Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Monocytes Acquire the Ability to Prime Tissue-Resident T Cells via IL-10-Mediated TGF-ß Release.

Using non-human primates (NHPs), mice, and human primary cells, we found a role for interleukin-10 (IL-10) in the upregulation of the tissue-resident memory T cell (TRM) marker CD103. In NHPs, intravenous, but not subcutaneous, immunization with peptide antigen and an adjuvant combining an agonistic anti-CD40 antibody plus poly(IC:LC) induced high levels of CD103+ TRMs in the lung, which correlated with early plasma IL-10 levels. Blocking IL-10 reduced CD103 expression on human T cells stimulated in vitro with the adjuvant combination as well as diminished CD103 on lung-resident T cells in vivo in mice. Monocyte-produced IL-10 induced the release of surface-bound transforming growth factor ß (TGF-ß), which in turn upregulated CD103 on T cells. Early TGF-ß imprinted increased sensitivity to TGF-ß restimulation, indicating an early commitment of the T cell lineage toward TRMs during the priming stage of activation. IL-10-mediated TGF-ß signaling may therefore have a critical role in the generation of TRM following vaccination.

Primary hyperparathyroidism, hypercalciuria, and bone recovery after parathyroidectomy.

BACKGROUND: In primary hyperparathyroidism, successful parathyroidectomy leads to improved bone mineral density in the majority of cases. Our aim was to further explore the relationship between hypercalciuria, kidney function, and bone recovery after parathyroidectomy. METHODS: Bone mineral density, estimated glomerular filtration rate, and 24-hour urinary calcium were analyzed before and one year after parathyroidectomy in a cohort of 150 primary hyperparathyroidism patients (119 women; median age 60 [range 30-80] years) taking part in a clinical trial. The patients were randomized to 1-year daily treatment with either cholecalciferol 1,600 IU and calcium carbonate 1,000 mg or calcium carbonate alone. RESULTS: Baseline 24-hour urinary calcium correlated directly with s-calcium, parathyroid hormone, 25-OH-D, the bone markers beta C-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide, and estimated glomerular filtration rate (r = 0.19-0.30; P < .05) and inversely with age (r = -0.25; P = .004); 24-hour urinary calcium decreased and bone mineral density in lumbar spine and hip increased similarly in the 2 groups. Baseline 24-hour urinary calcium in the highest quartile (>10 mmol/d) was associated with greater increases in all locations. In a multivariable model adjusting for age, sex, smoking, diabetes, body mass index, estimated glomerular filtration rate, baseline bone mineral density, and vitamin D group, the increase in total hip bone mineral density remained independently associated with baseline 24-hour urinary calcium in the highest quartile (>10 mmol/d) and with plasma parathyroid hormone. Patients with persistent increases in 24-hour urinary calcium at follow-up (14%) had similar bone mineral density improvement. CONCLUSION: Overall, 24-hour urinary calcium > 10 mmol/d was an independent determinant of improvement in bone mineral density and should be taken into account when considering parathyroidectomy.

FGF23, metabolic risk factors, and blood pressure in patients with primary hyperparathyroidism undergoing parathyroid adenomectomy.

BACKGROUND: Fibroblast growth factor-23 (FGF23), a regulator of secretion of parathyroid hormone (PTH), is implicated in the development of cardiovascular disease. The role of FGF23 in primary hyperparathyroidism (pHPT) is unclear. METHODS: A total of 150 consecutive patients with pHPT were examined with ambulatory blood pressure monitoring ((24h)ABP) before parathyroid adenomectomy (PTX). Blood samples were collected 6 ± 2 weeks before and 6 ± 2 weeks after PTX. RESULTS: Plasma FGF23 levels decreased after PTX from a median of 45.2 pg/mL (interquartile range 37.6-54.8) to 36.8 pg/mL (26.7-48.7); P < .001. This postoperative decrease correlated with the decrease in ionized calcium (r = 0.24; P < .01). Greater FGF23 concentrations at baseline were associated with a greater weight of the adenoma and PTH levels, as well as with body mass index, triglycerides, and insulin levels and greater postoperative decreases in FGF23, ionized calcium, insulin growth-like factor 1, and insulin. FGF23 and PTH both correlated with greater blood pressures on (24h)ABP, especially at nighttime (r = 0.31 and r = 0.28; P ≤ .01), whereas after multivariate adjustment, only PTH remained independently associated with (24)ABP. CONCLUSION: Circulating FGF23 is increased in pHPT and is associated independently with the metabolic risk profile. The long-term benefit of decreasing FGF23 in pHPT after PTX remains to be established.

Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight.

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness.

Health-related quality of life after successful surgery for primary hyperparathyroidism: no additive effect from vitamin D supplementation: results of a double-blind randomized study.

OBJECTIVE: Vitamin D insufficiency is common in primary hyperparathyroidism (pHPT). Patients with pHPT frequently have a reduced health-related quality of life (HRQoL). Our objectives were to evaluate whether HRQoL in pHPT is associated with vitamin D insufficiency and whether vitamin D supplementation after parathyroidectomy (PTX) could improve HRQoL. DESIGN: A randomized, double-blind study (ClinicalTrials.gov identifier: NCT00982722). METHODS: The study included 150 pHPT patients randomized, 6 weeks after PTX, to daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D+) or calcium carbonate alone (D-). HRQoL was estimated with SF-36 before and after PTX and after 12 months of study medication. RESULTS: Three-quarters (77%) of the pHPT patients had vitamin D insufficiency, defined as 25OHD <50 nmol/l. The pHPT patients scored lower than a reference population in all domains of SF-36. A total of 135 patients completed the entire study period. Improvements in nearly all domains were registered at the follow-up 6 weeks after PTX. At the end of the study medication period, the D+ group had a significantly higher median serum (s-) 25OHD concentration (76 (65; 93) (lower; upper interquartile ranges) vs 48 (40; 62) nmol/l, P<0.001) and a lower plasma (p-) parathyroid hormone concentration (40 (34; 52) vs 49 (38; 66) ng/l, P=0.01) than the D- group. The improvements in HRQoL remained unchanged at the follow-up 1 year after PTX. Postoperative vitamin D supplementation had no obvious effect on HRQoL. CONCLUSION: PTX resulted in significant improvements in HRQoL. Despite a high prevalence of vitamin D insufficiency, 1 year of postoperative vitamin D supplementation had no obvious beneficial effect on HRQoL.

