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Background Infusion of high-dose intravenous methotrexate (MTX) has been demonstrating to penetrate the blood-brain barrier. The aim of this present study was to assess the efficacy and safety of high dose MTX in patients with central nervous system (CNS) metastases of breast cancer. Methods Twenty-two patients with CNS metastases treated by MTX (3 g/m2) between April 2004 and October 2009 were enrolled. Clinical response rate, time to progression (TTP), overall survival (OS), and safety were assessed. Results In terms of brain metastases, 2 patients (9%) achieved a partial response, 10 patients (45%) had disease stabilization, and 10 patients (45%) had disease progression. In others metastatic sites, 7 patients (39%) achieved a disease stabilization, and 11 patients (61%) had disease progression. TTP and OS were 2.1 (95%CI 1.4–2.9) and 6.3 (95%CI 1.8–10) months, respectively. Conclusion High-dose MTX demonstrated a moderate activity at 3 g/m2. Nonetheless, the favorable toxicity profile should suggest the possibility to increase the dosage and further study are planned.

Background In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC. Patients and methods Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Results Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Conclusion Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. ClinicalTrials.gov NCT03125902.

Identification of pathologic parathyroid glands in primary hyperparathyroidism, traditionally based on neck ultrasound (US) and/or 99mTc-Sestamibi scintigraphy, can be challenging. PET/CT with 18F-Fluorocholine (18F-FCH) might improve the detection of pathologic parathyroid glands. We aimed at comparing the diagnostic performance of 18F-FCH-PET/CT with that of dual-phase dual-isotope parathyroid scintigraphy and neck US. Thirty-four consecutive patients with primary hyperparathyroidism were prospectively enrolled, 7 had normocalcemic hyperparathyroidism, and 27 had classic hypercalcemic hyperparathyroidism. All patients underwent high-resolution neck US, dual-phase dual-isotope 99mTc-Pertechnetate/99mTc-Sestamibi scintigraphy, and 18F-FCH-PET/CT. In the whole patients’ group, the detection rates of the abnormal parathyroid gland were 68% for neck US, 71% for 18F-FCH-PET/CT, and only 15% for 99mTc-Sestamibi scintigraphy. The corresponding figures in normocalcemic and hypercalcemic hyperparathyroidism were 57 and 70% for neck US, 70 and 71% for 18F-FCH-PET/CT, and 0 and 18% for 99mTc-Sestamibi scintigraphy, respectively. In the 17 patients in whom the abnormal parathyroid gland was identified, either at surgery or at fine needle aspiration cytology/biochemistry, the correct detection rate was 82% for neck US, 89% for 18F-FCH-PET/CT, and only 17% for 99mTc-Sestamibi scintigraphy. 18F-FCH-PET/CT can be considered a first-line imaging technique for the identification of pathologic parathyroid glands in patients with normocalcemic and hypercalcemic hyperparathyroidism, even when the parathyroid volume is small.

Identification of pathologic parathyroid glands in primary hyperparathyroidism, traditionally based on neck ultrasound (US) and/orThirty-four consecutive patients with primary hyperparathyroidism were prospectively enrolled, 7 had normocalcemic hyperparathyroidism, and 27 had classic hypercalcemic hyperparathyroidism. All patients underwent high-resolution neck US, dual-phase dual-isotopeIn the whole patients' group, the detection rates of the abnormal parathyroid gland were 68% for neck US, 71% for

Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with

Hematopoietic cell transplantation (HCT) is a curative treatment for hematological malignancies. This therapeutic approach is associated with a profound immune deficiency and an increased rate of opportunistic infections. Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell-mediated immunity, such as AIDS patients or transplant recipients. Diagnosis of nocardiosis can be challenging, as signs and symptoms are non-specific. Routine prophylaxis with trimethoprin/sulfamethoxazole (TMP/SMZ) does not prevent the risk of infection. Between May 2001 and December 2009, five cases of nocardiosis were diagnosed from the 366 allogeneic HCT recipients in our centre. Four patients developed a disseminated nocardiosis within the first year after HCT. The fifth patient presented a localized cutaneous nocardiosis. In disseminated cases, median total CD4+ T-cells were below 100 cells/μL. Naive CD4+ CD45RA+/RO− T-cells were almost undetectable. CD8+ T-cells and NK cells were below the normal range and CD19+ B-cell reconstitution was completely deficient. In a localized case, we observed a lack of naive thymic emigrants CD4+ CD45RA+/RO− T-cells.

