Vincenza Granata

Early Assessment of Colorectal Cancer Patients with Liver Metastases Treated with Antiangiogenic Drugs: The Role of Intravoxel Incoherent Motion in Diffusion-Weighted Imaging

Purpose To assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM) of Diffusion-weighted imaging (DWI) in the assessment of liver metastases treated with targeted chemotherapy agents. Methods 12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI) were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST) as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC) analysis were performed. Results 24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp) values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively. Conclusions IVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

Surveillance of HCC patients after liver RFA: Role of MRI with hepatospecific contrast versus three-phase CT scan - Experience of high volume oncologic institute

Purpose. To compare the diagnostic accuracy of hepatospecific contrast-enhanced MRI versus triple-phase CT scan after radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) patients. Methods. Thirty-four consecutive HCC patients (42 hepatic nodules) were treated with percutaneous RFA and underwent MR and CT scans. All patients were enrolled in a research protocol that included CT with iodized contrast medium injection and MR with hepatospecific contrast medium injection. All patients were restaged within four weeks and at 3 months from ablation. The images were reviewed by four different radiologists to evaluate tumor necrosis, residual or recurrence disease, and evidence of new foci. Results. Thirty-two nodules were necrotic after treatment; 10 showed residual disease. Six new HCCs were identified. At first month followup CT has identified 34 necrotic lesions and 8 residual diseases; no new foci were recognized. At MRI instead, 32 complete necrotic lesions were identified, 10 lesions showed residual disease, and 2 new HCCs were found. At three months, CT demonstrated 33 completely necrotic lesions, 9 residual diseases, and 2 new HCCs. MR showed 31 complete necrotic lesions, 11 cases of residual disease, and 6 new HCCs. Conclusions. Hepatospecific contrast-enhanced MRI is more effective than multiphase CT in assessment of HCC treated with RFA.

Curcumin AntiCancer Studies in Pancreatic Cancer

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC.

Intravoxel incoherent motion (IVIM) in diffusion-weighted imaging (DWI) for Hepatocellular carcinoma: correlation with histologic grade

Purpose To assess the correlation between DWI diffusion parameters obtained using Intravoxel Incoherent Motion Method (IVIM) and histological grade of Hepatocellular carcinoma (HCC). Results According to Edmondson-Steiner grade lesions were classified with grade 1 (14), grade 2 (30), grade 3 (18), and grade 4 (0). Apparent Diffusion Coefficient (ADC), perfusion fraction (fp), tissue diffusion coefficient (Dt) median values were statistically different in HCC groups with 1, 2, 3 histological grade (p<0.001). A significant correlation was reported between ADC, fp, Dt and histologic grade respectively of 0.687, 0.737 and 0.674. Receiver operating characteristic (ROC) analysis demonstrated that an ADC of 2.11×10-3 mm2/sec, an fp of 47.33% and an Dt of 0.94×10-3 mm2/sec were the optimal cutoff values to differentiate high histological grade (3) versus low histological grade (1-2), with a sensitivity and specificity for ADC of 100% and 100%, for fp of 100% and 89%, for Dt of 100% and 74%, respectively. Material and Methods A retrospective approved study was performed including 34 patients with 62 HCCs. IVIM was performed to obtain ADC, fp, pseudo-diffusion coefficient (Dp), Dt coefficients. Kruskal Wallis, Spearman Correlation Coefficient, ROC analysis were performed. Conclusions ADC and IVIM-derived fp showed significantly better diagnostic performance in differentiating high-grade from low-grade HCC, and significant correlation was observed between ADC, fp, Dt and histological grade.

Electrochemotherapy in locally advanced pancreatic cancer: Preliminary results

OBJECTIVE Report the preliminary results on electrochemotherapy (ECT) in the treatment of locally advanced pancreatic cancer of a phase I/II study and described the new functional imaging tools to assess ECT response in Magnetic Resonance (MR) imaging compared to morphological Computer Tomography (CT), ultrasound (US) without and with contrast enhancement (CEUS) and MR Imaging. MATERIALS AND METHODS Thirteen patients were enrolled in an ongoing clinical phase I/II study approved by Ethical Committee of National Cancer Institute G. Pascale Foundation - IRCCS of Naples. ECT with bleomycin was performed during open surgery. All patients underwent US and CT scan, before and after ECT treatment; 7 patients were evaluated using morphological and functional (dynamic contrast enhancement-DCE and diffusion weighted- DW) parameters in MR; 5 patients underwent CEUS. RECIST criteria were used to evaluate ECT response on US, CT and MR images. Functional parameters were also used to evaluate ECT response on MR images. RESULTS No acute (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed; no clinically significant electrocardiographic, hemodynamic, or serum biologic changes were noted. No clinically relevant elevation of amylase or lipase levels was observed and no bleeding or damage to surrounding viscera occurred. In three patients had seen splenic infarction without thrombosis of the splenic vessels. CONCLUSION Electrochemotherapy is feasible and safe treatment modality in patients with locally advanced pancreatic adenocarcinoma. Dynamic and diffusion MR imaging in comparison to MR morphological sequence alone and to UC and CT imaging is more suitable to assess ECT treatment response. CEUS is not indicated in follow up after ECT.

