Valentina Battaglia

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

Complete response for advanced liver cancer during sorafenib therapy: Case Report

BackgroundHepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC.Case presentationAn 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was obserdved. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response.ConclusionsThis case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.

Assessment of response to sorafenib in advanced hepatocellular carcinoma using perfusion computed tomography: Results of a pilot study

AIMS This prospective pilot study investigated the feasibility of perfusion computed tomography parameters as surrogate markers of angiogenesis and early response following sorafenib administration in patients with advanced hepatocellular carcinoma. METHODS Ten patients were evaluated with perfusion computed tomography before starting sorafenib and after 3 months. Blood flow, blood volume, mean transit time, hepatic arterial fraction, and permeability surface-product were compared in tumour lesions and in hepatic parenchyma at baseline and at follow-up. Correlation between these parameters and changes in alpha-fetoprotein levels was calculated. RESULTS At baseline, blood volume, blood flow, hepatic arterial fraction and permeability surface values were higher in lesions compared to those in hepatic parenchyma, while mean transit time was lower (p<0.05). After sorafenib treatment, only mean transit time was significantly increased versus baseline (p<0.05). At follow-up, plasma alpha-fetoprotein levels decreased in all patients. At follow-up, an inverse correlation was observed between baseline mean transit time and changes in alpha-fetoprotein (r=-0.6685, p=0.0125), as well as a correlation between baseline blood flow and alpha-fetoprotein (r=0.6476, p=0.0167). CONCLUSION This pilot study suggests that after sorafenib treatment an increase in mean transit time observed in tumour lesions is inversely correlated with alpha-fetoprotein reductions after therapy. Mean transit time may represent a possible marker of response irrespectively of alpha-fetoprotein values.

HCC Diagnosis with Liver-Specific MRI – Close to Histopathology

Thanks to the sensible and continuous improvements achieved, magnetic resonance imaging (MRI) can nowadays be considered the most accurate modality to image the liver. Moreover, the technique is the only one able to provide at the same time information about intracellular and vascular changes occurring in parenchymas. For these reasons, MRI plays a major role in the surveillance and follow-up of patients with cirrhosis. If a baseline MR study investigates the progressive alteration of lesion architecture, grading, stromal component, as well as intracellular content of fat, glycogen, or metal ions, thus leading to a frequent confident diagnosis of lesion nature, a dynamic study provides additional information about lesion vascular enhancement, which may represent the only clue for the differential diagnosis between premalignant and malignant lesions. In addition, the introduction of hepatobiliary contrast agents has further implemented the diagnostic confidence of the technique, permitting to explore the so-called grey area in which significant histological changes are already present without an evident arterial supply of the nodule. Although in the evaluation of liver pathologies MRI is mainly applied in the study of cirrhosis, the technique also plays a fundamental role in the assessment of other primitive liver malignancies, such as fibrolamellar carcinoma or cholangiocarcinoma. In these cases in particular, MRI is required to pose a differential diagnosis with other liver malignancies (such as metastases), and, once the nature of the neoplasm is assessed, to give an accurate locoregional staging.

Hepatocellular nodules in liver cirrhosis: contrast-enhanced MR

Nowadays, the diagnosis of hepatocellular carcinoma (HCC) is increasingly demanded to imaging techniques. Anyway, imaging cirrhotic patients still remains a challenging issue, since pre-neoplastic hepatocellular lesions, as dysplastic nodules (DNs), may frequently mimic small neoplasms. Differently from other imaging modalities, magnetic resonance (MR) can give an accurate evaluation of both intracellular and vascular changes occurring during the carcinogenetic pathway from dysplasia to full malignancy. Both DNs and HCC may in fact show a large variety of signal intensities, strictly reflecting nodules’ characteristics, such as lesion architecture, grading, stromal components, as well as intracellular contents. In these last years, the introduction of dedicated contrast media has increased MR diagnostic efficacy, permitting to explore both vascular as well as the pathological changes occurring in the biliary and reticuloendothelial systems during the carcinogenetic process. MR performed with tissue specific contrast agents (hepatobiliary and reticulo-endothelial) may thus give an insight on this “gray area”, in whom significant histological changes are already present without an evident nodule arterial supply. This peculiar MR prerogative permits to give predictive information about the evolution trend in a cirrhotic parenchyma and to identify patients at high risk for developing carcinoma who would benefit from well-timed treatments.

Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine

Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM.

Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer

Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P<0.001). Although there was no statistically significant difference in the overall survival of the entire group, this result was observed when the analysis was restricted to both the follicular histotype and the group of senior patients (>65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population.

Evaluation of vascular infiltration in resected patients for pancreatic cancer: comparison among multidetector CT, intraoperative findings and histopathology

BackgroundTo assess vascular infiltration is crucial in surgical planning of pancreatic cancer. Our aim was to assess the capability of multidetector CT in detecting vascular infiltration.MethodsWe evaluated 37 patients with pancreatic tumors. The relation between tumor and vessels was classified: grade 0: no contact between lesion and vessel; grade I: focal contiguity without modification of the vessel caliber; grade II: lesion surrounding the vessel, without reduction of its lumen; grade III: cancer surrounding the vessel with reduction or obstruction of its lumen. CT grades were compared to intraoperative findings and histopathology.ResultsWe evaluated 52 critical vessels with the following CT grades: grade 0 (4 cases), grade I (13 cases), grade II (17 cases), grade III (18 cases). Vascular resection was performed in 26 patients, with a total of 31 resected vessels (3 of grade 0, 5 of grade I, 8 of grade II, 15 of grade III). Histopathology excluded vascular infiltration in 4/4 cases with grade 0 and in 10/13 cases with grade I and confirmed it in 14/17 cases with grade II and 14/18 cases with grade III.ConclusionsMultidetector CT is accurate in detecting vascular involvement and provides pre-operative information to effectively plan resection.

Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: A pilot study

BACKGROUND AND OBJECTIVES Electrochemotherapy is a novel ablation technique combining chemotherapeutic agents with reversible cell membrane electroporation. Previous experiences have shown its efficacy for cutaneous tumors. Its application for deep-seated malignancies is under investigation. We performed a prospective, pilot study to evaluate the feasibility, safety, and efficacy of intraoperative electrochemotherapy for otherwise unresectable colorectal liver metastases. METHODS Electrochemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pretreatment plan. The primary endpoints were: feasibility, as ratio of completed to planned treatments; safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST. The secondary endpoint was overall and progression-free survival at month 6. RESULTS A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications. No intraoperative complications were observed. At day 30, complete response was 55.5% and stable disease 45.5%. All (5) patients reached a 6 months overall survival, and 4 out of 5 patients had 6 months progression free survival. CONCLUSIONS Electrochemotherapy is a feasible and safe adjunct to open surgery for treatment of unresectable colorectal liver metastases. Larger studies and longer follow-ups are favored to better define its role in the treatment of secondary liver malignancies.

Multidetector CT in the evaluation of retroperitoneal fat tissue infiltration in ductal adenocarcinoma of the pancreatic head: correlation with histopathological findings

BackgroundNeoplastic infiltration of the retroportal fat tissue is a critical parameter in tumor staging and in surgical planning because it frequently represents a site of persistence and recurrence of disease.MethodWe evaluated 64 patients affected by ductal adenocarcinoma of the pancreatic head/uncinate process, submitted to curative surgery. Suspicion of infiltration (micro or macroinfiltration) of the retroportal margin arose at MDCT in cases of obliteration, irregularity, or abnormal density of the fatty layer localized between the medial surface of the pancreatic head/uncinate process and the mesenteric artery.ResultsCT suggested the infiltration of the retroportal tissue in 27 cases (10 microinfiltration, 17 macroinfiltration). At histopathology, the presence of infiltration was confirmed in 21/27 (78%) cases. In all CT cases of microinfiltration, the retroperitoneal resection margin was not infiltrated, while all cases (6) with infiltration of the retroperitoneal margin were macroinfiltrated at CT. The sensitivity of CT was 80%, specificity of 84% with an overall diagnostic accuracy of 82%.ConclusionMDCT is accurate in the assessment of the neoplastic infiltration of the retroportal fat tissue.