The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: Presentation of an inbred family and a novel truncating mutation in exon 3.

Pulmonary alveolar microlithiasis is a disorder in which many tiny fragments (microliths) of calcium phosphate gradually accumulate in alveoli. Loss of function mutations in the gene SLC34A2 coding for the sodium phosphate co-transporter (NaPi-IIb) are responsible for genetic forms of alveolar microlithiasis. We now report a consanguineous Italian family from Calabria with two affected members segregating alveolar microlithiasis in a recessive fashion. We describe, for the first time, a novel loss of function mutation in the gene coding for NaPi-IIb. A careful description of the clinical phenotype is provided together with technical details for direct sequencing of the gene.

Differential activation of signaling pathways by low-osmolar and iso-osmolar radiocontrast agents in human renal tubular cells.

Radiocontrast media (RCM)-induced nephrotoxicity (CIN) is a major clinical problem accounting for 12% of all hospital-acquired cases of acute kidney injury (AKI). The pathophysiology of AKI due to RCM is not well understood, but direct toxic effects on renal cells have been postulated as contributing to CIN. It is believed that iso-osmolar RCM (IOCM) are less nephrotoxic than low-osmolar RCM (LOCM) but clinical data have been controversial. We have investigated the intracellular signaling pathways that may be affected by the LOCM iomeprol (IOM) and the IOCM iodixanol (IOD). Both IOM and IOD caused a dramatic decrease in phosphorylation of the kinase Akt at Ser473 and Thr308 in human renal tubular (HK-2) cells, with IOM having a greater effect; IOM also caused a greater decrease in cell viability. IOM also had a greater effect on phosphorylation of p38 MAP kinases, JNKs, and NF-kB (Ser276), and caused a marked decrease in the phosphorylation of forkhead box O3a (FOXO3a) and signal transducer and activator of transcription 3 (STAT3). However, IOD caused a greater decrease in the phosphorylation of mTOR (Ser2448) and phospho-ERK 1/2 while both RCM caused a similar decrease in the phosphorylation of phospho-p70S6 kinase (Ser371). In vivo studies showed that both IOM and IOD caused a significant decrease in both pAkt (Ser473) and pERK 1/2 in rat kidneys. Our study gives an insight into the possible mechanism of toxicity of RCM via their action on intracellular signaling pathways and may help in developing pharmacological interventions for their side-effects.

Whole-body MRI and PET/CT in multiple myeloma patients during staging and after treatment: personal experience in a longitudinal study.

PURPOSE: Diagnostic imaging plays a pivotal role in staging and prognostic assessment of multiple myeloma (MM) as well as planning and monitoring treatment. The aim of our study was to estimate the diagnostic accuracy of wholebody magnetic resonance imaging (WB-MRI) and positron emission tomography/computed tomography (PET/CT) in MM patients studied before and after treatment. MATERIALS AND METHODS: We considered 22 consecutive patients (10 males, 12 females; age range, 48-83 years) with newly diagnosed MM (NDMM group), and the same 22 patients underwent at least one re-assessment after treatment (previously treated MM, PTMM group). WBMRI and PET/CT were performed within days from each other in both the NDMM (22 studies) and PTMM (29 studies) group. The imaging findings were compared to the results of bone marrow aspiration. RESULTS: PET/CT was positive in 18/22 NDMM patients, whereas WB-MRI correctly identified 100% of patients. Of 20 responder patients in the PTMM group, 16 were negative at PET/CT and 12/20 at MRI. By contrast, of the nine nonresponder patients, MRI correctly detected active disease in all cases, and PET only in seven. CONCLUSIONS: WB-MRI proved superior to PET/CT in detecting MM, especially in diffuse disease. PET/CT appears to be more sensitive in the assessment of MM after treatment.

Bone metastases radiopharmaceuticals: an overview.

