Marco Salvatore

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability.

BACKGROUNDnFatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated.nnnOBJECTIVEnTo study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability.nnnMETHODSnWe studied 222 relapsing remitting MS patients with low disability (scores <or=2 at the Kurtzke Expanded Disability Status Scale). Lesion load, WM and GM were measured by fully automated, operator-independent, multi-parametric segmentation method. T1 and T2 lesion volume were also measured by a semi-automated method. Fatigue was assessed by the Fatigue Severity Scale (FSS), and patients divided in high-fatigue (FSS>or=5; n=197) and low-fatigue groups (FSS<or=4; n=25).nnnRESULTSnHigh-fatigue patients showed significantly higher abnormal white matter fraction (AWM-f), T1 and T2 lesion loads, and significant lower WM-f, and GM-f. Multivariate analysis showed that high FSS was significantly associated with lower WM-f, and GM-f. Females and highly educated patients were significantly less fatigued.nnnCONCLUSIONnThese results suggest that among MS patients with low disability those with high-fatigue show higher WM and GM atrophy and higher lesion load, and that female sex and higher levels of education may play a protective role towards fatigue. Furthermore, they suggest that in MS, independent of disability, WM and GM atrophy is a risk factor to have fatigue.

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40–85xa0years, and with disease duration ≤3xa0years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH)xa0+xa0arginine test. The initial dose of GH was 2xa0IUxa0s.c. every other day, and was progressively increased to a maximum of 8xa0IU. Primary endpoint was N-acetylaspartate/(creatinexa0+xa0choline) (NAA/Crexa0+xa0Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at monthsxa00, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Crexa0+xa0Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRHxa0+xa0arginine stimulation test (10.4xa0±xa07.0 versus 15.5xa0±xa08.1xa0ng/mL; pxa0<xa00.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1xa0±xa01.0 at baseline to 4.6xa0±xa01.9 at 12xa0months (pxa0<xa00.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435xa0±xa04,477xa0ng/mL at baseline to 3,250xa0±xa01,780xa0ng/mL at 12xa0months (pxa0<xa00.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.

Dynamic imaging: scintimammography

Although mammography remains the technique of choice for the early detection of breast cancer, new emerging breast imaging techniques such as ultrasound, magnetic resonance and radionuclide scanning have been investigated and included in many diagnostic protocols. This overview discusses the current problems related to radionuclide breast imaging trying to define its role in the management of women with suspicious breast lesions at mammography. A number of tumor-imaging agents have been recently used for the differential diagnosis of malignant and benign lesions in radiographically dense breasts and breasts with architectural distortions from prior biopsy or surgery or following radiation therapy. 99mTc-MIBI is the most used tracer which has become the paradigm of this new class of compounds suitable for breast imaging. The current sensitivity and specificity rates for breast scintigraphy with 99mTc-MIBI depend on a number of factors including lesion size and site. Sensitivity and specificity rates and positive and negative predictive values of 92, 89, 81 and 96%, respectively, have been reported in a large series of patients with palpable breast lesions, which figures have been confirmed in many other series. On the contrary, lower sensitivity has been reported for nonpalpable breast abnormalities or for lesions smaller than 1 cm. This observation, confirmed by many authors, implies that a new nonpalpable lesion that is suspicious for malignancy at mammography needs a histologic diagnosis. We also report the results of our recent studies on functional imaging with 99mTc-MIBI of the multidrug resistance phenotype in breast cancer patients. These studies followed an observation that this tracer is a suitable transport substrate for the P-glycoprotein (P-gp) which is commonly associated with the development of a multidrug resistance phenotype. We examined 30 patients with histologically confirmed breast carcinoma who had received no previous chemotherapy or preoperative local irradiation. We found a positive and significant correlation between the efflux rates of 99mTc-MIBI determined by in vivo kinetic analysis and the P-gp levels measured in vitro by quantitative autoradiography in the same tumors (r = 0.62; p < 0.001). More recently, we tested whether tumor clearance of 99mTc-MIBI can predict the response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Thirty-nine patients with stage III disease underwent 99mTc-MIBI scanning before neoadjuvant chemotherapy and the time to half-clearance of the tracer was calculated. The patients then received epirubicin and underwent mastectomy after completing chemotherapy. This study showed that a rapid tumor clearance of 99mTc-MIBI (< or = 204 min) can predict the lack of tumor response to neoadjuvant chemotherapy with drugs affected by multidrug resistance phenotype in advanced breast carcinoma patients. However, slower tracer clearance (> or = 204 min) did not guarantee an objective tumor response to chemotherapy in all patients, in agreement with the existence of several P-gp-independent mechanisms of drug resistance. We conclude that the preliminary study of this phenotype would allow to predict the response to (neo)adjuvant chemotherapy and select the appropriate treatment regimen for each patient. Finally, radionuclide breast scanning may be helpful in the differential diagnosis of malignant and benign breast lesions as a guide to subsequent chemotherapy.

