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.

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.

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.

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper.

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.

Early prediction of pancreatic cancer from new-onset diabetes: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper.

Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening for patients at higher risk of PC could be a promising approach, this is not recommended in asymptomatic adults with new-onset diabetes, due to the much higher incidence of hyperglycaemia than PC and to the lack of a safe and affordable PC screening test. Prompted by a well-established and productive multidisciplinary cooperation, the Italian Association of Medical Oncology (AIOM), the Italian Medical Diabetologists Association (AMD), the Italian Society of Endocrinology (SIE), and the Italian Society of Pharmacology (SIF) here review available evidence on the mechanisms linking diabetes and PC, addressing the feasibility of screening for early PC in patients with diabetes, and sharing a set of update statements with the aim of providing a state-of-the-art overview and a decision aid tool for daily clinical practice.

Pulsatile antagonism on bradykinin 2-receptor (BK2R) by icatibant triggers the most effective kinin-dependent post-conditioning on rat hearts.

OBJECTIVE: Pharmacological post-conditioning (PC) by intermittent but not continuous administration of exogenous bradykinin (BK) reduces ischemia/reperfusion (I/R) injury via the Reperfusion Injury Salvage Kinase (RISK) pathway activation. We evaluated whether intermittent administration with icatibant (HOE140), a BK2R antagonist, may represent an effective PC strategy, with the advantage of limiting the potential risks of supra-physiologic BK activity. MATERIALS AND METHODS: Hearts from male Sprague-Dawley (SD) rats on a Langendorff system were exposed to I/R injury (30/120 min). BK (100 nM) and HOE140 (1 µM) were administered post-ischemically during the first 3 min of reperfusion, under continuous or intermittent infusion (10 s/each). Hearts were randomly assigned to 5 groups: 1) I/R alone (n=5); 2) continuous HOE140 (cHOE n=6); 3) intermittent HOE140 (iHOE n=6); 4) continuous BK (cBK n=6); 5) intermittent BK (iBK n=6). End-diastolic left ventricular pressure (LVEDP), developed left ventricular pressure (dLVP) and coronary flow (CF) were monitored throughout reperfusion. Left ventricular infarct mass (IM) was quantified together with the phosphorylated levels of Akt and GSK3ß (RISK pathway kinases) at the end of reperfusion. RESULTS: IM was not significantly changed in cBK or cHOE groups (vs. I/R). Conversely, both iBK and iHOE groups showed a significant limitation in IM (vs. I/R, p<0.05, p<0.01, respectively). Akt and GSK3ß phosphorylation levels were higher in iBK and iHOE groups (vs. I/R, p<0.05). When compared to I/R group, both LVEDP values (p<0.05, first 60-min reperfusion), as well as dLVP values (p<0.01) were improved only in iHOE group. CF values did not vary among all groups. CONCLUSIONS: In isolated rat hearts, intermittent modulation of the endogenous kallikrein-kinin system by a selective BK2R antagonist mediates PC cardioprotection via RISK signaling.

Panic disorder as a risk factor for post-partum depression: Results from the Perinatal Depression-Research & Screening Unit (PND-ReScU) study.

BACKGROUND: Although the role of anxiety disorders on the development of Post-partum Depression (PPD) have already been studied in literature, that of individual anxiety disorders has not received specific attention. The aim of this study is to investigate the role of Panic Disorder (PD) and family history for PD as risk factors for PPD. METHODS: Six hundred women were recruited in a prospective, observational study at the 3rd month of pregnancy and followed up until the 6th month after delivery. At baseline, risk factors for PPD, Axis-I disorders and family history for psychiatric disorders were assessed. We investigated minor and major depression (mMD) occurred at 1st, 3rd and 6th months post-partum. Logistic regression models were used to estimate the association between PD, family history for PD and PPD. RESULTS: Forty women had mMD in the post-partum. PD during pregnancy (RR=4.25; 95%CI:1.48-12.19), a history of PD (RR 2.47; 95%CI:1.11-5.49) and family history for PD (RR=2.1; 95%CI:1.06-4.4) predicted PPD after adjusting for lifetime depression and risk factors for PPD. LIMITATIONS: The response rate is moderately low, but it is similar to other studies. The drop out rate is slightly high, however the 600 women who completed the 6th month follow-up did not differ from the presence of PD at baseline. CONCLUSIONS: PD is an independent risk factor for PPD, underscoring need to assess PD symptoms during pregnancy. Furthermore, PD represents an important risk factor for the development of PPD and should be routinely screened in order to develop specific preventive interventions.

Generation of a novel antibody probe to the apical sodium-dependent bile acid transporter that inhibits ileal bile acid absorption.

