averaging 5.2 points on a pain VAS score, with 84% of patients treated experiencing either a partial or a total reduction in pain after about 2.5 years.

Peripheral blood mononuclear cells exhibit increased mitochondrial respiration after adjuvant chemo- and radiotherapy for early breast cancer.

BACKGROUND: Adjuvant chemo- and radiotherapy cause cellular damage to tumorous and healthy dividing cells. Chemotherapy has been shown to cause mitochondrial respiratory dysfunction in non-tumorous tissues, but the effects on human peripheral blood mononuclear cells (PBMCs) remain unknown. AIM: We aimed to investigate mitochondrial respiration of PBMCs before and after adjuvant chemo- and radiotherapy in postmenopausal patients with early breast cancer (EBC) and relate these to metabolic parameters of the patients. METHODS: Twenty-three postmenopausal women diagnosed with EBC were examined before and shortly after chemotherapy with (n = 18) or without (n = 5) radiotherapy. Respiration (O2 flux per million PBMCs) was assessed by high-resolution respirometry of intact and permeabilized PBMCs. Clinical metabolic characteristics and mitochondrial DNA (mtDNA) content of PBMCs (mtDN relative to nuclear DNA) were furthermore assessed. RESULTS: Respiration of intact and permeabilized PBMCs from EBC patients significantly increased with adjuvant chemo- and radiotherapy (p = 6 × 10-5 and p = 1 × 10-7 , respectively). The oxygen flux attributed to specific mitochondrial complexes and respiratory states increased by 17-43% compared to before therapy initiation. Similarly, PBMC mtDNA content increased by 40% (p = 0.002). Leukocytes (p = 0.0001), hemoglobin (p = 0.0003), and HDL cholesterol (p = 0.003) concentrations decreased whereas triglyceride (p = 0.01) and LDL (p = 0.02) concentrations increased after treatment suggesting a worsened metabolic state. None of the metabolic parameters or the mtDNA content of PBMCs correlated significantly with PBMC respiration. CONCLUSION: This study shows that mitochondrial respiration and mtDNA content in circulating PBMCs increase after adjuvant chemo- and radiotherapy in postmenopausal patients with EBC. Besides the increased mtDNA content, a shift in PBMC subpopulation proportions towards cells relying on oxidative phosphorylation, who may be less sensitive to chemotherapy, might influence the increased mitochondrial respiration observed iafter chemotherapy.

Influence of the anti-oestrogens tamoxifen and letrozole on thyroid function in women with early and advanced breast cancer: A systematic review.

INTRODUCTION: Breast cancer (BC) is a common type of cancer in women. Advances in therapy options have resulted in higher overall survival rates but side effects of cancer treatment are increasingly in the spotlight. The beneficial effects of anti-oestrogen therapy with tamoxifen and letrozole in the prevention of BC recurrence are well documented. While the most common side-effects of this therapy are well-defined, less is known about its effects on thyroid function. In women treated for early BC, an average of 1-5 kg weight gain has been observed after treatment with chemotherapy/anti-oestrogens. We aim to evaluate the current knowledge on the side effects of tamoxifen and letrozole treatments on thyroid function, followed by its potential influence on the observed weight gain. METHODS: We searched PubMed and found 16 publications on thyroid function and tamoxifen treatment in pre- and post-menopausal women with early- and advanced BC, whereas five publications on letrozole treatment in post-menopausal women with advanced BC. RESULTS: According to the current literature, there is an overall tendency towards a mild and transient thyroid dysfunction, that is, subclinical hypothyroidism in tamoxifen-treated patients. Only one publication reported further significant changes in thyroid hormones beyond one year of tamoxifen treatment. No significant changes in thyroid function have been observed among letrozole-treated patients. CONCLUSION: Tamoxifen-treated patients can develop mild and transient thyroid dysfunction within the first 12 months, yet further significant changes in thyroid function beyond one year of tamoxifen treatment have been reported in a single study. There is no evidence of thyroid dysfunction in letrozole-treated patients. Current literature does not focus on subclinical hypothyroidism as a possible cause of weight gain in patients with BC. Subgrouping of BC patients and studies with a longer observation of thyroid hormones and weight changes during and after anti-oestrogen treatment are needed to further elucidate how anti-oestrogens affect thyroid function.

Weight Change in Post-Menopausal Women with Breast Cancer during Chemotherapy-Perspectives on Nutrition, Activity and Bone Metabolism: An Interim Analysis of a 5-Year Prospective Cohort.

