Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.

BACKGROUND: Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC. PATIENTS AND METHODS: A total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period. RESULTS: Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit. CONCLUSION: Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.

The impact of age and gender on papillary thyroid cancer survival.

CONTEXT: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. OBJECTIVE: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. DESIGN: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). PARTICIPANTS AND SETTING: Patients were followed in a prospective registry. MAIN OUTCOME MEASURE: The relationships between gender, age, and PTC outcomes were analyzed. RESULTS: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). CONCLUSIONS: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.

Application of the "VARICOL" process to the separation of the isomers of the SB-553261 racemate.

A new continuous chromatographic process (VARICOL) has been presented recently. The basic principle of the new VARICOL process consists of an asynchronous shift of the inlet/outlet lines in a multi-column system on a recycle loop. This process has been used to perform the separation of the optical isomers of the SB-553261 racemate. In this paper, we illustrate that for this specific separation, the VARICOL process is more efficient than the well-known SMB process.

Photochemically induced formation of the "Al13" tridecameric polycation in the presence of Fe(III) and organic acids.

We found that light-induced Fe(III) reduction associated with the oxidation of a simple hydroxy-carboxylic acid (lactate) caused the formation of the AlO4Al12(OH)24(H2O)12 polycation ("Al13"). Initial conditions were a lactate:Al:Fe ratio of 1:0.76:0.11 in a partially neutralized solution. Base was added rapidly and no Al13 was detected in samples kept in the dark. With exposure to light, Fe(III) reduction was rapid and Fe(II) reached a maximum within 1 day. After the maximum, steady-state Fe(II) declined from 54% to 43% over eight days. During this same time period, the lactate concentration fell to 2% of the original, pH rose from 4.05 to 4.46, and the Al13 detectable by 27Al NMR increased to 2.3 mmol l(-1) (51% of the total solution Al). The formation of Al13 is attributed to the pH rise resulting from the removal of the organic acid buffer. Similar photo-induced chemical changes occur in natural waters and may promote the formation of Al13, conditions permitting.

Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease.

Third generation thyroid stimulating hormone (TSH) assays have emerged as the single most useful test of thyroid function, and are used widely and appropriately as a screening test. TSH measurement alone may be misleading in complicated patients and those undergoing treatment for thyroid dysfunction. Before obtaining thyroid function tests, clinicians need to consider whether the patient might have pituitary or hypothalamic disease or severe nonthyroidal illness, and whether assessment of the pituitary-thyroid axis reflects steady-state conditions. Subclinical hyperthyroidism is associated with adverse effects on the skeleton and the heart, and is best assessed by measurement of serum TsH with a third-generation assay.

Phosphate release from seasonally flooded soils: a laboratory microcosm study.

Phosphorus derived from agricultural practices has been targeted as a leading cause of water quality degradation in Lake Champlain. Mobilization of P from seasonally flooded agricultural soils is a concern. Using 14 soils from a research farm in New York's Champlain Valley, we characterized the available P status, extractable Fe and Al, P sorption capacities, and soluble phosphate release in flooded laboratory microcosms. Quantities of NH4-acetate available P ranged from 3 to 100 mg kg(-1) and fluoride-extractable P from 10 to 211 mg kg(-1). Flooding soils induced significant release of phosphate to the porewater over a 60- to 90-d period in 13 of the 14 soils studied. Porewater phosphate increases ranged from 2.2 to 27.0 times the initial phosphate concentrations. However, floodwater phosphate increases were much lower, with a maximum of 3.6 times the initial concentration. Average porewater phosphate concentrations over the flooding period ranged from 0.046 to 7.0 mg L(-1) and average floodwater P from 0.032 to 3.70 mg L(-1). Ammonium-acetate P and the degree of phosphorus saturation (DPS) were highly correlated with the average porewater and floodwater phosphate concentration. Average ratio of porewater to floodwater phosphate concentrations ranged from 1.0 to 3.3. Five soils that were lower in fluoride-extractable P had increasing porewater phosphate accompanied by increasing porewater Fe2+ and decreasing floodwater phosphate. Results suggest that P solubility and mobility were a function of both the available P status and redox cycling.

Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.

Serum CrossLaps is a new assay for measuring carboxy-terminal collagen crosslinks (CTX) in serum. This measurement is reported to be more specific to bone resorption than other measurements. However, the utility of this and other markers in monitoring patients on antiresorptive therapy depends on how often changes anticipated with therapy exceed changes attributable to random variability. In a study where subjects received either placebo or pamidronate, we calculated the minimum significant change (MSC), that is, the change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate (APD) (30 mg i.v. in 500 ml D5W over 4 hours) to see how often observed changes in turnover after treatment exceeded the MSC. The MSC for serum CTX was 30.2%, and was significantly (P < 0.05) lower than the MSC for urinary NTX (54.0%), and not significantly different from the MSC of urinary DPD (20.6%). Ninety percent of subjects treated with APD had a decline in serum CTX that exceeded the MSC, compared with 74% for bone-specific alkaline phophatase (BSAP), 57% for urinary N-telopeptide cross-links (NTX), and 48% for free deoxypyridinoline. Changes in serum CTX correlated reasonably well with changes in spine BMD after 2 years (r = 0.47), but this correlation did not quite reach statistical significance because of the small number of subjects. In conclusion, the serum CTX assay shows greater utility for assessing efficacy of antiresorptive treatment than some previously described markers.