Although useful prognostic and predictive insights can be gained from patient and tumour characteristics in early-stage breast cancer, it is not always straightforward to predict the likely risk of recurrence for each individual patient following breast surgery. One of the most difficult challenges faced by clinicians is identifying patients who may benefit most from adjuvant chemotherapy, and distinguishing these cases from those where endocrine therapy may be sufficient for cure. Genomic tests such as the Oncotype DX

Here we report an unusual case of primary systemic amyloidosis. The cutaneous lesions were polymorphic and included involvement of both external auditory canals. The visceral involvement was covert. Mapping of amyloid deposits was performed using scintigraphy with technetium-99m (V) dimercaptosuccinic acid ([99mTc (V)] DMSA). Therapy with melphalan, prednisone and colchicine resulted in considerable improvement.

The somatostatin receptor scintigraphy (SRS), using octreotide radiolabelled with 111In (octreoscan, OCTs), is a consolidated diagnostic procedure in patients with neuroendocrine tumors. A higher accuracy has been demonstrated with single photon emission computed tomography-CT, while a further improvement has been obtained with positron emission tomography (PET)-CT, using somatostatin analogues radiolabeled with 68Ga, significantly increasing the number of detected lesions. Although the well-known presence of an OCTs uptake in many benign diseases, when in an active phase, the application of SRS in these patients did not find any clinical relevance yet. In this paper we discuss two fields of endocrinological interest where SRS could play a clinical role. In patients with Graves exophtalmos, the capability to differentiate between active and non-active disease can be helpful in define prognosis and therapeutic strategies. In patients with endocrine paraneoplastic syndromes (PNS), SRS can help in finding the underlying neoplasm, contributing to its characterization as premise to a therapeutic choice. The possible role of a surgery guided by OCTs is also explained and suggested. The incremental value of PET-CT with Ga-68 peptides is hypothesized to reduce the number of unknown neoplastic lesions frequently present in patients with PNS.

The use of somatostatin (SS) analogues in humans takes advantage by the availability of many related chemical forms that can be used for receptor therapy and, after radiolabelling, for diagnostic imaging and radionuclide therapy. The first proposed radiocompound, yet clinically widely diffuse, has been (111)In-octreotide (OCT), followed by positron emission tomography (PET) and beta emitter tracers. The main field of clinical applications is in neuroendocrine tumours (NET), starting by the demonstration of SS receptors (SSR) on the majority of NET, particularly on gastroenteropancreatic (GEP) tumours. Uptake of SS analogues can also be due to a SSR expression on non malignant cells when activated, as lymphocytes, macrophages, fibroblasts , vascular cells. Because of this uptake clinical indications can be found also in active benign diseases, as Grave's ophthalmopathy, rheumatoid arthritis, histiocitosis, sarcoidosis, idiopatic pulmonary fibrosis. Moreover, these cells can also determine the OCT in vivo uptake in tumours non expressing in vitro SSR, as non-snall cell lung cancer (NSCLC). Because of a different kinetic respect to SCLC a differential histotype diagnosis could be obtained. Starting from this premise OCT can also allows radioguided surgery in tumours non expressing SSR. Finally a relevant clinical role can be defined in the a priori recruitment and as marker of therapeutic efficacy in all the therapeutic strategies utilizing SSR, both in malignant and benign diseases.

Lonidamine is a substituted indazole carboxylic acid with a unique mechanism of action and early clinical studies have reported anti-tumour activity. In a phase II study 32 patients with previously treated advanced breast cancer were given Lonidamine in a daily divided oral dose of 600 mg. Of 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months) and three (11%) a minor response. Two patients have stable disease (greater than 3 months) and 20 progressed. Toxicity was very mild. Sixteen (53%) of 31 patients had myalgia which lasted a median of 2 weeks. This was investigated with nuclear magnetic resonance spectroscopy in four patients but the changes were unrelated to the degree of myalgia. No other major side-effect was seen, and no dose reduction was required. Lonidamine pharmacokinetics have been investigated in 17 patients 1 month after the start of therapy. Lonidamine was detected in the plasma of all patients, but there was no clear relationship between Lonidamine levels and clinical response or toxicity. Lonidamine appears to be active against advanced breast cancer and its low toxicity would allow combination studies with chemotherapy.