Women with breast cancer are a growing population due to improved screening and treatment. It has been described that chemotherapy can negatively affect patients' metabolism. The aim of this study is to assess weight gain during chemotherapy treatment in an interim analysis on an ongoing prospective cohort of women with early breast cancer. To help untangle the many possible reasons for weight change, we examine blood tests, Patient-Reported Outcomes (PROs), and bone mineral density (BMD). We find that the 38 women that have measurements taken after chemotherapy have an average weight gain of 1.2 kg although not significant. Together with this, there is a significant drop in HDL cholesterol, an increase in triglycerides, and a non-significant tendency towards decreased insulin sensitivity. PROs show that although the women experience more pain and fatigue, they have higher activity levels. BMD is at an expected level according to age. All in all, we see an increased focus on physical activity and nutrition, leading to less severe metabolic changes as previously reported. However, even though more measures are taken, we still see an overall negative metabolic impact with unknown long-term implications.

Vibration Perception Threshold and Heart Rate Variability as methods to assess chemotherapy-induced neuropathy in women with breast cancer - a pilot study.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a recognized adverse effect of standard (neo)adjuvant chemotherapy in breast cancer (BC) treatment. However, there is no consensus on a validated method for assessing CIPN. Heart rate variability (HRV) and vibration perception threshold (VPT) could be used as objective measures to describe CIPN. The aim of this pilot study was to investigate whether subjectively reported CIPN was associated with altered HRV and VPT in BC patients. METHODS: We performed a cross-sectional pilot study evaluating 30 BCE patients previously treated with chemotherapy, 26 BCE patients who did not receive chemotherapy, and 22 controls without breast cancer. Self-reported CIPN was registered for the BC patients. All participants were subjected to multi-frequency vibration analyses to determine VPT along with short ECG measurements to determine HRV measures. RESULTS: Self-reported CIPN was registered in 14 (46.6%) BC patients treated with chemotherapy. The VPT at 64 Hz (P = 0.022) and mean HR (P = 0.022) were significantly higher and the HRV measures SDNN (P = 0.023), RMSSD (P = 0.007), LF (P = 0.050) and HF (P = 0.045) were significantly lower in BC patients reporting CIPN compared to controls when adjusted for age. VPT at 64 Hz and 125 Hz were significantly higher in BC patients not reporting CIPN compared to controls when adjusted for age. CONCLUSION: We found elevated VPT and mean HR along with decreased HRV parameters in 14 BCE patients reporting CIPN. These findings support the need for further investigation into whether HRV and vibration analysis could contribute to an objective assessment of CIPN.

Denosumab vs. zoledronic acid treatment in post-menopausal breast cancer: a 2-year prospective observational study.

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(-0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (-0.001g/cm2) and a small significant decrease at the femoral neck (-0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference.Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA.Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.

Exercise-A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights.

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.

Heart rate variability and vibration perception threshold to assess chemotherapy-induced neuropathy in women with breast cancer - a systematic review.

BACKGROUND: It is well known that breast cancer (BC) patients often suffer from chemotherapy-induced peripheral neuropathy (CIPN). However, it is not always recognized that they have higher risk of falling, dizziness and other signs of dysfunctional autonomous nervous system. We performed a systematic review of the literature on vibration perception threshold (VPT) and heart rate variability (HRV) as methods to objectively assess (CIPN) in BC-patients. Could VPT and HRV describe coexisting sensory and autonomic nerve damage? MATERIALS AND METHODS: PubMed was searched in September 2019. The included studies had to address HRV and/or VPT in BC-patients who received chemotherapy. RESULTS: Seven studies assessed VPT and six studies assessed HRV in BC-patients. Studies showed lowered perception of vibrations after chemotherapy reflected in higher VPT and no changes in HRV after taxane-based chemotherapy. No studies evaluated VPT and HRV at the same time. CONCLUSION: The results were limited by short follow-up, small sample sizes, and different chemotherapy regimens which makes generalizability problematic. A standard assessment method of CIPN is still missing and further research is needed to evaluate if VPT and HRV could contribute to an objective assessment of CIPN. With higher survival rates for BC-patients autonomous and sensory nerve damage will be an increasing task. However, our literature review showed that no one have focused on the combination of autonomous and sensory affection measured by the simple methods VPT and HRV. Therefore, we encourage the development of international guidelines for the objective measure of nerve damage in BC-patients.