Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

Oral sucrosomial iron versus intravenous iron in anemic cancer patients without iron deficiency receiving darbepoetin alfa: a pilot study.

PURPOSE: Erythropoiesis-stimulating agents (ESAs) are often used in treatment of patients with chemotherapy-induced anemia. Many studies have demonstrated an improved hemoglobin (Hb) response when ESA is combined with intravenous iron supplementation and a higher effectiveness of intravenous iron over traditional oral iron formulations. A new formulation of oral sucrosomial iron featuring an increased bioavailability compared to traditional oral formulations has recently become available and could provide a valid alternative to those by intravenous (IV) route. Our study evaluated the performance of sucrosomial iron versus intravenous iron in increasing hemoglobin in anemic cancer patients receiving chemotherapy and darbepoetin alfa, as well as safety, need of transfusion, and quality of life (QoL). MATERIALS AND METHODS: The present study considered a cohort of 64 patients with chemotherapy-related anemia (Hb >8 g/dL <10 g/dL) and no absolute or functional iron deficiency, scheduled to receive chemotherapy and darbepoetin. All patients received darbepoetin alfa 500 mcg once every 3 weeks and were randomly assigned to receive 8 weeks of IV ferric gluconate 125 mg weekly or oral sucrosomial iron 30 mg daily. The primary endpoint was to demonstrate the performance of oral sucrosomial iron in improving Hb response, compared to intravenous iron. The Hb response was defined as the Hb increase ≥2 g/dL from baseline or the attainment Hb ≥ 12 g/dL. RESULTS: There was no difference in the Hb response rate between the two treatment arms. Seventy one percent of patients treated with IV iron achieved an erythropoietic response, compared to 70% of patients treated with oral iron. By conventional criteria, this difference is considered to be not statistically significant. There were also no differences in the proportion of patients requiring red blood cell transfusions and changes in QoL. Sucrosomial oral iron was better tolerated. CONCLUSION: In cancer patients with chemotherapy-related anemia receiving darbepoetin alfa, sucrosomial oral iron provides similar increase in Hb levels and Hb response, with higher tolerability without the risks or side effects of IV iron.

Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study.

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician's decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18 months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

MiRNA dysregulation underlying common pathways in type 2 diabetes and cancer development: an Italian Association of Medical Oncology (AIOM)/Italian Association of Medical Diabetologists (AMD)/Italian Society of Diabetology (SID)/Italian Society of Endocrinology (SIE)/Italian Society of Pharmacology (SIF) multidisciplinary critical view.

Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.

Diabetes management in cancer patients. An Italian Association of Medical Oncology, Italian Association of Medical Diabetologists, Italian Society of Diabetology, Italian Society of Endocrinology and Italian Society of Pharmacology multidisciplinary consensus position paper.

Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Effects of anti-neoplastic treatment on sperm aneuploidy rate in patients with testicular tumor: a longitudinal study.

OBJECTIVE: The adjuvant radio/chemotherapy, usually employed after orchidectomy in patients with testicular tumors, allows a long-term survival with a consequent increased request for fertility. However, little is known about the effects of the anti-neoplastic treatment on sperm cytogenetic asset. Therefore, this prospective, longitudinal study was designed to evaluate the effects of radio- and/or chemotherapy on sperm chromosome. METHODS: Eleven patients with testicular tumor were enrolled and underwent sperm aneuploidy rate evaluation before and after 3, 6, 9, 12, 18, 24, and 36 months from radio- and/or chemo-therapy ending. A double and triple multicolor fluorescence in-situ hybridizations for chromosomes 8, 12, 18, X and Y were used to evaluate the sperm aneuploidy rate. To define normal sperm aneuploidy rate, 18 healthy, normozoospermic men were selected as controls. RESULTS: Before treatment, testicular tumor patients had a higher total sperm aneuploidy rate compared with normal men. Total sperm aneuploidy rate showed a slight, but statistically significant increase 6 months after anti-neoplastic treatment. This increase was mainly related to the high sperm aneuploidy rate found in 2 patients which remained elevated up to 12 months in both of them. CONCLUSION: These results showed that anti-neoplastic treatment caused only slight and transient sperm malsegregation events in patients with testicular tumor. However, since a subset of them had an elevated sperm aneuploidy rate for about 1 yr, we suggest to counsel them to refrain from fatherhood for this length of time.

COVID-19 infection in cancer patients: what has been the contribution of Associazione Italiana Oncologia Medica (AIOM) to oncological care since the beginning of the first pandemic wave?

