Giovanni Milazzo

Cancer risk in patients with cold thyroid nodules: Relevance of iodine intake, sex, age, and multinodularity☆

PURPOSE We evaluated the frequency of thyroid cancer in patients with cold thyroid nodules in relation to iodine intake, sex, age, and multinodularity in a consecutive series of patients with nodular thyroid diseases. PATIENTS In the period from 1980 to 1990, 5,637 patients were studied: 4,176 patients were from an iodine-sufficient area (ISA) and 1,461 from an adjacent iodine-deficient area (IDA). Surgery was performed in 792 patients on the basis of a suspicious or malignant finding at fine-needle aspiration biopsy. RESULTS The overall thyroid cancer frequency was 4.6% (259 patients had cancer). Iodine intake affected the cancer rate in patients with cold nodules. The frequency of cancer in patients with cold thyroid nodules was 5.3% in the ISA and 2.7% in the IDA. This difference, however, was significant only in females. Sex had a major influence on the malignant rate of cold nodules; although female patients were more frequently observed (n = 5,028) than male patients (n = 609), the frequency of cancer was significantly lower in female patients with cold nodules (4.2%) than in males (8.2%). Age was an important factor in both sexes. The proportion of nodules that were malignant was smallest in patients of the 4th decade and was greatest in patients younger than 30 years or older than 60 years. Multivariate analysis showed that sex and age interact in determining the cancer risk in patients with thyroid nodules. Finally, the frequency of thyroid cancer in patients with a solitary nodule was not different from the frequency in patients with multiple nodules. CONCLUSION Our study indicates that thyroid cancer risk in a patient with a nodular goiter varies markedly according to iodine intake, sex, and age but not in relation to multinodularity, as assessed by clinical examination. The knowledge of these epidemiologic aspects of thyroid cancer may increase the accuracy of the preoperative selection of patients with cold nodules of the thyroid.

Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye

Background/aims: Several studies have reported that sodium hyaluronate is able to improve both symptoms and signs in patients with dry eye but none have demonstrated an improvement of conjunctival epithelial cell abnormalities of the ocular surface. The aim of this study was to explore the effect of sodium hyaluronate-containing eye drops on the ocular surface of patients with dry eye during long term treatment. Methods: A randomised double blind study was undertaken in 86 patients with medium to severe dry eye (that is, rose bengal and/or fluorescein test score of at least 3, tear film break up time <10 seconds, or Schirmers test <5.5 mm). Patients were treated with either preservative-free sodium hyaluronate or saline for 3 months at a dose of one drop 4–8 times a day. Bulbar impression cytology, slit lamp examinations, and subjective symptoms were evaluated after 1, 2, and 3 months. Impression cytology was considered the primary efficacy parameter of the study. Results: The efficacy analysis was performed on a total of 44 patients who were able to fully adhere to the protocol. After 3 months of treatment sodium hyaluronate improved impression cytology score (p = 0.024 v baseline). At the same time also the difference with respect to placebo was statistically significant (p = 0.036). Study medication was well tolerated and no treatment related adverse events occurred during the study. Conclusions: Sodium hyaluronate may effectively improve ocular surface damage associated with dry eye syndrome.

ASPB10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: evidence for enhanced interactions with the insulin-like growth factor-I receptor.

The human insulin analogue ASPB10 has been reported to have increased affinity for the insulin receptor and to cause breast cancer in female rats. In the study reported here, we investigated whether ASPB10 has an increased mitogenic potency and induces a transformed phenotype in cultured human breast cells. In both MCF‐10 cells (a non‐malignant human breast line) and MCF‐7 cells (a human breast cancer cell line), ASPB10 was approximately twofold more potent than insulin in competing for 125I‐insulin binding but sevenfold to tenfold more potent than insulin in competing for 125I‐insulin‐like growth factor (IGF)‐I binding. In addition, ASPB10 was twofold more potent than insulin in stimulating insulin receptor autophosphorylation but significantly more potent in stimulating IGF‐I receptor autophosphorylation in both cell lines. Moreover, ASPB10 was approximately sevenfold more potent than insulin in stimulating the growth of MCF‐10 and MCF‐7 cells. This increased mitogenic effect of ASPB10 was significantly inhibited (but not abolished) when cells were cultured in the presence of α‐IR3, a monoclonal antibody to the IGF‐I receptor. ASPB10, but not insulin, caused phenotypic changes (focus formation) in MCF‐10 cells. Neither agent caused colony formation in soft agar in MCF‐10 cells, but ASPB10 was more potent than insulin in stimulating colony formation in MCF‐7 cells. These observations indicate that in human breast cells, ASPB10 has enhanced mitogenic effects and induces phenotypic changes as a consequence of its activation of both insulin and IGF‐I receptors. Mol. Carcinog. 18:19–25, 1997.