A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer.

Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.

Hypercalcemia in a woman with hypoparathyroidism associated with increased parathyroid hormone-related protein during lactation.

OBJECTIVE: To report a case of postpartum hypercalcemia in a woman with hypoparathyroidism associated with increased serum concentrations of parathyroid hormone-related protein (PTHrP) during lactation. METHODS: The clinical and laboratory data for our patient and the related literature are reviewed. RESULTS: A 35-year-old woman with long-standing surgical hypoparathyroidism treated with dihydrotachysterol and calcium carbonate gave birth to a healthy boy at 40 weeks of gestation and began lactating normally. Two and a half weeks later, hypercalcemia developed in association with nausea, vomiting, and myalgias. Subsequently, an increased serum PTHrP concentration was noted. After saline diuresis and corticosteroid therapy to correct the hypercalcemia, a normal serum calcium level was maintained without vitamin D preparations or calcium supplements until the 12th postpartum week, when hypocalcemia reappeared. The serum PTHrP level was no longer increased, and treatment with calcitriol and calcium carbonate was resumed. Subsequent serum calcium concentrations have been normal. CONCLUSION: This case suggests that PTHrP stimulation of the parathyroid hormone-PTHrP receptor during lactation may compensate for the absence of parathyroid hormone in lactating women with hypoparathyroidism and that treatment with pharmacologic doses of vitamin D preparations during the postpartum period may result in hypercalcemia.

Acute onset of chest pain in a soccer player.

A 36-year-old soccer player with retrosternal chest pain was brought to the emergency department. The patient was visiting from Egypt and did not speak English. A friend who accompanied the patient was able to give a limited history.

Acute atraumatic quadriparesis in a college football player.

Transverse myelitis is a rare neurologic disorder. It is an interruption of spinal cord function not caused by macrotrauma. Symptoms develop rapidly and consist of ascending paralysis, diminished or absent sensation below the cervical or thoracic region, and often urinary retention. Etiologies include parainfectious events, multiple sclerosis, autoimmune disorders, vascular insufficiency, paraneoplastic myelopathy, postvaccinial events, idiopathic occurrence, and minimal trauma. Treatment generally consists of supportive measures. The use of steroids to hasten recovery remains controversial but is routine in most cases. The time period and degree of recovery is variable. We present a case of rapid onset of neurologic symptoms in a college football player right before a game. No other sports related cases have been reported in the sports medicine literature. Diagnostic, therapeutic, and historical aspects of this rare but important disorder are discussed.

Utility of biochemical markers of bone turnover in the follow-up of patients treated with bisphosphonates.

Biochemical markers of bone turnover are often measured in patients treated with antiresorptive agents to monitor the effects of therapy. In order for a change in these markers to clearly indicate treatment effect, the change in the markers must exceed the amount of spontaneous variation typically seen with no treatment. Based on the measured long-term variability of markers in untreated patients, we defined a minimum significant change (MSC), that is, a change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate to see how often observed changes in turnover after treatment exceeded the MSC. We found that urinary markers of bone resorption are best measured on 2-hour fasting samples, because results on random urine showed poor precision and less decline with therapy. We also found that of all the markers, urinary N-telopeptide cross-links (NTX) had the greatest decline after therapy (58%), although it also had the highest long-term variability (29.5%). The marker that most often showed a decline with treatment that exceeded the MSC was serum bone-specific alkaline phosphatase where 74% of observed changes exceeded the MSC. Other markers that often showed a decline with treatment that exceeded the MSC were 2-hour fasting urine NTX and free deoxypyridinoline, where 57% and 48%, respectively, of changes in therapy exceeded the MSC. The ideal marker would combine the large decline after treatment characteristic of NTX (60-70%) with the good precision of bone-specific alkaline phosphatase.

Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry.