Intestinal bile acid absorption is mediated by a sodium-dependent transporter located in the brush border apical membrane of ileocytes. The transmembrane topology and the role of individual amino acid residues in the bile acid transport process have been investigated by means of various experimental approaches, leading to multiple hypotheses. We raised a monoclonal antibody against a segment of the transporter comprising vicinal cysteine residues, in order to evaluate its functional role. A 14 amino acid peptide, corresponding to amino acids 104-117 of the transporter, was synthesized, and a monoclonal anti-peptide antibody was raised. In vitro uptake-inhibition studies in the presence of the monoclonal anti-peptide antibody were performed using ileal brush border membrane vesicles. Rabbit ileum was perfused in vivo with 5 mM taurocholic acid in the presence of the monoclonal antibody, and bile acid absorption inhibition was evaluated. The anti-peptide monoclonal antibody significantly reduced the in vitro uptake and in vivo absorption of taurocholic acid. The present data demonstrate the functional relevance of the 104-117 peptide segment and report the generation of a novel antibody against the apical sodium-dependent bile acid transporter (ASBT) that may be used as a therapeutic agent in hypercholesterolemia and in cholestatic pruritus.

Transjugular intrahepatic portosystemic shunt: a case report of rescue management of unrestrainable variceal bleeding in a pregnant woman.

Liver cirrhosis complications in pregnant women are frequent and death rate secondary to variceal bleeding is relevant. Both sclerotherapy and banding ligation seem to be safe procedures in pregnancy; when bleeding is not arrested endoscopically an emergency transjugular intrahepatic portosystemic shunt should be considered, but data regarding pregnant cirrhotic women are scarce. We describe the case of a pregnant woman at 14 weeks of gestation who underwent management of acute variceal bleeding by transjugular intrahepatic portosystemic shunt. Transjugular intrahepatic portosystemic shunt may represent a rescue treatment for failed attempts of band ligation or sclerotherapy.

Photorefractive keratectomy in high myopic defects with or without intraoperative mitomycin C: 1-year results.

PURPOSE: To study the results of the prophylactic use of mitomycin C (MMC) to reduce haze formation and refractive regression after excimer laser photorefractive keratectomy (PRK) for high myopic defects (>5 diopters). METHODS: Prospective, consecutive, observational study. A total of 124 eyes of 62 patients were divided into two groups of 31 patients, 62 eyes each (Groups A and B). Only Group A was treated with MMC 0.02%. The data of the two groups of eyes, related to the best-corrected visual acuity (BCVA), to the difference of refraction pre- and post-treatment, and to the corneal haze, were analyzed through combined permutation tests by using the NPC Test software . RESULTS: BCVA of Group A, 1 year after treatment, was better than that of the control Group B (one-sided p value = 0.013): Group A - 3 eyes (4.8%) had a loss of a decimal fraction and no eyes > 1; Group B - 13 eyes (20.9%) had a loss of a decimal fraction and 1 eye (1.6%) of 2. There was a smaller difference between attempted and achieved SE correction in Group A with respect to Group B (one-sided p value = 0.068): Group A - 43 eyes (69.3%) within +/- 0.50 D; Group B - 31 eyes (50%) within +/- 0.50 D. there was a smaller incidence of corneal haze in the group for which MMC was used (one-sided p value = 0.005). CONCLUSIONS: In this study, the application of MMC 0.02% solution immediately after PRK produced lower haze rates and had better predictability and improved efficacy 1 year after treatment.

Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179).

Vasodilator actions of insulin are mediated by activation of endothelial nitric-oxide synthase (eNOS) and subsequent production of NO. Phosphatidylinositol 3-kinase and Akt play important roles in insulin-signaling pathways leading to production of NO in vascular endothelium. Here we dissected mechanisms whereby insulin activates eNOS by using the fluorescent dye DAF-2 to directly measure NO production in single cells. Insulin caused a rapid increase in intracellular NO in NIH-3T3(IR) cells transiently transfected with eNOS. The stimulation of NO production by lysophosphatidic acid (LPA) was abrogated by pretreatment of cells with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Remarkably, in the same cells, insulin-stimulated production of NO was unaffected. However, cells expressing the eNOS-S1179A mutant (disrupted Akt phosphorylation site) did not produce detectable NO in response to insulin, whereas the response to LPA was similar to that observed in cells expressing wild-type eNOS. Moreover, production of NO in response to insulin was blocked by coexpression of an inhibitory mutant of Akt, whereas the response to LPA was unaffected. Phosphorylation of eNOS at Ser(1179) was observed only in response to treatment with insulin, but not with LPA. Interestingly, platelet-derived growth factor treatment of cells activated Akt but not eNOS. Results from human vascular endothelial cells were qualitatively similar to those obtained in transfected NIH-3T3(IR) cells, although the magnitude of the responses was smaller. We conclude that insulin regulates eNOS activity using a Ca(2+)-independent mechanism requiring phosphorylation of eNOS by Akt. Importantly, phosphorylation-dependent mechanisms that enhance eNOS activity can operate independently from Ca(2+)-dependent mechanisms.

Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial.

OBJECTIVES: The aims of this long-term, prospective randomized study were to evaluate the clinical usefulness of alpha-interferon in treating chronic HBV infection and to establish whether clearance of viral replication markers and normalization of liver function tests induced by alpha-interferon were sustained. METHODS: Sixty-four patients with chronic wild type (HBeAg-positive) hepatitis B, enrolled between 1983 and 1987, were randomized into two groups. Thirty-three patients received alpha-interferon (5 MU/m2 three times weekly for 6 months; treated group), and 31 were not treated (controls). Treated and control patients were prospectively followed for a mean of 86.4 +/- 6.96 and 79.7 +/- 6.8 (p = NS) months, respectively. RESULTS: Clearance of the following viral markers was found in treated and control patients as follows: HBV-DNA, 26 (78.9%) and 18 (58.1%) (p = 0.106); HBeAg, 30 (90.9%) and 19 (61.2%) (p < 0.007); and HBsAg, 12 (36.4%) and three (9.8%) (p < 0.017). Persistent abnormal ALT levels were found in 11 (33.3%) treated and in 22 (70.9%) control patients (p < 0.025). Four control and three treated patients developed portal hypertension whereas two control and one treated patient developed hepatocellular carcinoma. Seven patients (five treated and two controls) were retrospectively found to have hepatitis C virus (HCV) coinfection before enrollment. To date, all coinfected patients remain positive for HCV-RNA. Also, all HCV coinfected patients, except one in the treated group, had persistent increased serum ALT levels. One of the coinfected patients developed portal hypertension. CONCLUSIONS: Chronic HBV hepatitis patients responding to interferon treatment had a faster, more complete, and sustained clearance of viral markers than controls; HCV coinfection does not seem to negatively affect the clearance of HBV replicative markers. However when coinfection occurs, hepatic disease persists despite HBV marker clearance.

Specific antibodies reactive with the 22-kilodalton major outer surface protein of Borrelia anserina Ni-NL protect chicks from infection.

An outer surface lipoprotein of 22 kDa was identified in the avian pathogen Borrelia anserina Ni-NL by using antibody preparations reactive with bacterial surface-exposed proteins. Amino acid sequence analysis of the 22-kDa protein demonstrated 90% identity with VmpA of B. turicatae, suggesting that the protein belongs to the family of 20-kDa outer surface proteins of the genus Borrelia. All of the 60 chicks intramuscularly treated with antibodies specifically reacting with the 22-kDa protein and infected with strain Ni-NL were completely protected from infection, since no spirochetemia was detected, and from death. Control chicks were treated with immune sera raised against apathogenic strain B. anserina Es, which expresses a prominent 20-kDa polypeptide that is also a member of the Vmp family but does not cross-react immunologically with the 22-kDa protein of the Ni-NL strain. These animals, infected with B. anserina Ni-NL, showed a high degree of spirochetemia 10 days after infection, and all died between 14 and 21 days after infection. The results showed that the 22-kDa surface protein of B. anserina Ni-NL is a determinant of the pathogenic potential of the strain and also confirmed that only strain-specific antibodies are protective against B. anserina infection.

Relevance of hydration state of the fat free mass in estimating fat mass by body impedance analysis.

Body impedance analysis (BIA) is widely used to assess body composition, however, accurate estimates of fat mass (FM) are sometimes rendered impossible due to over- or dehydration states. In fact, BIA is accurate in total body water (TBW) estimates, and TBW can be converted into fat free mass (FFM) assuming 73% hydration; but, if there is an alteration in the hydration state, such a fixed value does not fit with the real content of fluids in the FFM compartment, thus causing wrong estimates of FFM and in turn of FM. For this reason, phase-sensitive bioelectric analyzers operating at a single frequency or at multiple frequencies have recently been under investigation in order to produce an equation that is also able to estimate the volume of extracellular water (ECW). Some authors, rather than trying to find the best equation or the best instrument approach, have tested the direct use of resistance, reactance and phase angle values derived from 50 kHz impedance measurements, assuming that normal bioelectrical values are associated with normal hydration states. Using a large series of data we have found strong correlations between BIA-derived FM and BMI, and our data show that screening the subjects with normal hydration states using the direct bioelectrical parameters (BIAGRAM) improves the predictivity of standard equations, since it avoids trying to estimate FM in overhydrated subjects.