High mortality rates in elderly patients or in those with underlying chronic illnesses and/or a compromised immune system is a peculiar feature of COVID-19 infection. The possible coexistence of a cancer and COVID-19 infection in the same individual prompted concerns regarding their synergistic effect on prognosis. In order to balance patients' needs with the risks related to the infection, the question oncologists have asked from the beginning of the first wave of the pandemic has been: 'how can we deal with COVID-19 infection in cancer patients?' In pursuing its mission, the Associazione Italiana Oncologia Medica (AIOM) has made every possible effort to support cancer patients, health care professionals and institutions in the decision-making processes the pandemic has engendered within this scenario. The relevant documents as well as the educational and institutional initiatives the AIOM has taken are reported in this article.

Does prolactin induce apoptosis? Evidences in a prostate cancer in vitro model.

BACKGROUND: Prolactin (PRL) regulates prostate growth and differentiation. Some studies have suggested that PRL has a pro-apoptotic effect on a myeloma cell line and in newt spermatogonia. The proliferative effect of PRL on prostate cancer cell lines is, however, a controversial area. AIM: On this account, we evaluated the effects of PRL on the prostate cancer cell lines LNCaP and PC3 apoptosis and proliferation. MATERIALS AND METHODS: LNCaP and PC3 cells were exposed to increasing concentrations of PRL for 24, 48, 72 and 96 hours. Staining with propidium iodide (PI) and TUNEL assay followed by flow cytometry were used to detect apoptosis. LNCaP and PC3 proliferation was assessed by optical microscopy counting. RESULTS: PRL induced a dose-dependent decrease of DNA content and an increase of DNA fragmentation in LNCaP after 96 hours of incubation. These effects were observed with physiological concentrations of PRL and were counteracted by a prolactin receptor antagonist. On the other hand, PRL did not have any effect on DNA content or fragmentation in PC3 cells. No effect of PRL on LNCaP and PC3 proliferation was found. CONCLUSIONS: This study indicates that PRL induces apoptosis in the androgen-responsive cell line LNCaP, whereas no effect was observed in the androgen-insensitive PC3 cell line. These findings suggest that androgen responsiveness may be required for PRL to be effective on prostatic cells.

Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

Comprehensive normal-phase x reversed-phase liquid chromatography coupled to photodiode array and mass spectrometry detection for the analysis of free carotenoids and carotenoid esters from mandarin.

In the present work, a novel strategy including the use of two different comprehensive HPLC methods has been employed to study the whole carotenoid composition of mandarin essential oil. Thus, two different fully orthogonal two-dimensional HPLC methods have been used. A silica microbore column was coupled to a C(18) monolithic column to study the mandarin saponified extract, while the coupling of a cyano microbore column to a C(18) monolithic column was employed to study the intact mandarin essential oil sample in order to characterize the native carotenoid esters composition. Detection was performed by connecting a photodiode array detection (DAD) system in parallel with a MS detection system operated with an atmospheric pressure chemical ionization (APCI) interface. Thus, the carotenoid identification was carried out by combining the information provided by the DAD and MS systems and the peaks relative position in the two-dimensional chromatograms.

Elevated insulin receptor content in human breast cancer.

The growth of breast cancer cells is under the regulation of hormones, growth factors, and their receptors. In the present study, we have employed a new, sensitive, and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0.95 + 0.68, P less than 0.001) and in six normal specimens obtained from reduction mammoplasty (0.84 +/- 0.78, P less than 0.001). The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino, V., V. Papa, V. Trischitta, A. Brunetti, P.A. Goodman, M.K. Treutelaar, J.A. Williams, B.A. Maddux, R. Vigneri, and I.D. Goldfine, 1989. Am. J. Physiol. 257:E451-457). The insulin receptor in breast cancer retained its ability to both bind insulin and undergo insulin-induced tyrosine kinase activation. Immunostaining of the specimens revealed that the insulin receptor was present in malignant epithelial cells, but was not detected in stromal and inflammatory cells. Univariant analysis revealed that the insulin receptor content of the tumors correlated positively with tumor size (P = 0.014), histological grading (P = 0.030), and the estrogen receptor content (P = 0.035). There were no significant correlations between insulin receptor content and the age, body weight, menopausal status, and nodal involvement of the patients. These studies indicate, therefore, that the insulin receptor content is increased in breast cancers and raise the possibility that the insulin receptor may have a role in the biology of these tumors.

DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1.