Uterine leiomyosarcomas are rare tumours and the results of treatment of advanced disease are poor. Ifosfamide and Adriamycin are both known to be active drugs in soft-tissue sarcomas. We present our experience using ifosfamide alone and in combination with Adriamycin in advanced or recurrent uterine leiomyosarcomas. Ifosfamide alone was given as a 24-h infusion at doses ranging from 5 to 7.5 g/m2, with mesna rescue. In the combination regimen, ifosfamide was given at a dose of 5 g/m2 and Adriamycin, at a dose of 40 or 60 mg/m2. Ten patients were treated with ifosfamide alone, with only one partial response lasting 6 months. In all, 11 patients were treated with ifosfamide and Adriamycin, which resulted in 1 complete response that lasted 11 months. Although many of the patients had extensive disease and some had undergone prior treatment with other chemotherapy, ifosfamide would appear to have only modest activity at the dose and schedule used.

Local synthesis of 1alpha,25(OH)D3 in breast tissue may contribute to maintenance of normal cell function and could be impaired with low circulating levels of the precursor 25hydroxyvitamin D. The aims of this study were to: i) assess the association between breast cancer risk and plasma 25OHD3 concentration and ii) define the significance of expression of the 25OHD activating enzyme CYP27b1 in non-malignant and malignant models of breast epithelial cells.Breast cancer patients and control women were recruited and their 25OHD levels measured by enzyme-linked immunosorbent assay (ELISA). MRNA expression of CYP271b and the 1,25(OH)2D3 inactivating enzyme CYP24 were measured in breast cancer cell lines by RT-PCR and correlated with immunoblotting approaches to the translated proteins.For women with 25OHD50 nM the odds ratio for breast cancer compared with women with 25OHD50 nM was 3.54 (CI 1.89-6.61, p0.001). CYP271b and CYP24 were detected in non-malignant and malignant cell models. Protein levels of 24OHase but not 1alphaOHase were decreased at confluence in the cell lines.Impaired local generation of 1,25OHD3 may contribute to the development of breast cancer.

The role of a procedure depends not only on its own capabilities but also on a cost/effective comparison with alternative techniques giving similar information. Starting from the definition of emergency as a sudden unexpected occurrence demanding immediate action, the role of nuclear medicine (NM) is difficult to identify if it is not possible to respond 24 h a day, 365 days a year, to clinical demands. To justify a 24 h NM service it is necessary to reaffirm the role in diagnosis of pulmonary embolism in the spiral CT era, to spread knowledge of the capabilities of nuclear cardiology in reliably diagnosing myocardial infarction (better defining admission and discharge to/from the emergency department), to increase the number of indications. Radionuclide techniques could be used as first line, alternative, complementary procedures in a diagnostic tree taking into account not only the diagnosis but also the connections with prognosis and therapy in evaluating cerebral pathologies, acute inflammation/infection, transplants, bleeding, trauma, skeletal, hepatobiliary, renal and endocrine emergencies, acute scrotal pain.

The steroid hormone 1,25 dihydroxyvitamin D3 is thought to protect against breast cancer. Its actions are mediated via the vitamin D receptor (VDR) and a number of polymorphisms in the VDR gene have been identified, some of which may alter susceptibility to breast cancer. This study has investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a UK Caucasian population. Female breast cancer patients (n = 313) and control women with a negative screening mammogram (n = 410) were recruited and their VDR polymorphisms were determined. The 3' VDR polymorphism BsmI was significantly associated with breast cancer risk; odds ratio bb vs. BB genotype = 1.79 (95% CI, 1.12-2.86; P = 0.0221). In addition, over 70% of seven commonly used breast cancer cell lines were found to have the at-risk genotype bb. The 5' FokI gene variant was not associated with breast cancer risk. Further investigations into how these different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.