Vitamin D supplementation after parathyroidectomy: effect on bone mineral density-a randomized double-blind study.

Patients with primary hyperparathyroidism (PHPT) have higher bone turnover, lower bone mineral density (BMD), and an increased risk of fractures. They also have a high incidence of low vitamin D levels (25-OH-vitamin D <50 nmol/L) that could worsen the negative effect on the bone. In this double-blinded clinical trial, 150 patients with PHPT were randomized, after successful parathyroidectomy (PTX), to 1-year daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D+) or calcium carbonate alone (D-). BMD was measured in the lumbar spine, femoral neck, total hip, distal and 33% radius using dual-energy X-ray absorptiometry (DXA) before surgery and after 1 year of study medication. Median age was 60 (range 30-80) years and there were 119 (79%) women and 31 (21%) men; 76% had 25-OH-D <50 nmol/L before PTX and 50% had persistent elevated parathyroid hormone (PTH) 6 weeks after PTX. A similar increase in BMD in the lumbar spine, femoral neck, and total hip was observed in both groups (D+ : 3.6%, 3.2%, and 2.7%, p<0.001, respectively; and D-: 3.0%, 2.3%, and 2.1%, respectively, p<0.001). Patients with vitamin D supplementation also increased their BMD in distal radius (median 2.0%; interquartile range, -1.7% to 5.4%; p=0.013). The changes in BMD, especially in the hips, were correlated to the baseline concentrations of PTH, ionized calcium, and bone markers (p<0.001). A benefit from vitamin D substitution was observed among patients with a persistent postoperative PTH elevation, who also improved their BMD at 33% radius and radius ultradistal (p<0.05). In conclusion, except for a minor improvement of radius BMD, our data show no beneficial effect on BMD or bone turnover markers of vitamin D supplementation after PTX. Preoperative PTH seems to have the strongest association with improvement in BMD.

Primary hyperparathyroidism and metabolic risk factors, impact of parathyroidectomy and vitamin D supplementation, and results of a randomized double-blind study.

BACKGROUND: Vitamin D insufficiency may increase the risk for cardio metabolic disturbances in patients with primary hyperparathyroidism (PHPT). OBJECTIVE: To analyze the vitamin D status and indices of the metabolic syndrome in PHPT patients and the effect of vitamin D supplementation after parathyroid adenomectomy (PTX). DESIGN AND METHODS: Double-blinded, randomized clinical trial (ClinicalTrials.gov identifier: NCT00982722) performed at Karolinska University Hospital, Sweden, April 2008 to November 2011. One hundred and fifty consecutive patients with PHPT (119 women) were randomized after PTX, 75 to oral treatment with calcium carbonate 1000 mg daily and 75 to calcium carbonate 1000 mg and cholecalciferol 1600 IU daily over 12 months. Changes in metabolic profile and ambulatory blood pressure (BP) were analyzed. Main outcome measures were changes in metabolic factors, BP, and body composition. RESULTS: The 25-hydroxyvitamin D (25-OH-D)-level was <50 nmol/l in 76% of the patients before PTX. After PTX, glucose, insulin, and IGF1 decreased, while the 25-OH-D and the IGF-binding protein 1 increased and remained unchanged at follow-up after study medication. One year of vitamin D supplementation resulted in lower parathyroid hormone (PTH) (40 (34-52) vs 49 (38-66) ng/l) and higher 25-OH-D (76 (65-93) vs 49 (40-62) nmol/l; P<0.05). Other laboratory parameters were stable compared with after PTX. Systolic BP decreased and total bone mineral content increased in both groups. CONCLUSION: Except for the lowering of the PTH level, no additive effect of vitamin D supplementation was seen. However, PTX proved effective in reducing insulin resistance.

Breast cancer associated with primary hyperparathyroidism: a nested case control study.

BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with an increased risk of developing breast cancer, but little is known about the underlying factors. The aim of this study was to compare women with a history of pHPT and a reference population in terms of standard factors predictive of prognosis and response to therapy for breast cancer. METHODS: We analyzed data collected from the National Swedish Cancer Register and from two regional oncologic center registries. Seventy-one women with breast cancer and a history of parathyroid adenomectomy were compared with 338 matched controls with breast cancer only. Tumor size, stage, hormone receptor status, lymph node status, cause of death, and cumulative survival were analyzed. RESULTS: The mean age was 69 ± 11 years (95% confidence interval [CI]: 68-70) in both groups and the mean time interval between the parathyroid surgery and breast cancer diagnosis was 91 ± 68 months (95% CI: 72-111). There were no differences between the two groups regarding size, stage, lymph node metastases, or survival, but none of the cases with a history of pHPT were found in Stage III or IV. CONCLUSION: In conclusion, factors predictive of prognosis and response to therapy in women with a history of pHPT and breast cancer are similar to those in breast cancer patients without pHPT.