NKX3.1 is a member of the NK class of homeodomain proteins and is most closely related to Drosophila NK-3. NKX3.1 has predominantly prostate-specific expression in the adult human. Previous studies suggested that NKX3.1 exerts a growth-suppressive effect on prostatic epithelial cells and controls differentiated glandular functions. Using a binding site selection assay with recombinant NKX3.1 protein we identified a TAAGTA consensus binding sequence that has not been reported for any other NK class homeoprotein. By electromobility shift assay we demonstrated that NKX3.1 preferentially binds the TAAGTA sequence rather than the binding site for Nkx2.1 (CAAGTG) or Msx1 (TAATTG). Using mutated binding sites in competitive gel shift assays, we analyzed the nucleotides in the TAAGTA consensus sequence that are important for NKX3.1 binding. The consensus binding site of a naturally occurring polymorphic NKX3.1 protein with arginine replaced by cysteine at position 52 was identical to the wild-type binding sequence. The binding affinities of wild-type and polymorphic NKX3.1 for the TAAGTA consensus site were very similar, with values of 20 and 22 nM, respectively. Wild-type and polymorphic NKX3.1 specifically repressed transcription of luciferase from a reporter vector with three copies of the NKX3.1-binding site upstream from a thymidine kinase promoter. The data show that among NK family proteins NKX3.1 binds a novel DNA sequence and can behave as an in vitro transcriptional repressor.

Anti-inflammatory activity of extract and fractions from Nepeta sibthorpii Bentham.

Several species of Nepeta genus are utilized in folk medicine for treatment of contusions, rheumatic pains, fever, cutaneous eruptions. Some species are employed for their anti-inflammatory properties. In this paper, we report the results of phytochemical studies on aerial parts of Nepeta sibthorpii Bentham (Lamiaceae), an endemic plant of Greece. The bioassay-guided fractionation of methanol extract led to the isolation of ursolic acid and polyphenol fraction. By HPLC, we determined some phenolics: chlorogenic acid (0.315 mg/g) and the flavonoids rutin (0.091 mg/g), luteolin-7-O-glucoside (0.387 mg/g) and a luteolin derivative. We assayed the radical scavenging activity of Nepeta sibthorpii methanol extract by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. Moreover, we studied the anti-inflammatory activity of Nepeta sibthorpii methanol extract (50 mg/kg, os), ursolic acid and polyphenol fraction (dose corresponding to 50 mg/kg of methanol extract, os) in the carrageenan-induced paw oedema in rat. In this experimental model, we observed a significant inhibition of paw oedema. We suppose that the anti-inflammatory effect of methanol extract could be related to the free radical scavenging activity and that it depends on a synergic action of all the components of the methanol extract, even if ursolic acid can be considered the main responsible for this activity.

Cardiac metastasis from primary anaplastic thyroid carcinoma: report of three cases and a review of the literature.

BACKGROUND: Clinically evident cardiac metastases from malignant neoplasms are uncommon. The frequency of thyroid metastasis to the heart is very low. To our knowledge, over the last 20 years only a few cases have been reported in the entire literature. Metastatic cardiac involvement occurs most often during the terminal stage. PATIENTS: We present three cases of anaplastic thyroid cancer with metastatic involvement of the heart. RESULTS: Two of the patients died from cardiac problems. The absence of early symptoms makes the clinical diagnosis of metastatic carcinoma difficult. CONCLUSIONS: Anaplastic thyroid cancer is an aggressive cancer with a dismal prognosis. It should be borne in mind as a source of cardiac metastasis and a cause of cardiac death.

Outcome of differentiated thyroid cancer in Graves' patients.

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.

Early diagnosis by genetic analysis of differentiated thyroid cancer metastases in small lymph nodes.

We report a PCR-based technique for detecting thyroid cancer metastases in small nodes <1.5 cm diameter by the amplification of thyroid specific transcripts TSH-receptor and thyroglobulin. A 100% correspondence with the histopathological diagnosis was observed in the 41/46 nodes (89%) in which an adequate sample was obtained at fine needle aspiration. The genetic analysis resulted more sensitive and accurate than both the cytological analysis (28% inadequate samples, 17% false negative diagnoses) and the thyroglobulin measurement in the aspirates (39% false negatives). The PCR-based genetic analysis may provide a useful tool for diagnosis and follow-up of thyroid cancer.

Increased aggressiveness of thyroid cancer in patients with Graves' disease.