Cholinergic stimulation and nonadrenergic, noncholinergic relaxation of human colonic circular muscle in idiopathic chronic constipation.

The aim of our study was to further investigate the pathophysiological mechanism underlying idiopathic chronic constipation (ICC), a disorder of colonic motility. A possible alteration of excitatory and inhibitory neurotransmission and also the role of inhibitory neurotransmitters such as nitric oxide (NO), 5'-adenosine triphosphate (ATP), and vasoactive intestinal peptide (VIP) has been evaluated on preparations of distal colon from patients with or without ICC. The isometric tension was recorded from isolated circular muscle strips of both experimental groups during pharmacological and electrical field stimulation (EFS). The contractile response obtained by acetylcholine (ACh 20 microM), EFS (20 Hz, 20 V, 1 msec, pulse trains lasting 1 min) and substance P (SP 1 microM) was significantly lower in ICC than in control preparations. The effect of inhibitory nonadrenergic, noncholinergic innervation was evaluated using EFS at low frequencies (0.5-8 Hz), after cholinergic and sympathetic blockade with atropine (3 microM) and guanethidine (3 microM). The maximum relaxation value expressed as percentage of inhibition of SP-induced contraction was significantly higher in ICC than in control preparations (87+/-2.4 and 67+/-6.3, respectively; P<0.05). Experiments with substances that antagonize or reduce the effect of putative inhibitory mediators (VIP 6-28, apamin and N(G)-nitro-L-arginine) suggest that an alteration in NO and ATP release is present in ICC preparations. In particular at a higher inhibitory frequency NO-mediated relaxation is enhanced in ICC vs control, supporting the hypothesis that excessive NO production may be involved in pathophysiological mechanism of constipation.

Beta-adrenoceptor responsiveness of splenic macrophages in normotensive and hypertensive rats.

The aim of the present study was to investigate putative mechanisms implicated in the impaired phagocytic response of spontaneously hypertensive rats (SHR)1. The effect of in vitro treatment with isoproterenol (ISO), a beta-adrenergic drug, on phagocytosis and respiratory burst by splenic macrophages (SpMø) from normotensive Wistar-Kyoto rats (WKY) and SHR with established hypertension, respectively, was evaluated. Furthermore, the relaxant effect of ISO was determined in phenilephrine-precontracted thoracic aorta strips from SHR compared with age-matched WKY rats. Results indicate that exposure of rat SpMø to ISO generate a significant and dose-dependent reduction of phagocytosis and oxidative burst which was antagonized, almost completely, by the beta-adrenergic antagonist propranolol (PRO). Unlike normotensive, in hypertensive rats treatment with ISO fail to modulate phagocytosis and respiratory burst activity by SpMø. At vascular level, aortic relaxation by ISO was reduced in SHR when compared to WKY rats. These findings suggest that SHR exhibit changes not only in vascular, but also in macrophage beta-adrenoceptor-mediated responses. It is postulable that sympathetic overactivity could be responsible for impaired phagocytic functions and beta-receptor alterations observed in SHR.

Characterization of a soluble LHRH-degrading activity in the rat ventral prostate.

Recent evidence supports the hypothesis of a direct action of LHRH at the level of the prostate. Since peptidases able to degrade the hormone are present in several LHRH target structures, it was deemed of interest to investigate whether the prostate of adult normal male rats might possess LHRH degrading activities (LHRH-DA). Through the use of RP-HPLC, it has been observed that LHRH-DA is present in the soluble fraction of the rat ventral prostate homogenate, and is able to hydrolyze synthetic LHRH and to generate fragments 1-3 and 1-5 of the decapeptide. The degradation of [pGlu-3H]LHRH is inhibited by LHRH itself, and affected by several LHRH agonists and antagonists with different kinetics and potencies. TRH, the enkephalin analog [D-Ala2-D-Leu5]enkephalin and rat prolactin do not inhibit the degradation of [pGlu-3H]LHRH by the soluble fraction of prostate homogenate; on the contrary, this is inhibited by graded doses of somatostatin. The prostatic LHRH-DA is also inhibited, in a dose dependent manner, by bacitracin, serine protease inhibitors (diisopropylfluorophosphate and phenylmethansulfonylfluoride), the metal chelating agent EDTA, HgCl2, and dithiothreitol. No inhibitory effect on [pGlu-3H]LHRH hydrolysis was observed after incubation of the prostatic extract in the presence of captopril. The prostatic LHRH-DA seems to be different from that present in other tissues of the rat (e.g., hypothalamus, pituitary, gonads), and to be decreased by castration performed 3 weeks before. These results suggest that (1) an LHRH-DA is found in the soluble fraction of rat prostate homogenate; (2) this enzymatic activity exhibits the characteristics of a metallo- and thiol-dependent neutral endopeptidase; (3) it appears to be different from similar hydrolytic activities found in other tissues; and (4) it is influenced by the hormonal milieu, since castration causes a significant decrease of its activity.