Thyroid and Parathyroid Tumors

Thyroid cancer occurred in approximately 45,000 patients, in the USA in 2010. There is a 3:1 ratio of women to men. Histologic types are divided into categories of differentiated thyroid cancer (DTC): papillary, mixed papillary and follicular, and follicular—including Hurthle cell variant, undifferentiated (anaplastic), and medullary cancer (arising from parafollicular C-cells). Other rare thyroid carcinoma accounts non-epithelial tumors, lymphoma and carcinomas characterized by the presence of mucin-producing cells and keratin. Differentiated thyroid cancer usually presents as a thyroid nodule. Thyroid ultrasonography is useful to detect and characterize thyroid nodules, as well as guide fine needle aspiration (FNA) biopsy. Radioiodide or 99mTc-pertechnetate thyroid scan has a low diagnostic specificity and sensitivity for characterizing thyroid nodules. X-ray of the neck is useful to disclose a deviation of the trachea or lumen restriction, in large nodules and in multinodular goiter. CT or MRI are generally reserved for mediastinal thyroid masses, or the identification of regional or distant metastasis. The most widely used staging system for thyroid carcinoma is the TNM classification system defined jointly by the UICC and by AJCC. 131I-iodide thyroid remnant ablation is indicated in differentiated thyroid cancer patients with a moderate to high likelihood of recurrence. 131I-iodide therapy is usually administered in the amount of 1.85 to 3.7 GBq for ablation. Patients are prepared with rhTSH and low iodine diet. Whole body scan (preferably with SPECT/CT of the neck) is performed 4–7 days after radioiodine therapy to detect lymph node involvement or unexpected metastases. The major diagnostic modalities employed to follow patients with differentiated thyroid cancer treated with remnant ablation is measurement of serum Tg, 131I-WBS, and neck US examination. Neck US examination is an integral component of follow-up evaluation in all DTC patients. If a lymph node metastasis is suspected, an FNA should be performed. Serum Tg levels that become detectable upon TSH stimulation indicate the need for further evaluation, possibly with additional radioiodine therapy. Although CT and MRI can in principle localize very small lesions in the neck, chest, and bones, the features of such lesions are rarely specific for recurrent/metastatic DTC. Patients with recurrent thyroid cancer may develop lesions which cannot concentrate radioiodide. [18F]FDG PET/CT is useful in these patients to determine the sites and extent of these metastases. The anaplastic thyroid carcinoma (ATC) is a rare tumor (<3% of all thyroid cancers) with poor prognosis derived from follicular cells. The most clinical presentation of an ATC is a new, large, firm thyroid nodule, often associated with signs/symptoms of local compression/invasion. Multimodality treatment of ATC includes surgery, EBRT, and combination chemotherapy. Therapy with 131I-iodide is not useful, since these tumors rarely concentrate radioiodide. Preoperative imaging with US, CT, MRI play an important role, and [18F]FDG PET is useful. Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor arising from the parafollicular, calcitonin-producing C cells. Its prevalence is 5–10% in all thyroid malignancies. Sporadic and familial forms are recognized. Elevated baseline serum levels of calcitonin (above 10 ng/mL) are diagnostic for MTC. Following surgery, MTC patients are monitored with serum calcitonin and CEA levels, and serial neck US examinations are performed. Calcitonin doubling time in serum is the most sensitive biomarker for MTC progression. Scintigraphy with 123I-MIBG has very high sensitivity for staging patients with MEN II and familial MTC. However, it has a low sensitivity in patients with increased serum calcitonin but no clinical site of disease. [18F]FDG PET is accurate in detecting lymph node involvement. Radionuclide therapy with the radiolabeled somatostatin analog 90Y-DOTA-Tyr3-octreotide (90Y-DOTA-TOC) has been tested in metastatic MTC. Parathyroid carcinoma is a very rare endocrine malignancy that occurs in <1% of primary HPTH. The initial clinical manifestations of parathyroid carcinoma are primarily linked to the effects of markedly elevated serum PTH levels. At initial presentation, very few patients have metastasis at regional lymph nodes or at distant sites. Parathyroid carcinoma tends to infiltrate adjacent structures in the neck. US, CT, and MRI have been used to localize parathyroid carcinomas and to detect mediastinal and thoracic recurrences or distant metastases. 99mTc-Sestamibi scintigraphy can be successful for preoperative localization of the neoplasia and can identify metastases in lymph nodes and at distant sites. PET with [18F]FDG can also detect metastatic parathyroid cancers. Parathyroid carcinoma recurs in more than 50% of the cases and imaging studies should be performed in all patients before reoperation.

