Douglas S. Ross

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Subclinical Hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-Thyroxine

Spontaneous hyperthyroidism and that due to excessive administration of thyroid hormone result in osteopenia. Bone density was measured in 28 white premenopausal female patients who were taking commonly prescribed suppressive doses of L-thyroxine (mean dose 0.171 +/- 0.035 g) for five or more years. The thyroxine level was 13.5 +/- 2.6 micrograms/dl (normal 8.0 +/- 2.4 micrograms/dl), the free thyroxine index was 4.4 +/- 1.0 (normal 2.4 +/- 0.8), and the triiodothyronine value was 154 +/- 26 ng/dl (normal 132 +/- 32 ng/dl). Basal thyrotropin was undetectable (less than 0.08 microIU/ml) in 23 patients, and thyrotropin measured 20 minutes after thyrotropin-releasing hormone administration was not demonstrable in 13 patients and subnormal in 10 patients. Women who had taken L-thyroxine for 10 or more years (n = 12, age 37 +/- 4 years) had a 9 percent reduction in bone density (0.667 +/- 0.044 g/cm2, p less than 0.01) compared with normal premenopausal age-matched control subjects (n = 56, age 35 +/- 6 years, bone density 0.733 +/- 0.055 g/cm2). It is concluded that prolonged suppressive L-thyroxine treatment may result in mild subclinical hyperthyroidism with adverse effects on bone. Patients requiring suppression of the pituitary-thyroid axis should be given the smallest dose of L-thyroxine necessary to achieve a satisfactory clinical response.

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.

Abstract: 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.

Prevalence of HIV-1 Drug Resistance after Failure of a First Highly Active Antiretroviral Therapy Regimen in KwaZulu Natal, South Africa

BACKGROUND Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy in resource-limited settings. The prevalence of resistance was assessed among patients from KwaZulu Natal, South Africa, following failure of their first highly active antiretroviral therapy (HAART) regimen. METHODS Genotypic resistance testing was performed on plasma virus samples from patients who experienced virologic failure of their first HAART regimen at 2 clinics in KwaZulu Natal. Clinical and demographic data were obtained from medical records. Regression analysis was performed to determine factors associated with > or =1 significant drug resistance mutation. RESULTS From January 2005 through August 2006, a total of 124 antiretroviral-treated adults who experienced virologic failure were enrolled. The predominant subtype was HIV-1C. Virus samples from 83.5% of participants carried > or =1 significant drug resistance mutation. Dual-class drug-resistant virus was present in 64.3% of participants, and 2.6% had virus with triple-class drug resistance. The most common mutation was M184V/I (64.3% of patients); K103N was present in virus from 51.3%, and V106M was present in virus from 19.1%. Thymidine analog resistance mutations were found in virus from 32.2% of patients, and protease resistance mutations were found in virus from 4.4%. CONCLUSIONS Antiretroviral drug-resistant virus was detected in >80% of South African patients who experienced failure of a first HAART regimen. Patterns of drug resistance reflected drugs used in first-line regimens and viral subtype. Continued surveillance of resistance patterns is warranted to guide selection of second-line regimens.

The “ART” of Linkage: Pre-Treatment Loss to Care after HIV Diagnosis at Two PEPFAR Sites in Durban, South Africa

Background Although loss to follow-up after antiretroviral therapy (ART) initiation is increasingly recognized, little is known about pre-treatment losses to care (PTLC) after an initial positive HIV test. Our objective was to determine PTLC in newly identified HIV-infected individuals in South Africa. Methodology/Principal Findings We assembled the South African Test, Identify and Link (STIAL) Cohort of persons presenting for HIV testing at two sites offering HIV and CD4 count testing and HIV care in Durban, South Africa. We defined PTLC as failure to have a CD4 count within 8 weeks of HIV diagnosis. We performed multivariate analysis to identify factors associated with PTLC. From November 2006 to May 2007, of 712 persons who underwent HIV testing and received their test result, 454 (64%) were HIV-positive. Of those, 206 (45%) had PTLC. Infected patients were significantly more likely to have PTLC if they lived ≥10 kilometers from the testing center (RR = 1.37; 95% CI: 1.11–1.71), had a history of tuberculosis treatment (RR = 1.26; 95% CI: 1.00–1.58), or were referred for testing by a health care provider rather than self-referred (RR = 1.61; 95% CI: 1.22–2.13). Patients with one, two or three of these risks for PTLC were 1.88, 2.50 and 3.84 times more likely to have PTLC compared to those with no risk factors. Conclusions/Significance Nearly half of HIV-infected persons at two high prevalence sites in Durban, South Africa, failed to have CD4 counts following HIV diagnosis. These high rates of pre-treatment loss to care highlight the urgent need to improve rates of linkage to HIV care after an initial positive HIV test.

