Alexander Gorshtein

Clinical course and outcome of nonfunctioning pituitary adenomas in the elderly compared with younger age groups.

OBJECTIVE Nonfunctioning pituitary adenomas (NFPAs) are the most common type of pituitary adenomas diagnosed in older patients. However, there are insufficient data regarding the clinical course, risk of regrowth, and long-term prognosis in elderly versus younger patients. METHODS This retrospective cohort study observed 105 adult patients with NFPAs diagnosed between 1995 and 2012. Patients were stratified into 3 age groups: 18 to 44 years (29 patients), 45 to 64 years (38 patients), and 65 years and over (38 patients). The impact of age on presenting symptoms, disease course, and outcome was analyzed. RESULTS Adenoma size was larger in patients <45 years (mean, 2.9 ± 1.2 cm) compared to patients aged 45 to 64 years and those ≥65 years old (2.3 ± 0.9 and 2.5 ± 0.8 cm, respectively; P = .05), with transsphenoidal surgery being the treatment of choice in all 3 groups (83, 92, and 84%, not significant). After a mean follow-up of 6 years, there were higher recovery rates from hypopituitarism in patients <45 years old (58% vs. 27% and 24%; P = .04). Visual fields improved in most affected patients in each group following surgery (74, 94, and 86%), with a trend toward more full normalization in the youngest age group (58% vs. 44% and 41%; P = .09). There were no significant differences in the risk of remnant growth (29 to 39%), rates of radiation therapy, or need for repeated surgeries. There was no disease-related mortality. CONCLUSION Elderly patients with NFPA have lower rates of recovery from hypopituitarism after treatment compared to younger patients, but the rates of regrowth and need for salvage surgery are similar.

Intravenous immunoglobulin in therapy of peripheral neuropathy

Peripheral neuropathy (PN) can be a manifestation of various neurological, infectious, metabolic, autoimmune, rheumatic, and malignant diseases. During the past decade, intravenous immunoglobulin (IVIg) has been increasingly used in the therapy of PN. Compared with other immunomodulatory therapies, IVIg has an excellent safety profile. IVIg is used today as a first-line therapy in the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. Some small studies and reports of clinical cases presented in this article found benefit from IVIg in treating PN associated with diabetes, paraproteinemia, HIV, multisystem rheumatic diseases, and paraneoplastic PN. No clear recommendations can be made relating the use of IVIg in these conditions. Prospective, randomized trials are required to clarify this issue.

IGF1 induces cell proliferation in human pituitary tumors – Functional blockade of IGF1 receptor as a novel therapeutic approach in non-functioning tumors

Insulin-like growth factor (IGF1) and its receptor display potent proliferative and antiapoptotic activities and are considered key players in malignancy. The objective of the study was to explore the role of IGF1 and its downstream pathways in the proliferation of non-functioning pituitary tumor cells and to develop a targeted therapeutic approach for the treatment of these tumors. Cultures of human non-functioning pituitary adenomas and the non-secreting immortalized rat pituitary tumor cell line MtT/E were incubated with IGF1, IGF1 receptor inhibitor or both, and cell viability, proliferation and signaling were examined. Our results show that IGF1 elevated cell proliferation and enhanced cell cycle progression as well as the expression of cyclins D1 and D3. IGF1 also induced the phosphorylation of ERK, Akt and p70S6K. On the other hand, the selective IGF1R inhibitor NVP-AEW541 abrogated IGF1-induced cell proliferation as well as IGF1 receptor phosphorylation and downstream signaling.

Calcium levels on admission and before discharge are associated with mortality risk in hospitalized patients

AimInvestigate the association of calcium levels on admission and change in levels during hospitalization with hospitalization outcomes.MethodsHistorical prospective data of patients hospitalized to units of internal medicine between 2011 and 2013. Albumin-corrected-calcium levels were classified to marked hypocalcemia (<7.5 mg/dL), mild hypocalcemia (7.5–8.5 mg/dL), normal calcium (8.5–10.5 mg/dL), mild hypercalcemia (10.5–11.5 mg/dL), marked hypercalcemia (>11.5 mg/dL). Main outcomes were length-of-hospitalization, in-hospital and long-term mortality.ResultsCohort included 30,813 patients (mean age 67 ± 18 years, 51% male). Follow-up (median ± standard deviation) was 1668 ± 325 days. Most patients had normal calcium on admission (93%), 3% had hypocalcemia, 3% had hypercalcemia. Common causes for marked hypercalcemia were malignancy (56%) and hyperparathyroidism (22%). Last calcium levels before discharge or death were normal in 94%, with similar rates of hypercalcemia or hypocalcemia (3% each). Compared to in-hospital mortality with normal calcium on admission (6%), mortality was higher with mild (8%) and marked hypocalcemia (11%), and highest with mild (18%) and marked hypercalcemia (22%). Mortality rate at the end of follow-up was 48% with normal calcium or mild hypocalcemia, 51% with marked hypocalcemia, 68 and 79% with mild and marked hypercalcemia, respectively. Patients with normal calcium on admission and before discharge had the best prognosis. Hypercalcemia on admission or before discharge was associated with a 70% mortality risk at the end of follow-up. Normalization of admission hypercalcemia had no effect on long-term mortality risk.ConclusionsAbnormal calcium on admission is associated with increased short-term and long-term mortality. The excess mortality risk is higher with hypercalcemia than hypocalcemia. Calcium normalization before discharge had no effect on mortality.