High-affinity insulin binding to an atypical insulin-like growth factor-I receptor in human breast cancer cells.

We studied the nature of insulin receptor binding in MCF-7 breast cancer cells. In both intact cells and solubilized receptor preparations, high-affinity insulin binding was seen. However, unlabeled insulin-like growth factor-I (IGF-I) was five-fold more potent in inhibiting 125I-insulin binding than insulin itself. With monoclonal antibodies to the insulin receptor, 30% of 125I-insulin binding was inhibited. In contrast when alpha-IR3, a monoclonal antibody that recognizes typical IGF-I receptor, was employed over 60% of 125I-insulin binding was inhibited. The B29-MAB-125I-insulin photoprobe was then cross-linked to MCF-7 membranes. Cross-linking was inhibited by both unlabeled insulin and IGF-I. Further, the B29-MAB-125I-insulin photoprobe cross-linked to MCF-7 membranes was strongly immunoprecipitated by alpha-IR3. Employing sequential affinity chromatography with insulin-Affi-gel followed by insulin receptor monoclonal antibody agarose, atypical insulin binding activity was separated from insulin receptor binding activity. This atypical receptor had intrinsic tyrosine kinase activity. Both insulin and IGF-I stimulated the phosphorylation of the receptors beta subunit. In MCF-7 cells both IGF-I and insulin stimulated [3H]thymidine incorporation; alpha-IR3 blocked all of the IGF-I effect but only 50-60% of the insulin effect. This study demonstrates in MCF-7 cells that, in addition to typical insulin and IGF-I receptors, there is another receptor that binds both insulin and IGF-I with high affinity.

Comparison of Hypotonic and Isotonic Solutions Containing Sodium Hyaluronate on the Symptomatic Treatment of Dry Eye Patients

This study was designed to compare the efficacy of two artificial tears both containing hyaluronic acid but differing in their osmolarity. A multicentric double-masked, crossover clinical trial was performed in which 158 subjects were randomized to receive either hypotonic or isotonic artificial tears up to 6 times a day. Both treatments were effective in improving signs and symptoms to a similar extent. No adverse events were reported. It was concluded that hypotonic and isotonic eye drops are comparable for the symptomatic treatment of patients suffering from dry eye syndrome.

Treatment of acute bacterial conjunctivitis with topical netilmicin

Purpose. This study compares the clinical and microbiologic value of topical netilmicin with that of gentamicin in the treatment of acute bacterial conjunctivitis. Methods. A double-blind, randomized, prospective, controlled study was performed in 209 patients. One to two drop(s) of either antibiotic was applied to the affected eye(s) four times a day for up to 10 days. Patients were examined at the time of diagnosis and after 3, 5, and 10 days. Clinical efficacy was measured as the cumulative sum score (CSS) of the key signs and symptoms of acute bacterial ocular infection. Sensitivity/resistance was evaluated using the disk diffusion method. Results. Drug efficacy assessment was restricted only to patients with positive baseline culture results (n = 121). Of the isolated organisms, 96.9% were sensitive to netilmicin, whereas only 75.0% were sensitive to gentamicin (p = 0.00001). Netilmicin provided a broad-spectrum coverage comparable with that of ciprofloxacin, ofloxacin, and norfloxacin. Netilmicin also was more effective than gentamicin in eradicating infections (p = 0.001 at day 5 and p = 0.037 at day 10) and in ameliorating the CSS (p = 0.037 at day 3, p = 0.001 at both day 5 and day 10). Only minor adverse events occurred in patients treated with either netilmicin or gentamicin. Conclusions. This study demonstrates that netilmicin is a safe and effective antibiotic that can be used as first-line therapy for the treatment of acute bacterial conjunctivitis.

Insulin-stimulated cell growth in insulin receptor substrate-1-deficient ZR-75-1 cells is mediated by a phosphatidylinositol-3-kinase-independent pathway.