Outcome after Treatment of High-Risk Papillary and Non-Hurthle-Cell Follicular Thyroid Carcinoma

The treatment of thyroid cancer has been investigated extensively, but disagreement remains about the degree of aggressiveness needed in its management. Despite the general perception that the prognosis is excellent, 9% of patients with thyroid cancer die of the disease [1]. Patients with the less differentiated types of thyroid cancer or those presenting at a more advanced stage face higher mortality rates [2, 3]. In addition, the recurrence rate after surgery is more than 20% in persons with differentiated thyroid cancer [2]. Therefore, the ability to define the most effective therapeutic interventions on the basis of patient stratification by histologic type and stage of cancer at initial presentation should improve survival and decrease recurrence rates. The initial treatment for thyroid cancer is surgery, but the extent of surgery needed to improve outcome remains controversial [4-6]. Some studies have shown that more extensive thyroid resection reduces the recurrence rate but has a less definite effect on survival [2, 7]. More extensive surgery may be associated with a higher prevalence of complications, usually hypoparathyroidism or recurrent laryngeal nerve damage (or both), in 3% to 15% of patients [8-10]. The indications for postoperative ablative radioiodine therapy and the required administered activity are also under debate. Multifocality and lymph node involvement at presentation in 46% of persons with papillary thyroid cancer (of whom 25% face persistent or recurrent disease) argue in favor of this therapy [2, 11, 12], despite the risk for sialoadenitis, gastrointestinal symptoms, occasional bone marrow suppression, and possible second cancers [13]. The role of external radiation in the treatment of differentiated thyroid cancer is also highly controversial. Increased recurrence [14], no therapeutic benefit [15-17], and improved local control [18, 19] have all been reported. The National Thyroid Cancer Treatment Cooperative Study Registry was established in 1986 to define clinical practice and to address the effectiveness of therapies on morbidity and mortality by prospectively enrolling a large population of patients from multiple institutions. Patients have been stratified by uniform criteria and followed prospectively from the time of initial diagnosis and treatment. This 9-year report from the registry describes outcomes in patients with high-risk, differentiated thyroid cancer, a group of patients expected to have substantial morbidity and mortality in this time period. Methods A total of 1607 patients in whom thyroid cancer was diagnosed on or after 1 January 1987 were prospectively enrolled in the registry by the 14 participating institutions. No more than 20% of cases came from any single institution or city. Data forwarded to the registry were coded, and individual identifiers, such as name and Social Security number, were kept confidentially by the principal investigator at each institution. Because the patients therapy was not altered by participation in the registry, requirements for informed consent were determined by the institutional review boards at each participating institution, and their mandates were followed. Age, sex, ethnic background, histologic diagnosis, size of primary tumor, multifocality, local invasiveness, and regional or distant metastases were documented. The histologic diagnosis was established at each institution. All variants of papillary cancer, including so-called mixed papillary and follicular carcinomas, were included in the papillary group. Analyses for papillary carcinomas that included and excluded the more aggressive tall-cell variant were performed. The Hurthle cell (oxyphilic) variant of follicular carcinoma was excluded from the follicular group. Patients were stratified on the basis of pathologic diagnosis, age, tumor size, local invasiveness, and extent of metastases at the time of first surgical intervention as determined by gross and histologic findings at surgery, whole-body radioiodine scans, chest radiographs, and other radiologic studies. This stratification system was established empirically before initiation of the registry by a group of experienced clinicians on the basis of information available in 1985. The criteria for categorization as high risk are noted in Table 1. Patients with preoperative vocal cord paresis or with postoperative hypocalcemia or vocal cord paresis that persisted 2 months or less were not designated as having these complications of surgery. The extent of initial surgery, use of postoperative radioiodine therapy, and application of external radiation therapy were analyzed for impact on outcome. With rare exceptions, all patients received thyroxine therapy. Table 1. Criteria for Stratification to High-Risk Groups Outcomes were death due to thyroid cancer or to complications of its treatment, progression (defined as a patient alive with progressive thyroid cancer or