Incidence of Nonthyroidal Primary Malignancy and the Association with 131I Treatment in Patients with Differentiated Thyroid Cancer

BACKGROUND The occurrence of nonthyroidal primary malignancy (NTPM) and the potential association of with radioiodine (RAI) treatment are important concerns in patients with differentiated thyroid cancer (DTC), but incidence data are conflicting. The aims of the present study were to investigate the incidence of NTPM and its association with RAI treatment in a cohort of DTC patients treated at a single tertiary medical center. METHODS The data of 1943 patients with DTC recorded in the Rabin Medical Center Thyroid Cancer Registry were cross-matched with data from the Israeli National Cancer Registry to identify those diagnosed with an NTPM. Patient medical files were reviewed. Second primary malignancy (SPM) was defined as new malignancy diagnosed at least two years after DTC diagnosis. RESULTS For 1434 of the 1943 patients (73.8%), the American Joint Committee on Cancer TNM stage was 1-2. The mean follow-up was 9.3 years. Of the 1943 patients, 1574 (81%) were treated with RAI, and 1467 were followed for at least 2 years, and of these, 1145 patients (78%) received a cumulative dose of ≤200 mCi. A total of 409 NTPMs were diagnosed in 368/1943 patients with DTC (18.9%; 265 female, mean age 53.9 ± 15 years), including 173 SPMs (42.3%) in 166/368 patients. The most common NTPM and SPM was breast cancer followed by hematologic malignancies. In patients followed for ≥2 years, SPMs were diagnosed in 9% of RAI-treated patients and 10.5% of non-RAI-treated patients. SPM rates were 10.2% and 7.8% for a cumulative RAI dose of ≤100 mCi and >100 mCi respectively. Hazard ratios for SPM in patients that received/did not receive RAI treatment was 1.27 (95% confidence interval 0.88-1.82; p = 0.1). There was no correlation between first or cumulative RAI dose and diagnosis of SPM. CONCLUSIONS NTPMs are not uncommon in patients with DTC and usually antecede the DTC. In a population of mostly low-risk DTC patients, in whom limited activities of RAI are usually administered, this treatment is apparently not associated with an overall increased risk of SPMs compared with subjects not receiving RAI treatment.

Thiazide Treatment in Primary Hyperparathyroidism-A New Indication for an Old Medication?

Context There is no therapy for control of hypercalciuria in nonoperable patients with primary hyperparathyroidism (PHPT). Thiazides are used for idiopathic hypercalciuria but are avoided in PHPT to prevent exacerbating hypercalcemia. Nevertheless, several reports suggested that thiazides may be safe in patients with PHPT. Objective To test the safety and efficacy of thiazides in PHPT. Design Retrospective analysis of medical records. Setting Endocrine clinic at a tertiary hospital. Patients Fourteen male and 58 female patients with PHPT treated with thiazides. Interventions Data were compared for each patient before and after thiazide administration. Main Outcome Measures Effect of thiazide on urine and serum calcium levels. Results Data are given as mean ± standard deviation. Treatment with hydrochlorothiazide 12.5 to 50 mg/d led to a decrease in mean levels of urine calcium (427 ± 174 mg/d to 251 ± 114 mg/d; P < 0.001) and parathyroid hormone (115 ± 57 ng/L to 74 ± 36 ng/L; P < 0.001), with no change in serum calcium level (10.7 ± 0.4 mg/dL off treatment, 10.5 ± 1.2 mg/dL on treatment, P = 0.4). Findings were consistent over all doses, with no difference in the extent of reduction in urine calcium level or change in serum calcium level by thiazide dose. Conclusion Thiazides may be effective even at a dose of 12.5 mg/d and safe at doses of up to 50 mg/d for controlling hypercalciuria in patients with PHPT and may have an advantage in decreasing serum parathyroid hormone level. However, careful monitoring for hypercalcemia is required.

Second Radioiodine Treatment: Limited Benefit for Differentiated Thyroid Cancer with Loforegional Persistent Disease