Percutaneous Ablation Therapy of Hepatocellular Carcinoma With Irreversible Electroporation: MRI Findings

OBJECTIVE Irreversible electroporation is a new ablation modality. Our purpose was to describe the MRI findings after irreversible electroporation treatment of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS In an 18-month period, we treated 24 HCC lesions in 20 patients who were not candidates for surgery. MRI was performed before and 1 month after irreversible electroporation. We used the liver-specific contrast medium gadoxetic acid. We evaluated the size, shape, signal intensity (T1-weighted, T2-weighted, and diffusion-weighted imaging), dynamic contrast enhancement pattern, and signal behavior during the liver-specific phase. Changes in the perilesional parenchyma, perfusion abnormalities, and complications were also recorded. RESULTS According to the modified Response Evaluation Criteria in Solid Tumors system, 22 of 24 lesions had a complete response, and two lesions showed a partial response and were retreated. The lesions showed a mean size increase of 10%, with a round or oval shape. On the T1-weighted images, we observed a hyperintense core and a hypointense rim. On the T2-weighted sequences, the signal was heterogeneously hypointense. On diffusion-weighted images, 83% of lesions showed restricted diffusion, with b values of 0-800 s/mm(2), whereas in 17% of the lesions, the signal was not clearly discernible for different b values. The apparent diffusion coefficient values did not show statistically significant differences between the baseline (800-1020 × 10(-3) mm(2)/s) and the reassessment after 1 month (900-1100 × 10(-3) mm(2)/s). The necrotic area did not show a signal increase after contrast material injection. Perfusion abnormalities, such as areas of transient hepatic intensity difference, were present in the tissue adjacent to six treated lesions. In two patients, a reduced or absent concentration of the contrast medium was observed during the liver-specific phase around the ablation zone. One patient had an arteriovenous shunt and another had biliary duct dilatation. CONCLUSION MRI detects characteristic morphologic and functional changes after irreversible electroporation treatment.

Prospective screening increases the detection of potentially curable hepatocellular carcinoma: results in 8900 high-risk patients

OBJECTIVES Historically, only 10% of patients with hepatocellular carcinoma (HCC) are diagnosed with early-stage, potentially curable disease. In this study, chronic hepatitis virus-infected patients were prospectively screened to determine: (i) the proportion of patients diagnosed with potentially curable HCC, and (ii) survival following curative therapy. METHODS The study included 8900 chronic hepatitis virus-infected patients enrolled in a prospective screening programme, of whom 1335 (15.0%) were infected with hepatitis B virus (HBV), 7120 (80.0%) with hepatitis C virus (HCV), and 445 (5.0%) with both HBV and HCV. Screening was conducted every 6 months and included serum alpha-fetoprotein (AFP) measurement and ultrasonography. Curative treatments included liver transplantation, resection, radiofrequency ablation and/or ethanol injection. RESULTS Hepatocellular carcinoma was diagnosed in 765 (8.6%) patients. Of 1602 patients with cirrhosis, 758 (47.3%) developed HCC. Curative treatment was possible in 523 (68.4%) of the 765 HCC patients. Two- and 5-year rates of overall survival in the curative treatment group were 65% and 28%, respectively, compared with 10% and 0% in the advanced disease group (P < 0.001). CONCLUSIONS Prospective screening of patients at high risk for the development of HCC increases the proportion of patients diagnosed with potentially curable disease. This may result in an increase in the number of longterm survivors. Screening strategies should focus on patients with chronic HBV or HCV infection who have progressed to cirrhosis because more than 40% of these patients will develop HCC.

