Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers

Added value of contrast-enhanced ultrasound (CEUS) with Sonovue® in the diagnosis of inferior epigastric artery pseudoaneurysm: report of a case and review of literature

The anatomical position of the inferior epigastric artery (IEA), within the rectus sheath, subjects patients to possible IEA injury during abdominal wall surgical and interventional procedures. Pseudoaneurysm arising from IEA is very uncommon with only 16 cases reported in the literature. We present a case of an IEA false aneurysm resulting from therapeutic paracentesis for ascites in a 71-year-old patient who came to our department for abdominal pain and signs of anemization. To our knowledge, no published reports are currently available describing an IAE pseudoaneurysm successfully diagnosed with contrast-enhanced ultrasound

Diagnostic performance and confidence of contrast-enhanced ultrasound in the differential diagnosis of cystic and cysticlike liver lesions

OBJECTIVE. The aims of this study were to assess the diagnostic performance of contrast-enhanced ultrasound (CEUS) in the characterization of atypical cystic and cysticlike focal liver lesions in comparison with conventional US and to determine whether the use of CEUS can reduce the need for further diagnostic workup. SUBJECTS AND METHODS. In a 3-year period 48 patients with 50 atypical cystic and cysticlike lesions found at conventional US underwent CEUS. Diagnostic confirmation was obtained in cytohistopathologic examinations, with other imaging modalities, and in follow-up. Overall, there were 24 cystic lesions and 26 cysticlike solid lesions, specifically 32 benign and 18 malignant lesions. The conventional US and CEUS images and cine loops were reviewed by two blinded readers independently. Sensitivity, specificity, area under the ROC curve (Az), and interobserver agreement were calculated. RESULTS. Diagnostic performance improved after review of CEUS examinations by both readers (conventional US Az = 0.781 vs 0.972; CEUS Az = 0.734 vs 0.957). Interreader agreement increased, although slightly (conventional US weighted = 0.894; CEUS weighted = 0.953). In terms of differential diagnosis, the occurrence of correctly characterized lesions increased after CEUS for both readers (reader 1, 62% to 98%; reader 2, 56% to 96%). CONCLUSION. The development of low-acoustic-power CEUS has made it possible to identify several imaging features of cystic and cysticlike focal liver lesions that, in association with history and clinical findings, may help to correctly characterize them. Our data indicate the usefulness of CEUS in the evaluation of patients with these lesions

The Tail and the String Sign: New Sonographic Features of Subcutaneous Melanoma Metastasis

No highly specific sonographic imaging findings to evaluate melanoma spread along the lymphatic vessels have ever been described. Between January 2009 and December 2012, a consecutive group of 531 melanoma patients at their initial stage or during follow-up for nodal or extra-nodal superficial metastasis were evaluated retrospectively to assess the presence of two sonographic findings demonstrating superficial lymphatic metastasis: a “tail” sign (a thin hypoechoic prolongation from one or both poles of a superficial metastasis) and a “string” sign (multiple in-transit lesions connected to each other in a rosary image). The total number of superficial metastatic lesions was 222. The tail sign was seen in 13 of the 222 lesions (5.9%). The string sign was detected in four patients (4.5%). These signs showed a low sensitivity with a very high specificity (100%). Tail and string signs may represent an additional finding of high specificity to be employed in the differential diagnosis of melanoma patients

Contrast-Enhanced ultrasound in the characterization of complex cystic focal liver lesions