The skeleton is one of the preferential sites for metastases of solid tumors, and metastatic disease is the most common malignancy of the bone. Diagnosis and evaluation of skeletal metastases require more frequently a combined approach of different diagnostic methods. Between the currently available imaging modalities, a major role is devoted to two radionuclide functional techniques namely scintigraphy and positron emission tomography (PET) imaging. Both these techniques require the use of different radiopharmaceuticals. The aim of this paper is to review the most important radiocompounds that can be successfully used to detect and/or characterize bone metastases.

Peptide imaging with somatostatin analogues: more than cancer probes.

Somastostatin (SS) scintigraphy (SRS) is an effective diagnostic tool for neuroendocrine tumours (NET). High diagnostic accuracy is based on the high affinity binding between SS and its receptors (sstr) expressed both in NET and in some non neoplastic cells. Different SS analogues have been proposed in clinical practice because of the short half-life of the native peptide. Among all synthetic compounds Pentetreotide labelled with In-111 is the most widely used for imaging because of high affinity for sstr 2 and 5. New tracers, showing a different and/or wider affinity, are now available and radio- labelling has been obtained both with gamma and positron emitters. The broader spectrum of interaction with sstr gives a better chance to detect, over NET, other pathological conditions, as chronic inflammation, because of the sstr expression on inflammatory cells, including activated lymphocytes, epithelioid and monocytes.

Differential activation of signaling pathways involved in cell death, survival and inflammation by radiocontrast media in human renal proximal tubular cells.

Radiocontrast media (RCM) are widely used in clinical medicine but may lead to radiocontrast-induced nephropathy (RCIN). The pathogenesis of acute renal failure secondary to RCM is not fully understood, but direct toxic effects are believed to be a major cause of RCIN. We have investigated the effect of different types of RCM on signaling pathways known to play a role in cell death, survival, and inflammation. HK-2 cells were incubated with sodium diatrizoate and iomeprol (IOM) at a concentration of 75 mg I/ml for 2 h. Both RCM caused an increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) (p38) and c-Jun N-terminal kinases (JNKs) and NF-κB (at Ser 276), with sodium diatrizoate having a more drastic effect. Although cell viability was reduced significantly by both RCM, in cells pretreated with IOM the cell viability recovered over a 22-h time period after removal of the RCM. However, viability of diatrizoate-treated cells rose at 5 h but then fell at 22 h after removal of the RCM. The decrease in cell viability in diatrizoate-treated cells corresponded with an increase in phosphorylation of JNKs, p38, and NF-κB and a decrease in phosphorylation of Akt, signal transducer and activator of transcription 3, and forkhead box O3a, as well as poly (ADP-ribose) polymerase and caspase-3 cleavage. The recovery in viability of IOM-treated cells corresponded most notably with an increase in STAT3 phosphorylation and induction of Pim-1 kinase. There was also an increase in interleukin-8 release by diatrizoate-treated cells indicating the possibility of proinflammatory effects of RCM. A knowledge of the signaling pathways by which RCM exert their cytotoxic actions may help in finding future therapies for RCIN.

Nuclear medicine in multiple myeloma -- more than diagnosis.

Multiple myeloma (MM) is a neoplastic monoclonal proliferation of plasma cells, mainly involving bone marrow. To properly stage and manage patients with MM the clinician needs, at first, a complete skeletal survey, being more rarely present also extra skeletal locations. Today none of the available diagnostic imaging methods is able alone to answer to all the questions regarding staging, treatment, and follow up. Continuing to be alive the role of traditional radiology, implemented information can be added by CT and MRI. Concerning nuclear medicine, bone scintigraphy is affected by its low sensitivity. Tc-99m MIBI has been proposed in staging and in follow up, with most relevant clinical information deriving from the correlation of its whole body uptake's distribution with extent and activity of the disease. The prognostic value of MIBI has also been demonstrated. PET-FDG has been proposed in MM for its ability to detect whole-body metabolic active disease, giving relevant information in staging and prognosis. First studies have demonstrated that PET-FDG is more sensitive than other imaging modalities for localizing extra medullary sites of disease.