To evaluate whether coexistence of Graves' disease affects the prognosis of thyroid cancer we examined the clinical and pathological characteristics of 22 differentiated thyroid carcinomas concomitant with hyperthyroidism; 13 were associated with Graves' disease, and 9 with autonomous thyroid nodules. Carcinomas were identified in a consecutive series of 359 hyperthyroid patients (132 with Graves' disease and 227 with autonomous thyroid nodules) who underwent surgery during a 6-yr period. One hundred and thirty-seven thyroid carcinomas were found in the 582 euthyroid patients operated on in the same period. In Graves' patients, carcinomas were more often multifocal (46.1% vs. 0%), locally invasive (61.5% vs. 11.1%), and metastatic to lymph nodes (61.5% vs. 11.1%) or to distant sites (23.0% vs. 0%) than in patients with autonomous thyroid nodules. In addition, carcinomas concomitant with Graves' disease were larger (3.3 +/- 1.8 vs. 1.0 +/- 0.7 cm) than the ones associated with autonomous thyroid nodules and showed a high recurrence rate. In euthyroid patients, aggressiveness of thyroid cancer was intermediate. Serum TSH levels were suppressed in all hyperthyroid patients with thyroid cancer. However, circulating thyroid-stimulating antibodies were present in 12 of 13 cancer patients with Graves' disease, but were absent in patients with autonomous thyroid nodules. Our study suggests, therefore, that TSAb may play a role in determining the high aggressiveness of thyroid cancer in Graves' disease patients and indicates that a vigorous treatment should be pursued in this subgroup of patients.

Relation between steroid receptor status and body weight in breast cancer patients.

Obesity is known to adversely affect breast cancer prognosis. Since obesity is associated with increased oestrogen levels, and oestrogens are growth stimulators of oestrogen receptor (ER)-positive breast carcinomas, we evaluated the relationship between the ER and progesterone receptor (PR) status of the neoplastic tissue and obesity in a series of 615 breast cancer patients. Both ER and PR concentrations were significantly and positively correlated with obesity by multiple regression analysis. Furthermore, the estimated probability of having an ER+/PR+carcinoma was significantly higher in obese patients (odds ratio 2.65, 95% confidence interval 1.56-4.48). This association between receptor-positive status and obesity was observed both in premenopausal and postmenopausal patients. Our data suggest, therefore, that obesity plays a role in determining the ER status of breast cancer and raise the possibility that ER presence in breast carcinomas occurring in obese patients is not indicative of a favourable prognosis.

Controversies in the management of cold, hot, and occult thyroid nodules.

Some aspects of thyroid nodule evaluation and management remain controversial. Radionuclide scanning provides functional information about nodules and differentiates cold from hot nodules. Although thyroid cancers are cold on scan, most cold nodules are benign. Ultrasonography visualizes the thyroid gland and nodules with remarkable clarity and provides structural information about location, number, size, and consistency of nodules. Widespread application of ultrasonography has resulted in the frequent discovery of incidental (occult) nodules in the general population. The clinical significance of these nodules remains unknown, and their management has created a dilemma for physicians. Current cost-effective evaluation of nodules does not include scanning or ultrasonography as routine frontline tests. In most centers, fine-needle aspiration biopsy has supplanted imaging studies as the routine initial procedure for differentiating benign from malignant nodules. Cytologic diagnosis is reliable and inexpensive, and it results in a better selection of patients for surgery. Limitations include false-negative diagnoses, nondiagnostic results, and indeterminate "suspicious" results. Laboratory test results are usually normal, but determination of serum thyrotropin may identify a hot nodule, and plasma calcitonin may help diagnose medullary thyroid carcinoma. Treatment of thyroid nodules is controversial. In some practices, benign colloid nodules are treated with suppressive doses of levothyroxine. Recent reports cast doubt on the efficacy of this approach, and it is no longer acceptable to select patients for surgical treatment on the basis of suppressive therapy. Furthermore, suppressive levothyroxine therapy may be associated with significant bone and cardiac side effects, especially in elderly patients and postmenopausal women. Our approach is observation for most patients, and we suggest a careful risk-benefit analysis when suppression is considered. Hot (autonomous) nodules can be treated with radioiodine, surgery, or ethanol injection. The use of sensitive thyrotropin assays has revealed that the "euthyroid" hot nodule is often associated with subclinical hyperthyroidism, warranting treatment if risks of osteoporosis are significant. Small (< 1.5 cm) occult nodules can be observed. Larger (> 1.5 cm) nodules can be selectively evaluated by ultrasonographically guided fine-needle aspiration. It is prudent to consider cost of care, risk-benefit analysis, and the low incidence of malignancy in thyroid nodules when diagnostic tests are selected and the treatment plan is outlined.