Objectives Radioactive iodine (RAI) treatment is often indicated after total thyroidectomy in differentiated thyroid cancer (DTC). However, its role in biochemical or locoregional persistent DTC is unclear. We aimed to investigate the effect of a second RAI treatment in patients with incomplete response to initial treatment and no evidence of distant metastases. Methods Patients who underwent at least two RAI treatments over a 20-year period at a tertiary hospital were identified. Thyroglobulin levels and neck imaging were compared before and 1 to 2 years after RAI retreatment and evaluated at the last visit. Results The cohort included 164 patients (103 female; mean age, 46.6 ± 17 years). Of 114 patients retreated without prior reoperation, 53 had structural disease. At 1 to 2 years after RAI retreatment, 10 of the 41 patients with sufficient data had structural progression, 5 resolution/shrinkage, and 26 stable disease. Stimulated thyroglobulin (stTg) measured 93.7.1 ± 108 ng/mL before and 102.2 ± 124 ng/mL after retreatment (P = NS). The other 61 patients had biochemical-only persistence. Their stTg levels decreased from 41.9 ± 56 to 24.6 ± 54 ng/mL (P = 0.003). The 50 patients who underwent neck reoperation before RAI retreatment showed no substantial change in stTg; 21 (42%) still had imaging findings 1 to 2 years later. At final follow-up, despite additional treatment in 63/164 patients (38.4%), only 56/164 (34.1%) had no evidence of disease. Conclusions This comprehensive study showed limited benefit of second RAI treatment in DTC patients with biochemical or locoregional structural persistent disease. Prospective studies are needed to distinguish patients for whom repeated RAI may be indicated to avoid unnecessary exposure.

Long-term outcomes in older patients with hyperglycemia on admission for ischemic stroke

AIMS Evaluate the association between admission blood glucose (ABG) and mortality in older patients with or without diabetes mellitus (DM) hospitalized for acute ischemic stroke (AIS). METHODS Observational data of patients ≥65years, admitted for AIS between January 2011 and December 2013. ABG levels were classified to categories: ≤70 (low), 70-110 (normal), 111-140 (mildly elevated), 141-180mg/dl (moderately elevated) and >180mg/dl (markedly elevated). Main outcome was all-cause mortality at the end-of-follow-up. RESULTS Cohort included 854 patients, 347 with (mean±SD age 80±8, 44% male), and 507 without DM (mean±SD age 78±8, 53% male). There was a significant interaction between DM, ABG and mortality at end-of-follow-up (p≤0.05). In patients without DM there was a dose-dependent association between ABG category and mortality: adjusted hazard ratios (95% CI) compared to normal ABG were 1.8 (1.2-2.8), 2.9 (1.6-5.2) and 4.5 (2.1-9.7), respectively, for mildly, moderately and markedly elevated ABG. In patients with DM there was no association between ABG and mortality. There was no interaction between DM, ABG and in-hospital mortality or length of stay (LOS). Irrespective of DM status, compared to normal ABG levels, increased ABG category was associated with increased in-hospital mortality: adjusted odds ratios were 3.9 (1.1-13.4), 7.0 (1.8-28.1), and 20.3 (4.6-89.6) with mildly, moderately and markedly elevated ABG, respectively. Mean LOS was 6±5, 7±8, 8±7, and 8±8days, respectively. CONCLUSION In older patients without DM hospitalized for AIS, elevated ABG is associated with increased long-term mortality. Irrespective of DM status, elevated ABG was associated with increased in-hospital mortality and LOS.

Outcomes of hyperglycemia in patients with and without diabetes hospitalized for infectious diseases

To examine the prognostic implications of diabetes mellitus (DM) and the importance of glycemic control during hospitalization for infectious diseases.

LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CANCER AND DISTANT METASTASES

OBJECTIVE Distant metastatic spread is the most frequent cause of thyroid cancer-related death. The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and distant metastases (DM) attending a single medical center and to investigate variables predictive of better long-term outcomes. METHODS The Rabin Medical Center Thyroid Cancer Registry was searched for patients with DM from DTC. RESULTS The cohort included 138 patients (58.7% female) diagnosed at age 54.7 ± 19.5 years. Mean primary tumor size was 33.9 ± 26 mm. Most patients (57.7%) were stage T3/T4; 48.7% had extrathyroidal extension; 53.5% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 66.7% and 13.8%, respectively, and intermediate/poorly differentiated carcinoma in 19.6%. All but 2 patients underwent total thyroidectomy, and 133/138 (96.4%) received radioactive iodine (RAI) therapy. DM were synchronous in 55.1%. The mean follow-up was 8.2 years from detection of metastases. The common sites of metastases were the lungs (85.6% of patients), bones (39.9%), brain (5.8%) and liver (3.6%). At last follow-up, resolution was documented in 24.6% of patients, improvement/stable disease in 31.6%, and structurally progressive disease in 43.4%. By the end of the study, 40.6% of patients died, 23.2% of DTC. Improved overall survival and disease progression were associated with younger age, lung-only DM, and metastatic RAI avidity. CONCLUSION Patients with DTC and DM treated by standard-of-care approaches frequently achieve favorable long-term outcomes. Novel therapies might be necessary in only a minority of these patients, and the reported prognostic factors can aid in their identification. ABBREVIATIONS CR = complete response; DM = distant metastases; DTC = differentiated thyroid cancer; ETE = extra-thyroidal extension; M0 = detected during follow-up; M1 = detected at diagnosis; MSKCC = Memorial Sloan Kettering Cancer Center; NED = no evidence of disease; OS = overall survival; PFS = progression free survival; PTC = papillary thyroid cancer; RAI = radioactive iodine; Tg = thyroglobulin.