dead because of thyroid cancer or complications of its treatment at last follow-up), and disease-free survival (defined as a patient alive with no known residual thyroid cancer or free of thyroid cancer at the time of death from other causes). Statistical Analysis All data were extracted by using a computer-based integrated data management package (Med-log, Information Analysis Corporation, Incline Village, Nevada). Cox proportional-hazards models were performed to determine whether each predictor variable was associated on univariate analysis (Table 2) with survival, progression, and disease-free survival (SAS Institute, Cary, North Carolina). The hazard model was also used to identify the set of predictor variables that best explained the probabilities of overall survival, cancer-specific mortality, progression of disease, or disease-free survival (Table 3). A P value of 0.05 or less was considered statistically significant. Risk ratios obtained from the Cox proportional-hazards analyses are given with 95% CIs. Risk ratios less than 1 indicate improved outcome, and those greater than 1 indicate a worsened outcome. Table 2. Variables Associated with Mortality, Progression, and Disease-Free Survival (by Univariate Analysis) Table 3. Variables That Best Predict Overall Mortality, Cancer-Specific Mortality, Progression of Disease, or Disease-Free Survival (by Multivariate Analysis) Results Follow-up Three hundred three patients with papillary carcinoma and 82 patients with follicular carcinoma were considered to have high-risk thyroid cancer. Twenty patients (5.2%) were lost to follow-up. An additional 64 patients were not included in the survival analyses because no information on patient status was available (n = 60), no cause of death was recorded (n = 2), or patients were alive with no cancer status reported (n = 2). Demographic characteristics of the two groups were similar regardless of whether these cases were included. Patients were followed for a mean of 3.1 years after the date of surgery; 35% were men. The mean (SD) age at entry was 57 15 years. Sex and Age Compared with men, women with papillary cancer had a lower risk for overall mortality (risk ratio [RR], 0.03 [95% CI, 0.23 to 0.92]) but not cancer-specific mortality. Older age did not affect outcome in patients with papillary carcinoma or those with follicular carcinoma, but an age effect might be masked by the fact that age was a factor in defining these high-risk patients. Histologic Type Only 18 patients with papillary cancer had the tall-cell variant (P not significant by multivariate analysis). By univariate analysis, radioiodine therapy was associated with reduced disease progression (risk ratio, 0.10 [CI, 0.01 to 0.72]; P = 0.02). Thyroid Surgery The first surgical procedure on the thyroid and any surgical therapy of the thyroid that occurred within the next 4 months were classified as initial thyroid surgery. Data were not sufficient to allow analysis of the effect of modified neck dissections on complication rates. Of 300 patients with papillary cancer, 256 (85.3%) had a total or near-total thyroidectomy as initial thyroid surgery, 10 (3.3%) had bilateral subtotal thyroidectomy, 26 (8.7%) had lobectomy, 1 (0.3%) had lumpectomy, 4 (1.3%) had biopsy only, and 3 (1.0%) had nonspecified surgery. Of 80 patients with follicular cancer, 57 (71.3%) had total or near-total thyroidectomy as initial thyroid surgery, 2 (2.5%) had bilateral subtotal thyroidectomy, 13 (16.3%) had lobectomy, 4 (5.0%) had lumpectomy, and 4 (5.0%) had biopsy only. The charts of all patients with reported surgical complications were reviewed. The complication rate of initial surgery varied among centers. The overall rate of some type of complication was 14.4% (52 of 360 patients). Specific data on complications were available for 286 of 303 patients with papillary cancer and 74 of 82 patients with follicular thyroid cancer. Hypoparathyroidism alone occurred in 19 of 286 (6.6%) patients with papillary cancer and 3 of 74 (4.0%) patients with follicular cancer. Vocal cord palsy alone was noted in 17 of 286 (5.9%) patients with papillary cancer and 6 of 74 (8.0%) patients with follicular cancer. Combined hypoparathyroidism and vocal cord palsy occurred in 4 of 286 (1.4%) patients with papillary cancer and no patients with follicular cancer. Data were not sufficient to allow analysis of any effect of modified neck dissections on complication rates. Overall mortality from papillary cancer improved with total or near-total thyroidectomy compared with other surgical procedures (RR, 0.41 [CI, 0.20 to 0.85]) (Table 2). Progression of disease and disease-free survival were not improved by more extensive surgery, and surgery did not affect mortality, progression, or disease-free survival in patients with follicular cancer by univariate (Table 2) or multivariate (Table 3) analyses. Radioiodine Therapy Postoperative radioiodine therapy with iodine-131 was administered to 258 of 302 (85.4%) patients with papillary cancer; the init