Molti studi hanno dimostrato la affidabilità della tecnica del linfonodo sentinella (SN) nella valutazione del parametro N nel cancro mammario tanto da indurre a limitare la dissezione ascellare alla biopsia del solo SN (SNB) in caso questo sia negativo. Dopo un periodo di messa a punto della tecnica di identificazione, biopsia ed esame istologico del SN (ottobre 97- gennaio 98) sempre seguita dalla dissezione completa dei tre livelli dell’ascella (ALND), abbiamo intrapreso uno studio per valutare la affidabilità di una dissezione limitata al solo I livello dell’ascella (FLND) in donne con T

Bone metastases are a common problem in the management of breast cancer and are associated with considerable morbidity. Bone pain, hypercalcaemia, fractures and cord compression all occur requiring interventions such as analgesia, radiotherapy and surgery. Bisphosphonates are drugs that are active in the bone microenvironment. Their effects on osteoclasts are well described: they potently inhibit osteoclast mediated bone resorption by delaying the maturation of immature osteoclasts and by directly inducing osteoclast apoptosis. It has been known for some time that bisphosphonates, in combination with intravenous rehydration, effectively treat hypercalcaemia associated with solid malignancies. It has now been demonstrated In clinical trials in breast cancer patients that regular bisphosphonate administration reduces the morbidity associated with osteolytic skeletal metastases. There is an emerging suggestion from clinical trial work that bisphosphonates may be able to reduce or delay the development of skeletal metastases although this remains controversial as the three published trials present conflicting results. The more potent third-generation bisphosphonates, such as zoledronate, are now being tested for each of these indications with promising results and may replace other bisphosphonates in the future. Laboratory studies have recently demonstrated that bisphosphonates have direct cytotoxic effects against breast cancer cells in vitro, inducing apoptosis and preventing adhesion to bone. This adds support to the hypothesis that bisphosphonates may have a genuine beneficial effect in the adjuvant setting.

The presence of at least three different types of somatostatin receptors in the thymus has been demonstrated using molecular biology techniques or radioimmunological methods. In view of the chemotactical activity shown by somatostatin in other lymphopoietic regions like bone marrow, it was hypothesised that this neuropeptide might play a role in regulating cell migration in the thymus. The selective expression of somatostatin receptors on specific immunocompetent cells, both circulating and in lymphatic organs, allows the neuropeptide to have a modulating action also on the immune system. Functional studies have also shown that somatostatin can influence cell proliferation, cytokine and immunoglobulin production, natural killer cytotoxic activity, the maturation and migration of immune cells in both blood and lymphopoietic tissues. More recent evidence has enabled us to evaluate the altered expression of somatostatin receptors on lymphomonocytes during systemic disease.

The diagnostic use of radiolabeled octreotide has shown that somatostatin receptor scintigraphy can be successfully used in various neoplasms with a strictly neuroendocrine derivation, because of a good correlation between in vitro receptor expression and in vivo uptake. Moreover, 111In-Octreotide uptake has been demonstrated in various pathologies owing to the receptorial expression on cell elements such as lymphocytes, fibroblasts and endothelium. Although main diagnostic role is in neuroendocrine tumours, octreotide can be also used to obtain an immunological imaging in other fields. The presence of type 2 receptors on activated lymphocytes has stimulated the use of somatostatin in both the treatment and diagnosis of disease activity in patients with Graves' ophthalmopathy. Somatostatin analogs have been successfully used for the treatment and imaging of various tumours of thymic origin. Our research group has evaluated the possible clinical role of octreotide scintigraphy in paediatric patients with thymic hyperplasia after chemotherapy for lymphoma. Even if not routinely applicable, these approaches offer interesting diagnostic, prognostic and therapeutic prospects.

Current therapeutic approaches in neuroendocrine tumours include surgery, radiotherapy and polychemotherapy. Different metabolic patterns of neuroendocrine tumours allow the use of a wide range of diagnostic options in nuclear medicine, due to the presence of a wide spectrum of radiotracers electively concentrating in these neoplasms. Nuclear medicine, and in particular 111In Octreotide (OCT) scintigraphy, 123I Methaiodobenzylguanidine (MIBG) and pentavalent 99mTc-DMSA (V-DMSA), together with biohumoral markers, are currently able to locate tumours also not detectable using traditional diagnostic techniques. Somatostatin analogs, such as octreotide have become increasingly important over the years in the treatment of patients with neuroendocrine tumours. At present the therapeutic use of somatostatin analogs can be schematised as 1) pharmacological treatment (with cold octreotide); 2) surgical treatment (radioguided surgery); 3) radiometabolic treatment (with marked octreotide). The development of new synthetic molecules and new radiocompounds will probably open up interesting scenarios in the near future.

Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of pro-caspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acid-mediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras. British Journal of Cancer (2002) 86, 1479–1486. DOI: 10.1038/sj/bjc/6600297 www.bjcancer.com © 2002 Cancer Research UK

The study evaluates the role of radio-guided surgery (RGS) with 111In-octreotide in the treatment of lung neoplasms. RGS with octreotide appears to be useful in surgery, above all during the intraoperative staging of the tumour; it can define with greater precision the extent of the resections extended towards the lung wall and ensure a radical approach in minimal lung resections.

OBJECTIVESThe aim of this study was to evaluate: 1) the effects of insulin administration on left ventricular ejection fraction (LVEF) during exercise, and 2) the eventual impairment of the cardiovascular response to insulin in noninsulin dependent diabetes mellitus.BACKGROUNDInsulin influences the cardiovascular system, but its effect on left ventricular function has yet to be established.METHODSThe effects of normal saline (test A) and insulin-glucose (insulin = 1.7 mU·kg−1·min−1; glucose = 6 mg·kg−1·min−1) (test B) infusions on systolic and diastolic functions at rest and during dynamic exercise were examined by radionuclide ventriculography. Twenty-two noninsulin-dependent diabetic patients and 22 gender, age and body mass index matched healthy subjects were investigated.RESULTSBoth groups had normal scintigraphic parameters at rest and during dynamic exercise. Rest- and stress-LVEF as well as rest- and stress-peak filling rate were significantly (p < 0.001) lower in diabetic than in healthy subjects, both in test A and B. Rest-LVEF was significantly higher during test B than it was in test A only in diabetic subjects (p < 0.01). Stress-LVEF was significantly higher (p < 0.05) during test B than it was in test A, in both groups. Insulin-glucose infusion did not modify rest- and stress-peak filling rate in either group. No difference in left ventricular end diastolic volume and in mean blood pressure was found between test A and B at rest and during exercise in either group. A significant linear correlation between LVEF and the index of insulin sensitivity was found in diabetic patients.CONCLUSIONSIn both normal and diabetic humans, insulin induces a very important rise in LVEF after submaximal work. However, the rise is significantly lower in diabetic than in nondiabetic subjects. The increase in exercise-LVEF on insulin is likely due to an enhancement of ventricular contractility. Insulin resistance could justify the lower angioscintigraphic indexes in diabetic subjects.

Radioimmunoguided surgery (RIGS) can be a valid option in the management of lung cancer as well as neoplasms in other anatomic sites.We evaluated the usefulness of radioimmunoguided surgery (RIGS) in the staging of primitive non small cell lung cancer. Intraoperatively, this technique can define the lymph nodes involvement and thus, the radicality of the resection. In the first stage of our study, we looked for the epitope TAG 72 in 45 patients with primary non small cell lung cancer. The epitope was found by immunochemistry in only 6 cases. The only one operable patient was injected with monoclonal antibody B 72.3, that was 125I-labelled.At the operation, the monoclonal antibody showed no selectivity for neoplastic cells. Neoplastic tissue and healthy tissue showed a similar detection of the monoclonal antibody both intraoperatively and at the histochemical study. Because of the problems related with this method--e.g. technical difficulties, excessive wasting of time and lack of imaging--we modified our strategy. In this second stage of our study we used fragments of murine anti-CEA monoclonal antibody F023C5. The protocol was performed in 11 patients with squamous cell lung cancer. In one patient operated on for an excavated cancer(not well-defined at the immunoscintigraphy) intraoperative detection was negative while the ex vivo counts were significant: the neoplastic tissue showed a radioactivity twice higher than healthy tissue. Furthermore, the RIGS found a small intraparenchimal lymph node that was seen neither by CT nor by immunoscintigraphy.Our data are still preliminary, but with improvement of the technique and the use of more specific monoclonal antibodies the RIGS could become a helpful method, able to improve the radicality of surgery for lung cancer.