Current status of PET/CT for tumour volume definition in radiotherapy treatment planning for non-small cell lung cancer (NSCLC).

Target volume delineation of lung cancer is well known to be prone to large inter-observer variability. The advent of PET/CT devices, with co-registered functional and anatomical data, has opened new exciting possibilities for target volume definition in radiation oncology. PET/CT imaging is rapidly being embraced by the radiation oncology community as a tool to improve the accuracy of target volume delineation for treatment optimization in NSCLC. Several studies have dealt with the feasibility of incorporating FDG-PET information into contour delineation with the aim to improve overall accuracy and to reduce inter-observer variation. A significant impact of PET-derived contours on treatment planning has been shown in 30-60% of the plans with respect to the CT-only target volume. The most prominent changes in the gross tumour volume (GTV) have been reported in cases with atelectasis and following the incorporation of PET-positive nodes in otherwise CT-insignificant nodal areas. Although inter-observer variability is still present following target volume delineation with PET/CT, it is greatly reduced compared to conventional CT-only contouring. PET/CT may also provide improved therapeutic ratio compared to conventional CT planning. Increased target coverage and often reduced target volumes may potentially result in PET/CT-based planning to yield better tumour control probability through dose escalation, while still complying with dose/volume constrains for normal tissues. Despite these exciting results, more clinical studies need to be performed to better define the role of combined PET/CT in treatment planning for NSCLC.

CT guided percutaneous fine needle biopsy of small lung lesions in outpatients. Safety and efficacy of the procedure compared to inpatients.

PURPOSE: To compare the safety and efficacy of CT-guided fine needle biopsy (FNAB) of small (<15 mm) lung lesions in inpatients and outpatients. MATERIALS AND METHODS: 108 consecutive inpatients (69 M, 39 F, mean age 56) and 121 consecutive outpatients (90 M, 31 F, mean age 50) who underwent CT-guided FNAB of small lung lesions were included. Lesion size, depth, number of needle passes, presence of emphysema were recorded. 22 G Chiba needles and the roll-over technique were used for all patients; if no significant pneumothorax was detected after FNAB, outpatients were allowed to go home and instructed to return in case of complications. The incidence of pneumothorax and other complications, sensitivity, specificity, diagnostic accuracy were calculated. RESULTS: 12 inpatients and 33 outpatients were lost to follow-up. No statistical differences were observed in lesion size, depth, needle passes, presence of emphysema between the groups. We had 15 pneumothoraces in inpatients, 4 requiring a chest tube, 12 in outpatients, 2 requiring a tube. Diagnostic accuracy was 92.7% in inpatients and 90.9% in outpatients. There were 7 false negatives in inpatients and 8 in outpatients, with negative predictive value of 79% and 78%, respectively. There were no false positives. All differences are nonsignificant. CONCLUSIONS: CT-guided FNAB of small lung lesions is an equally safe and effective procedure in inpatients and outpatients; outpatient performance of FNAB can decrease costs.

Multidetector row CT angiography of the abdominal aorta and lower extremities in patients with peripheral arterial occlusive disease: diagnostic accuracy and interobserver agreement.

PURPOSE: To evaluate the accuracy of four channel multidetector row CT angiography (MDCTA) of the abdominal aorta and lower extremities arteries compared with digital subtraction angiography (DSA). MATERIALS AND METHODS: In our prospective study 42 patients with peripheral vascular occlusive disease (27 M, 15 F, age range 40-79 years) underwent MDCTA and DSA within 5 days. Images were blindly interpreted by two radiologists. Maximum intensity projections (MIP), multiplanar (MPR) reformations, three-dimensional (3D) reconstructions as well as axial images were available for analysis of MDCTA. DSA were analyzed on hard copies. RESULTS: Overall sensitivity and specificity of MDCTA were 93 and 95%, respectively, with positive and negative predictive values of 90 and 97%. Overall diagnostic accuracy was 94%. Normal arterial segments and 100% occlusions were correctly identified in all cases by MDCTA. Moderately stenotic segments interpretation in the calves appeared to be more controversial, but no statistical difference in accuracy of MDCTA in the infrapopliteal district arteries was noted with respect to accuracy in the more proximal arterial bed. Good to excellent interobserver and intraobserver agreement were observed, with k values greater than 0.80. CONCLUSIONS: MDCTA of the abdominal aorta and lower extremities is an accurate imaging modality in clinical practice when compared with DSA.