Dynamic coupling of 99mTc-MIBI efflux and apoptotic pathway activation in untreated breast cancer patients

Abstract. Our previous studies showed that the efflux rate of technetium-99m methoxyisobutylisonitrile (MIBI) is directly correlated to P-glycoprotein (Pgp) levels in breast carcinoma. The aim of this study was to test whether the Pgp-dependent efflux of 99mTc-MIBI is related to the apoptotic pathway activation in breast carcinoma. Thirty-three untreated non-consecutive patients were intravenously injected with 740xa0MBq 99mTc-MIBI and serial images were obtained up to 4xa0h. The rate of efflux was determined by mono-exponential fitting of decay-corrected time-activity curves. Tumour specimens were then obtained at surgery and processed for the determination of the apoptotic index by in situ end-labelling of DNA fragments (Tunel). The rate of tumour cell proliferation was also determined using Ki67 monoclonal antibody. All breast carcinomas showed focal uptake of 99mTc-MIBI and the time to half clearance varied between 85 and 574xa0min. The apoptotic index ranged between 0.3% and 4.2%, whereas the rate of proliferation varied between 13% and 40%. We found a positive and significant correlation between the apoptotic index and the rate of proliferation (r=0.79, P<0.0001). The efflux rate of 99mTc-MIBI was directly and significantly correlated with the apoptotic index (r=0.74, P<0.0001) and with the rate of proliferation (r=0.58, P<0.001). After partial correlation analysis, only the apoptotic index showed a significant correlation with the efflux rate of 99mTc-MIBI (r=0.57, P<0.001). Our findings indicate that enhanced transport activity of Pgp is associated with increased activation of the apoptotic pathway, suggesting that inhibition of Pgp function with specific modulators may be effective in these patients. Furthermore, since mitochondria are central executioners of apoptosis and intracellular sites of 99mTc-MIBI sequestration, a model for the dynamic coupling of Pgp-dependent 99mTc-MIBI efflux and apoptotic pathway activation may be derived.

PET/CT in cancer research: from preclinical to clinical applications.

The identification of genetic and biochemical mechanisms underlying tumor growth and progression along with the unraveling of human genoma provided a plethora of new targets for cancer detection, treatment and monitoring. Simultaneously, the extraordinary development of a number of imaging technologies, including hybrid systems, allowed the visualization of biochemical, molecular and physiological aberrations linked to underlying mutations in a given tumor. In vivo evaluation of complex biological processes such as proliferation, apoptosis, angiogenesis, metastasis, gene expression, receptor-ligand interactions, transport of substrates and metabolism of nutrients in human cancers is feasible using PET/CT and radiolabeled molecular probes. Some of these compounds are in preclinical phases of evaluation whereas others have been already applied in clinical settings. Here we provide prominent examples on how some biological processes and target expression can be visualized by PET/CT in animal tumor models and cancer patients for the noninvasive detection of well-known markers of tumor aggressiveness, invasiveness and resistance to treatment and for the evaluation of tumor response to therapy.