Immediate adverse reactions to gadolinium-based MR contrast media: A retrospective analysis on 10,608 examinations

Background and Purpose. Contrast media (CM) for magnetic resonance imaging (MRI) may determine the development of acute adverse reactions. Objective was to retrospectively assess the frequency and severity of adverse reactions associated with gadolinium-based contrast agents (GBCAs) injection in patients who underwent MRI. Material and Methods. At our center 10608 MRI examinations with CM were performed using five different GBCAs: Gd-BOPTA (MultiHance), Gd-DTPA (Magnevist), Gd-EOBDTPA (Primovist), Gd-DOTA (Dotarem), and Gd-BTDO3A (Gadovist). Results. 32 acute adverse reactions occurred, accounting for 0.3% of all administration. Twelve reactions were associated with Gd-DOTA injection (0.11%), 9 with Gd-BOPTA injection (0.08%), 6 with Gd-BTDO3A (0.056%), 3 with Gd-EOB-DTPA (0.028%), and 2 with Gd-DTPA (0.018%). Twenty-four reactions (75.0%) were mild, four (12.5%) moderate, and four (12.5%) severe. The most severe reactions were seen associated with use of Gd-BOPTA, with 3 severe reactions in 32 total reactions. Conclusion. Acute adverse reactions are generally rare with the overall adverse reaction rate of 0.3%. The most common adverse reactions were not severe, consisting in skin rash and hives.

The role of nasoenteric intubation in the MR study of patients with Crohn’s disease: our experience and literature review

PurposeThe aim of this study was to compare magnetic resonance (MR) enteroclysis with MR enterography to verify whether nasoenteric intubation in patients affected by Crohn’s disease can provide supplementary information to that afforded by MR study of the small bowel.Materials and methodsIn a 12-month period, 40 patients (28 women and 12 men, mean age 35 years) affected by Crohn’s disease underwent MR imaging. Distension of the small-bowel loops was obtained by administering polyethylene glycol: 15 patients were given the mixture by mouth (MR enterography), whereas the remaining 25 received it via nasoenteric intubation (MR enteroclysis). Our study protocol included morphological sequences taken before and after intravenous injection of contrast medium and real-time functional sequences. Accuracy criteria for the execution of the examinations were designed according to 11 bands.ResultsComplete distension of the small-bowel loops was obtained in the 25 patients who underwent MR enteroclysis, with the additional advantage of a suitable assessment of those segments involved in the pathological process. This was not the case for the 15 patients who underwent MR enterography, because both the jejunum and the small-bowel loops appeared partially collapsed.ConclusionsMR enteroclysis is the most effective technique for studying the small bowel in Crohn’s disease, as it not only provides a suitable morphological assessment but also supplies functional information.RiassuntoObiettivoLo scopo di questo lavoro è quello di confrontare la resa della risonanza magnetica (RM) con somministrazione di mezzo di contrasto tramite sondino naso-enterico (MR-e) piuttosto che per via orale (MR-os), allo scopo di valutare se l’intubazione naso-enterica nei pazienti con morbo di Crohn fornisca un valore aggiunto alla RM dell’intestino tenue.Materiali e metodiIn un periodo di 12 mesi, 40 pazienti con morbo di Crohn (28 femmine e 12 maschi; età media 35 anni) sono stati sottoposti ad esame RM. La distensione delle anse dell’intestino tenue è stata ottenuta con polietilen glicole (PEG): 15 pazienti hanno assunto per os la miscela (MR-os), mentre a 25 pazienti è stata iniettata tramite sondino naso-enterico (MR-e). Il protocollo di studio ha incluso sequenze pre- e post-contrastografiche morfologiche e per la MR-e sono state effettuate sequenze funzionali real-time. I criteri di correttezza dell’esecuzione degli esami erano basati sulla valutazione di 11 parametri.RisultatiNei 25 pazienti sottoposti ad MR-e si è ottenuta una completa distensione di tutte le anse dell’intestino tenue con un’adeguata valutazione dei tratti interessati dal processo patologico, così non è stato nei 15 sottoposti ad MR-os poiché le anse del digiuno e del tenue prossimale sono risultate parzialmente collabite.ConclusioniLa MR-e è la tecnica più efficace nello studio dell’intestino tenue nei pazienti affetti da morbo di Crohn, fornendo un’adeguata valutazione morfologica, ma anche informazioni funzionali.

Critical role of bevacizumab scheduling in combination with pre- surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial

Background We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. Patients and methods This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. Results The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%–65%). Neutropenia was the most common grade ≥3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%–89%) and 85% (95%CI, 69%–93%), respectively, for the sequential-schedule. Conclusions These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.