Complex cystic focal liver lesions (FLLs) found at non-contrast ultrasound (US) may turn out to be malignant. In this prospective, monocentric study we investigated the value of contrast-enhanced US (CEUS) in the differential diagnosis of complex cystic FLLs. In the past 3years, all patients with complex cystic FLLs unclassifiable at US underwent CEUS with low-transmit insonation power. We evaluated 36 consecutive patients with 61 FLLs (1-6/patient, mean=2). The diameter of the lesions ranged from 1.1 to 7.9cm (mean=3.9cm). Sixteen patients had an extrahepatic malignancy. There were 42 malignant lesions and 19 benign lesions. No lesion had a certain diagnosis at conventional US, whereas 16 FLLs were classified as probable (benign or malignant) and 45 as uncertain. CEUS correctly categorized 95% of the malignant cases. CEUS was not able to differentiate the biliary cystadenoma from its malignant counterpart and misdiagnosed two abscesses. Complete non-enhancement throughout three phases or sustained enhancement in the portal/late phase was exhibited in most benign complex cystic FLLs, except for 1 (of the 3) cystadenomas and in 2 (of the 4) abscesses. On the other hand, all malignant lesions presented a contrast washout with a hypo-enhancing appearance. CEUS may provide added diagnostic value in all complex cystic FLLs found uncertain at conventional US, potentially avoiding the use of more invasive and expensive imaging modalities

Morphological and dynamic evaluation of complex cystic focal liver lesions by contrast-enhanced ultrasound: current state of the art

Complex cystic and cystic-like focal liver lesions (FLLs) encompass a spectrum of disorders ranging from non-neoplastic conditions to benign and malignant tumors. In this prospective, the possibility of non-invasive differentiation of these lesions is extremely important, because the clinical implications and therapeutic strategies vary considerably. Because of its advantageous cost/benefit ratio, widespread availability and easy execution, ultrasound (US) is the first-line imaging modality in most countries for the initial liver survey and represents the imaging technique that usually detects a complex liver cyst. However, US showed poor efficacy in the differential diagnosis of complex cystic FLLs. Thus, for years, computed tomography (CT) and magnetic resonance (MR) imaging have been used for further assessment of these lesions. Recently, the development of low mechanical index real-time contrast-enhanced ultrasound (CEUS) technique performed with the second generation of US contrast agents has led to an accurate depiction of macrovasculature and microvasculature. The technique yields information about contrast enhancement of the liver and FLLs almost as CT and MRI do, but in real time and without the use of ionizing radiation. To date, there is only a small amount of evidence about the role of CEUS in the less common setting of complex liver cysts. The aim of this review is to offer an up-to-date overview on the state of the art of CEUS in the study of the most common complex cystic focal liver lesions. To our knowledge, there are no literature comprehensive reviews on this topic

Superficial temporal artery pseudoaneurysm: what is the role of ultrasound?

Purpose: The superficial temporal artery (STA) is one of the terminal branches of the external carotid artery; STA pseudoaneurysms are uncommon vascular lesion, generally subsequent to blunt or penetrating trauma that could represent a trick for radiologist, especially when the only anamnestic information is “palpable superficial swelling”. In this article, we describe our ultrasonographic experience about STA pseudoaneurysm reporting several cases with different etiopatogenesis. Methods: Between January 2004 and March 2015 six patients (4F and 2M; aged 15–55 years, mean 36 year) presented at our department with superficial palpable swelling in temporal region (four with trauma history, two with iatrogenic cause) underwent to ultrasonographic study to assess the presence of STA pseudoaneurysm. Ultrasonographic findings suggestive of pseudoaneurysm was a well-defined, pulsatile, anechoic mass in B-mode, a swirling or disorganized pattern of blood flow in the lesion with demonstration of direct communication between arterial lumen and pseudoaneurysm at colour-Doppler and a typical to-and-fro waveform on pseudoaneurysm neck at pulsed-Doppler. Results: B-mode proves the presence of anechoic mass in five on six patients. Colour-Doppler demonstrates the presence of flow inside the lesion in five patients and a direct communication in all patients. To-and-fro typical waveform has been demonstrated in five patients. Ultrasound made diagnosis in all patients with a sensibility and specificity of 100 %. Conclusion: US is the imaging modality of choice, since it can provide detailed information about vascular anatomy without incurring the risks of invasive methods like angiography or radiation