Chemoembolization for hepatocellular carcinoma: effect of intraarterial lidocaine in peri- and post-procedural pain and hospitalization.

PURPOSE: To assess the efficacy of intraarterial lidocaine on peri- and post-procedural pain and on length of hospital stay in hepatocellular carcinoma (HCC) patients undergoing chemoembolization. MATERIALS AND METHODS: Twenty-eight patients (19M, 9F, age range 49-76) who underwent hepatic chemoembolization at our Institution between March 2000 and February 2002 were included in the study. Group A consisted of 14 patients who received intraarterial lidocaine immediately before and during chemoembolization, while in the 14 patients of group B lidocaine was substituted with saline solution. The doses of centrally acting narcotics (tramadol) administered periprocedurally and in the three days following the procedure were compared, as were the hospitalization times. Subjective pain was measured using the visual analogue scale. Chemoembolizations were performed with an emulsion of lipiodol, cisplatin and epirubicin followed by embolizing material (gelfoam of Contour particles) in order to achieve complete blood flow stop in the proper hepatic artery. RESULTS: No side effects were noted that could be due to systemic administration of lidocaine. All patients experienced some degree of post-embolization syndrome. Periprocedural, day 1 and day 2 post chemoembolization dosages of tramadol were significantly lower in group A with respect to group B patients. No group A patient required analgesia on day 3. No statistical difference was observed in time persistence of nausea and vomiting, fever and hospitalization time between the two patient groups. CONCLUSIONS: Intraarterial administration of lidocaine before and during chemoembolization is a safe and effective method for preventing or reducing peri- and post-procedural pain and dosage of narcotic analgesics in patients with HCC. Hospitalization times did not differ significantly between the two groups, probably because of the other components of post-embolization syndrome, such as fever, nausea and vomiting.

Upper thoracic sympathetic chain neurolysis under CT guidance. A two year follow-up in patients with palmar and axillary hyperhidrosis.

PURPOSE: To evaluate the efficacy, safety and middle-term results of upper thoracic sympathetic chain neurolysis performed under CT guidance in patients with palmar/axillary hyperhidrosis. MATERIALS AND METHODS: From April 1999 to July 2000 we performed 30 upper thoracic sympathetic chain neurolysis in 15 patients presenting with palmar/axillary hyperhidrosis (6 M, 9 F, mean age 29.5 years). Neurolysis was performed under CT guidance injecting 2-10 ml of a solution of phenol 8%, glycerine 20% and saline through 22 G needles placed in the paraspinal space at T3 level through a paraspinal extrapleural approach. At least one week was allowed between neurolysis of right and left thoracic sympathetic chain in the same patient. Procedures were performed on outpatient basis. Patients were followed up with interviews and/or physical examination every 6 months for 2 years. RESULTS: All patients experienced immediate cessation of symptoms. Three patients (20%) experienced one-sided recurrence of symptoms 5, 7 and 12 months respectively after the first neurolysis, which disappeared after a repeated procedure. Two (13%) patients showed a slight Horner's syndrome immediately after the procedure, which resolved in 1 and 2 months respectively. Two patients (13%) experienced pain in the arm on the same side of the neurolysis, which resolved in 1 week. Three (20%) patients experienced mild compensatory sweating. All patients declared they were satisfied with the outcome of the neurolysis when interviewed at 2 years follow up from the first procedure, with no recurrence of symptoms. CONCLUSIONS: Upper thoracic sympathetic chain neurolysis performed under CT guidance in patients with palmar/axillary hyperhidrosis is a safe procedure, with low rate of complications and good results at 2 years follow-up.