[Physiopathology and therapy of localized osteopenia]. / Fisiopatologia e terapia delle osteopenie distrettuali.

Osteopenia is a condition of reduced bone mineral content including osteoporosis, characterised by a reduced bone mass but normal mineral composition of bone tissue, and osteomalacia, characterised by unchanged bone mass but a deficient level of calcification of the protein matrix. Both conditions possess multifactorial etiopathogeneses and may affect the skeleton as a generalised or local manner, thus creating syndromes of circumscribed osteomalacia (osteomalacia of the patella, of the jaw). In some cases of local osteopenia, genetic, ethnic, dietary (inadequate intake of calcium, vitamin D), behavioural (abuse of smoking, coffee or alcohol), mechanical (reduced muscular exercise) and jatrogenic factors can play an important pathogenetic role. The definition of the exact nature of osteopenia (osteoporosis or osteomalacia), now possible using instrumental and laboratory tests, and the identification of the pathogenetic factors involved enable a correct therapy to be commenced.

Comparison between CEA, TPA, CA 15/3 and hydroxyproline, alkaline phosphatase, whole body retention of 99mTc MDP in the follow-up of bone metastases in breast cancer.

The development of bone metastases in cancer can be monitored easily using three markers: 24 h urinary hydroxyproline excretion (HOP) (an index of osteoclastic activity), serum alkaline phosphatase (Alk.Ph.) (an index of osteoblastic activity) and 24 h whole body retention of 99mTc-methylene diphosphonate (WBR%) (an index of bone turnover). To evaluate the effectiveness of this group of bone tumor markers in breast cancer we compared it with the following group of three markers which are commonly used in the monitoring of breast cancer and in the follow-up of advanced disease with or without bone metastases: carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and breast carcinoma antigen (CA 15/3). In 48 patients with bone metastases CEA, TPA and CA 15/3 were shown to be sensitive (79%, 85%, 90% respectively), while HOP, Alk.Ph. and WBR%, which are commonly accepted as reliable markers of bone activity, showed a lower sensitivity (67%, 46%, 75% respectively). These results may be explained by the lack of osteoclastic or osteoblastic (or both) activity at the time of diagnosis. This explanation is supported by the fact that the bone markers HOP, Alk.Ph. and WBR% were found to be more sensitive than the others in the subsequent follow-up study. We conclude that in our study, CEA, TPA and CA 15/3 are at first more sensitive than Alk.Ph., HOP and WBR% but during the follow-up Alk.Ph., HOP and WBR% are possibly both more specific and more sensitive.

[Calcitonin, parathyroid hormones, calcium ion, cyclic 3,5-adenosine monophosphate (cAMP) and erythrocyte deformability]. / Calcitonina, ormone paratiroideo, ione calcio, 3,5-adenosinmonofosfato ciclico (AMPc) e deformabilità eritrocitaria.

Calcium ion is one of the factors which modulate erythrocyte deformability. It is known that calciotropic hormones such as calcitonin (CT) and parathyroid hormone (PTH) exert hypocalcemizing and hypercalcemizing effects, respectively. Their action is mediated, at the level of their target cells, through adenylcyclase activation with the production of cyclic 3,5-adenosinmonophosphate (cAMP). Modifications of transmembrane calcium fluxes have been described and were attributed to these hormones. Erythrocyte deformability has been evaluated by Dormandy method of red blood cell filtration in hypocalcemic patients affected by hypoparathyroidism, in patients with hypercalcemia due to malignancy or primary hyperparathyroidism and in normal age- and sex-matched subjects. Erythrocyte filtration values resulted to be significantly increased with respect to normal values in hypercalcemic patients and at the lower limits of normality in hypocalcemic subjects. Subsequently, acute studies were performed in normal volunteers in whom venous infusions of synthetic salmon calcitonin determined a significant reduction of erythrocyte filtration values, whereas venous infusions of the 1-34 synthetic human PTH fragment induced a significant increase in filtration values of red blood cells. An infusion of a cAMP analogue, dibutyryl-cAMP, determined a slight reduction of erythrocyte filtration values. The calciotropic hormones influence erythrocyte deformability through mechanisms that are yet to be clarified.