In many human breast cancers and cultured cell lines, insulin receptor expression is elevated, and insulin, via its own insulin receptor, can stimulate cell growth. It has recently been demonstrated that the enzyme phosphatidylinositol‐3‐kinase (PI3‐K) mediates various aspects of insulin receptor signaling including cell growth. In order to understand the mechanisms for insulin‐stimulated cell growth in human breast cancer, we measured insulin‐stimulable PI3‐K activity in a non‐transformed breast epithelial cell line, MCF‐10A, and in two malignantly transformed cell lines, ZR‐75‐1 and MDA‐MB157. All three cell lines express comparable amounts of insulin receptors whose tyrosine autophosphorylation is increased by insulin, and in these cell lines insulin stimulates growth. In MDA‐MB157 and MCF‐10A cells, insulin stimulated PI3‐K activity three‐ to fourfold. In ZR‐75‐1 cells, however, insulin did not stimulate PI3‐K activity. In ZR‐75‐1 cells PI3‐K protein was present, and its activity was stimulated by epidermal growth factor, suggesting that there might be a defect in insulin receptor signaling upstream of PI3‐K and downstream of the insulin receptor. Next, we studied insulin receptor substrate‐1 (IRS‐1), a major endogenous substrate for the insulin receptor which, when tyrosine is phosphorylated by the insulin receptor, interacts with and activates PI3‐K. In ZR‐75‐1 cells, there were reduced levels of protein for IRS‐1. In these cells, both Shc tyrosine phosphorylation and mitogen‐activated protein kinase (MAP‐K) activity were increased by the insulin receptor (indicating that the p21ras pathway may account for insulin‐stimulated cell growth in ZR‐75‐1 cells).

Sporadic amplification of the insulin receptor gene in human breast cancer

Insulin receptor (IR) content is increased in most human breast carcinomas when compared to normal breast tissue. In the present study we investigated IR gene copy number by using both conventional DNA analysis (slot blot) and fluorescence in situ hybridization (FISH). Cultured human breast cell lines and primary breast carcinoma specimens were analyzed. In 6 breast cell lines in culture both techniques gave similar results: the relative IR copy number determined by FISH strongly correlated with slot blot results (r= 0.831), even if probes for different reference loci were used in the 2 methods. We find that in human breast cancer IR gene amplification is a sporadic event. It occurred in 1/5 cultured breast cancer cell lines (MDA-MB 231) and in 8/93 (8.6%) breast cancer specimens. In contrast an increased copy number of the entire chromosome 19 (which contains IR gene) was frequently observed in both breast cancer cell lines (100%) and breast cancer specimens (45%). When present, IR gene amplification always occurred at low level. These data indicate that IR gene amplification is an uncommon event in human breast carcinomas and that mechanisms other than gene amplification are responsible for IR protein overexpression in most human breast cancers.

Topical naproxen sodium for inhibition of miosis during cataract surgery. Prospective, randomized clinical trials

Purpose To assess corneal penetration of naproxen sodium and its efficacy in maintaining intraoperative mydriasis during cataract surgery.Methods Two double blind studies have been performed comparing the efficacy of naproxen ophthalmic solution to that of placebo or diclofenac in inhibiting pre-operative miosis. Study No. 1 was a placebo-controlled study and involved 194 patients undergoing extracapsular cataract extraction. Study No. 2 was an active-controlled study (vs diclofenac) concerning 214 patients undergoing phacoemulsification. In both studies treatment started the day before surgery. A balanced salt solution containing adrenaline was used in all patients. Pupil size was measured prior to the corneal section and at the end of surgery. An aqueous humor sample was taken immediately before corneal incision in a subset of 20 patients to measure naproxen aqueous concentration.Results In both studies the pupillary diameter decreased during surgery within each treatment group in a statistically significant manner (P < 0.001). Naproxen was more effective than placebo (P < 0.01) and as effective as diclofenac in controlling pupil diameter regression during cataract. Mean concentration level of naproxen in the aqueous humor was 372.3 ng/ml.Conclusions Naproxen sodium ophthalmic solution penetrates the cornea and it is effective in maintaining intraoperative mydriasis.

Dexamethasone-netilmicin : a new ophthalmic steroid-antibiotic combination. Efficacy and safety after cataract surgery

PurposeThe purpose of this study was to evaluate both efficacy and safety of a new ophthalmic steroid–antibiotic fixed combination containing dexamethasone and netilmicin in the postsurgical management of cataract surgery.MethodsIn total, 223 patients were randomly treated with dexamethasone 1 mg/ml plus netilmicin 3 mg/ml (n=148), or dexamethasone 1 mg/ml plus tobramycin 3 mg/ml (n=75, TOBRADEX®) four times in a day for 7±1 days starting immediately after surgery. Efficacy (anterior chamber (AC) inflammation, conjunctival hyperaemia, corneal and lid oedema, ocular infection, pain, photophobia and tearing) and safety (burning, stinging, blurred vision, intraocular pressure, and visual acuity) were analysed in the operated eye after 1 and 7±1 days. A follow-up visit was performed at day 14±2. The extent of AC inflammation, measured by slit-lamp according to a standard scoring system, was used as primary efficacy parameter.ResultsAt the primary end point (day 7) both fixed combinations were equally effective in reducing postoperative inflammation. The safety profile of the dexamethasone/netilmicin combination was excellent with no evidence of poor local tolerance or adverse reaction.ConclusionsA new fixed combination of dexamethasone and netilmicin was effective and safe in controlling ocular inflammation after cataract surgery.