The ideal therapy for differentiated thyroid cancer is uncertain. Although thyroid hormone treatment is pivotal, the degree of thyrotropin (TSH) suppression that is required to prevent recurrences has not been studied in detail. We have examined the relation of TSH suppression to baseline disease characteristics and to the likelihood of disease progression in a cohort of thyroid cancer patients who have been followed in a multicenter thyroid cancer registry that was established in 1986. The present study describes 617 patients with papillary and 66 patients with follicular thyroid cancer followed annually for a median of 4.5 years (range 1-8.6 years). Cancer staging was assessed using a staging scheme developed and validated by the registry. Cancer status was defined as no residual disease; progressive disease at any follow-up time; or death from thyroid cancer. A mean TSH score was calculated for each patient by averaging all available TSH determinations, where 1 = undetectable TSH; 2 = subnormal TSH; 3 = normal TSH; and 4 = elevated TSH. Patients were also grouped by their TSH scores: group 1: mean TSH score 1.0-1.99; group 2: mean TSH score 2.0-2.99; group 3: mean TSH score 3.0-4.0. The degree of TSH suppression did not differ between papillary and follicular thyroid cancer patients. However, TSH suppression was greater in papillary cancer patients who were initially classified as being at higher risk for recurrence. This was not the case for follicular cancer patients, where TSH suppression was similar for all patients. For all stages of papillary cancer, a Cox proportional hazards model showed that disease stage, patient age, and radioiodine therapy all predicted disease progression, but TSH score category did not. However, TSH score category was an independent predictor of disease progression in high risk patients (p = 0.03), but was no longer significant when radioiodine therapy was included in the model (p = 0.09). There were too few patients with follicular cancer for multivariate analysis. These data suggest that physicians use greater degrees of TSH suppression in higher risk papillary cancer patients. Our data do not support the concept that greater degrees of TSH suppression are required to prevent disease progression in low-risk patients, but this possibility remains in high-risk patients. Additional studies with more patients and longer follow-up may provide the answer to this important question.

Prospective multicenter study of thyroiscarcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group.

BACKGROUND: A novel prognostic staging classification encompassing all forms of thyroid carcinoma was created for the National Thyroid Cancer Treatment Cooperative Study (NTCTCS) Registry, with the goal of prospective validation and comparison with other available staging classifications. METHODS: Patient information was recorded prospectively from 14 institutions. Clinicopathologic staging was based on patient age at diagnosis, tumor histology, tumor size, intrathyroidal multifocality, extraglandular invasion, metastases, and tumor differentiation. RESULTS: Between 1987 and 1995, 1607 patients were registered. Approximately 43% of patients were classified as NTCTCS Stage I, 24% Stage II, 24% Stage III, and 9% Stage IV. Patients with follicular carcinoma were more likely to have "high risk" Stage III or IV disease than those with papillary carcinoma. Of 1562 patients for whom censored follow-up was available (median follow-up, 40 months), 78 died of thyroid carcinoma or complications of its treatment. Five-year product-limit patient disease specific survival was 99.8% for Stage I, 100% for Stage II, 91.9% for Stage III, and 48.9% for Stage IV (P < 0.0001). The frequency of remaining disease free also declined significantly with increasing stage (94.3% for Stage I, 93.1%for Stage II, 77.8% for Stage III, and 24.6% for Stage IV). The same patients also were staged applying six previously published classifications as appropriate for their tumor type. The predictive value of the NTCTCS Registry staging classification consistently was among the highest for disease specific mortality and for remaining disease free, regardless of the tumor type. CONCLUSIONS: The NTCTCS Registry staging classification provides a prospectively validated scheme for predicting short term prognosis for patients with thyroid carcinoma.

Randomized trial of pamidronate in patients with thyroid cancer: bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate.

Patients taking suppressive doses of T4 are thought to have accelerated bone loss and increased risk of osteoporosis. We therefore randomize 55 patients taking suppressive doses of T4 to treatment with pamidronate (APD) 30 mg i.v. every 3 months for 2 yr (APD/T4), or placebo (placebo/T4). Patients had measurements of bone mineral density (BMD) of the spine, hip, radius, and total body every 6 months for 2 yr. There was no significant bone loss at any site in the placebo/T4 group. Ninety five percent confidence intervals excluded a rate of bone loss > 0.89%/yr for the spine and > 0.31%/yr at the total hip. When men were excluded from the analysis, there still was no significant bone loss for the placebo/T4 group, and confidence intervals did not change. The APD/T4 group showed increases in spine (4.3%, P = 0.0001), total hip (1.4%, P < 0.05), and trochanteric (3.0%, P = 0.0001) BMDs. In conclusion, premenopausal women and men on suppressive therapy with T4 do not lose bone rapidly, and are not at increased risk of developing osteoporosis. A regimen of 30 mg APD given every 3 months for 2 yr causes significant suppression of bone resorption and increases in BMD, and may be an acceptable alternative treatment for osteoporosis in patients who cannot tolerate oral bisphosphonates.

Syndromes of thyrotoxicosis with low radioactive iodine uptake.

It is very important to diagnose correctly the etiology of thyrotoxicosis, because the course and treatment of thyrotoxicosis with low radioactive iodine uptake differ significantly from that of hyperthyroidism due to Graves' disease or toxic nodular goiter. Many causes of subacute thyroiditis have been identified producing a characteristic course of transient hyperthyroidism, followed by hypothyroidism, and usually recovery. Ectopic hyperthyroidism includes factitious thyroid hormone ingestion, struma ovarii, and, rarely, large deposits of functioning thyroid cancer metastases. Iodine-induced hyperthyroidism may be associated with low radioiodine uptakes. Amiodarone-associated hyperthyroidism may be the result of subacute thyroiditis or iodine-induced hyperthyroidism; assessment and treatment can be quite challenging.