Anti-CEA and other antibodies in the study of gastrointestinal tumors

Localization of gastrointestinal tumors by means of labeled monoclonal antibodies is a new, sensitive and suitable technique currently used in several centers. Encouraging results have been documented with several monoclonal antibodies by different authors. This article reviews our experience with radioimmunoscintigraphy in 59 patients with colorectal cancer in follow-up, using 131I and 111In labeled B72.3, and in 16 patients with primary gastrointestinal tumors using 99mTc anti-CEA monoclonal antibody (type F023C5). The sensitivity of both B72.3 and anti-CEA was greater than 70% either for primary tumors and abdominal recurrences or distant metastases except hepatic ones. A significant gradient in antibody uptake was measured on surgical biopsies between tumors and normal tissues allowing a good in vivo contrast for gamma detection. We have defined the impact of some factors affecting in vivo tumor targeting. In fact, pharmacodynamics of MAbs, percentage of injected dose bound to tissues were measured, and in particular antigenic content in tumor nodules was quantified. Furthermore, the results of RIS were compared to those obtained by CT and other imaging modalities.

Xanthogranulomatous pyelonephritis mimicking a renal cell carcinoma: a unique and challenging case

We describe an unusual case of xanthogranulomatous pyelonephritis (XGPN) in a 73-year-old woman diagnosed after a blunt abdominal trauma. This case is unique because of the atypical presentation, with absence of symptoms, normal laboratory exams, and unusual computed tomography and magnetic resonance imaging findings. The patient underwent radical nephrectomy because a renal cystic tumor was suspected. Only the histopathological findings suggested the final diagnosis of XGPN.

Simultaneous non-functioning neuroendocrine carcinoma of the pancreas and extra-hepatic cholangiocarcinoma. A case of early diagnosis and favorable post-surgical outcome.

CONTEXTnThanks to the wide use of diagnostic imaging modalities, multiple primary malignancies are being diagnosed more frequently and different associations of malignancies have been reported in this setting.nnnCASE REPORTnIn this paper, we describe the case of a patient with non-functioning well-differentiated neuroendocrine carcinoma of the head of the pancreas associated with extra-hepatic cholangiocarcinoma, in which an early diagnosis using magnetic resonance imaging allowed a good outcome.nnnCONCLUSIONnThe simultaneous association of neuroendocrine pancreatic tumors and cholangiocarcinoma has not yet been described; however, this association should be considered and, due to the high contrast of magnetic resonance imaging, this technique is recommended in such patient in order to reach an accurate diagnosis.

Diagnostic Imaging of Patients with Pancreato-Biliary Diseases: Comparison between Ultrasound, Computed Tomography and Magnetic Resonance

Diagnostic Imaging of Patients with Pancreato-Biliary Diseases: Comparison between Ultrasound, Computed Tomography and Magnetic Resonance nThe aim of this study was to directly compare the results of MR cholangio-pancreatography (MRCP) with those of ultrasound (US) and multi-slice computed tomography (MSCT) in patients with pancreatico-biliary diseases. A total of 110 patients (62 M, 48 F), ranging in age from 22 to 89 years, was studied before surgery (n=99) or after cholecystectomy (n=11) for lithiasis. MRCP was performed in all patients while US was acquired in 55 patients and MSCT was performed in 76 patients. Histology (n=34), biopsy (n=38), endoscopic retrograde cholangio-pancreatography (ERCP) (n=28) and/or clinical-imaging follow-up (n=10) data were considered as standard of reference. Patient population was divided in three groups; Group 1 (n=55) consisted of a comparison between MRCP and US in biliary tract diseases; Group 2 (n=37) consisted of a comparison between MRCP and MSCT in biliary tract diseases; Group 3 (n=40) consisted of a comparison between MRCP and MSCT in pancreatic masses. A regional imaging qualitative evaluation of biliary and pancreatic duct system (gallbladder and cystic duct, intra- and extra-hepatic ducts, main pancreatic duct) was performed.