Fatigue syndrome due to localized radiation

For cancer patients, fatigue is a disturbing symptom caused by many factors. Since fatigue is the most common side effect of localized radiation to the breast, this treatment provides a unique opportunity to follow patients prospectively as they develop one type of fatigue. We evaluated the effect of radiation treatment in 15 women with Stage I or II node-negative breast cancer who were otherwise healthy. Fatigue, contrary to our hypothesis, did not increase linearly with cumulative radiation dose over time. It dropped from the first to second week and rose in the third week. The cumulative effects reached a plateau in the fourth week (after an average of 17 fractions), which was maintained during the remaining weeks of treatment. Within 3 wk after treatment, fatigue had diminished. No patient had sustained depressive symptoms. Cardiopulmonary exercise capacity in 5 patients at 6 and 12 wk did not change from just before radiation. Other markers, including reverse triiodothyronine and pulse change with orthostatic stress, did not correlate with subjective fatigue nor cumulative radiation in 15 patients. The curve of the fatigue syndrome during treatment conforms to the adaptation of the organism to a continuing stress and begins to describe a mild fatigue syndrome associated with radiation.

Recurrence after treatment of micropapillary thyroid cancer.

BACKGROUND Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine. METHODS The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocal micropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years. RESULTS Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p = 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine. CONCLUSIONS Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer.

Who starts antiretroviral therapy in Durban, South Africa?… not everyone who should

Objective:To evaluate rates of antiretroviral therapy (ART) initiation within 12 months of a new HIV diagnosis in Durban, South Africa. Design:Prospective observational cohort. Methods:Adults (≥18 years) were enrolled before HIV testing at two outpatient clinics into the South African Test, Identify and Link cohort. Both sites offer comprehensive HIV care. HIV test results, CD4 cell counts, dates of ART initiation and dates of death were collected from medical records and 12-month patient/family interviews were conducted. ART eligibility was defined as a CD4 cell count less than 200 cells/μl within 90 days of HIV diagnosis. The primary endpoint was ART initiation within 12 months for ART-eligible subjects. Results:From November 2006 to October 2008, 1474 newly diagnosed HIV-infected outpatients were enrolled, 1012 (69%) of whom underwent CD4 cell count testing within 90 days. The median CD4 cell count was 159 cells/μl (interquartile range 65–299). Of those who underwent CD4 cell count testing, 538 (53%) were ART-eligible. Only 210 (39%) eligible enrollees were known to have initiated ART within 12 months. Among ART-eligible subjects, there were 108 known deaths; 82% occurred before ART initiation or with unknown ART initiation status. Men [rate ratio (RR) 1.3, 95% confidence interval (CI) 1.1–1.5] and subjects without an HIV-infected family member/friend (RR 1.3, 95% CI 1.1–1.7) were more likely not to start ART. Conclusion:Less than half of ART-eligible subjects started ART within 12 months. Substantial attrition and mortality follow HIV diagnosis before ART initiation in Durban, South Africa. Major efforts directed towards earlier HIV diagnosis, effective linkage to care and timely ART initiation are urgently needed.

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.