Veronica Ricci

Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab and has strong antitumor activity in advanced non-small-cell-lung cancer patients.

Background: We designed a translational clinical trial to investigate whether a dose/dense chemotherapy regimen is able to enhance in patients with non-small-cell-lung-cancer, the anti-angiogenic, and anti-tumor activity of bevacizumab, a murine/human monoclonal antibody to the vasculo-endothelial-growth-factor (VEGF) Patients and Methods: Forty-eight patients (42 males and 6 females) with stage IIIB/IV non-small-cell-lung-cancer, a mean age of 68 years, and ECOG ≤ 2 were enrolled in the study. They received every three weeks fractioned cisplatinum (30 mg/sqm, days 1-3) and oral etoposide (50 mg, days 1-15) and were divided in 5 cohorts receiving different bevacizumab dosages [0; 2.5; 5; 7.5; and 10 mg/kg] on the day 3. Results: The combined treatment was able of inducing a significant decline in the blood-perfusion of primary tumor (NMR-study); in serum levels of VEGF, angiopoietin-1, thrombospondin-1; and in the number of VEGF-transporting cells. In the group of 40 patients who received bevacizumab there was an objective response and a disease stabilization rate of 77.5% (95% CI, 75.63-93.17) and 15% respectively, with a time to progression of 7.6 months. Grade I-II hematological toxicity was the most common adverse event. Four early deaths within three months, three cases of pneumonia, and six cases of mood depression at higher bevacizumab dosage were observed. The most active biological and maximum tolerated dose were 5 and 7.5 mg/kg, respectively. Conclusion: The combination of bevacizumab with a dose/dense chemotherapy regimen resulted moderately safe but showed significant anti-angiogenic, and anti-tumor activity.

Assessment of response to chemoradiation therapy in rectal cancer using MR volumetry based on diffusion-weighted data sets: a preliminary report

PurposeThis study evaluated the feasibility of magnetic resonance (MR) volumetry using a diffusion-weighted data set (VDWI) and compared it with conventional T2-weighted volumetry (VC) in patients affected by rectal cancer treated with chemoradiation therapy (CHRT).Materials and methodsFourteen patients with a biopsy diagnosis of rectal cancer underwent MR examination before and after CHRT. T2-weighted images were used to extrapolate VC. A diffusion-weighted (DW) sequence was acquired [spin-echo diffusion-weighted echo-planar imaging (SE-DW-EPI)] with a b-value of 800 s/mm2 and volume (VDWI) was calculated by semiautomatic segmentation of tumour hyperintensity. Two radiologists independently assessed volumes and analysed data in order to establish interobserver agreement and compare and correlate volumes to tumour regression grade (TRG), as evaluable at pathological examination of the surgical specimen.ResultsInterobserver agreement was 0.977 [(95% confidence interval (CI) 0.954–0.989) and 0.956 (95% CI 0.905–0.980) for VC and VDWI and 0.964 (95% CI 0.896–0.988) and 0.271 (95% CI-0.267 to 0.686) between VC and VDWI before and after CHRT. The correlation between TRG and VC and VDWI was, respectively, rho = 0.597 (p<0.05) and r2=0.156 (p=0.162) and rho=0.847 (p<0.001).ConclusionsVDWI seems to be a promising tool for assessing response to CHRT in rectal cancer. Further studies on large series of patients are needed to refine the technique and evaluate its potential predictive value.RiassuntoObiettivoScopo del nostro lavoro è stato valutare la fattibilità della volumetria in risonanza magnetica (RM) con immagini pesate in diffusione (VDWI) e confrontare tale metodo con la volumetria convenzionale (VC) basata su immagini T2-pesate in pazienti affetti da neoplasia rettale trattati con chemio-radioterapia (CHRT).Materiali e metodiQuattordici pazienti affetti da neoplasia rettale documentata istologicamente sono stati esaminati con RM prima e dopo chemio-radioterapia. Due osservatori hanno estrapolato indipendentemente il VC dalle immagini T2-pesate e il VDWI dall’acquisizione spin echo (SE)-echo-planar imaging (EPI)-diffusion-weighted (DW) (b-value 800 s/mm2) mediante segmentazione semiautomatica dell’iperintensità patologica. Le due volumetrie sono state comparate e correlate al grado di regressione tumorale sul pezzo operatorio (tumor regression grade, TRG).RisultatiL’accordo inter-osservatore per VC e VDWI è stato di 0,977 (95% intervallo di confidenza 0,954–0,989) e 0,956 (95% intervallo di confidenza 0,905–0,980) e tra VC e VDWI pre- e post-CHRT di 0,964 (95% intervallo di confidenza 0,896–0,988) e 0,271 (95% intervallo di confidenza −0,267–0,686). La correlazione tra TRG e VC e VDWI è stata rispettivamente di rho=0,597 (p<0,05) e rho=0,847 (p<0,001).ConclusioniLa VDWI sembra essere promettente per valutare la risposta alla CHRT nelle neoplasie rettali, tuttavia sono necessari ulteriori studi su casistiche più ampie al fine di migliorare la qualità di tale metodo e per valutarne il reale valore predittivo.

Magnetic resonance imaging in the evaluation of the gastric emptying and antral motion: Feasibility and reproducibility of a fast not invasive technique

PURPOSE The aim of this study was to evaluate reproducibility of a fast MRI protocol to measure gastric emptying and motility of the gastric antrum. METHODS AND MATERIALS Gastric emptying and antral speed were measured in 12 type 1 diabetic patients (mean age 43 years) and 9 healthy volunteers (mean age 31 years). Subjects, fasting from 6h, were evaluated in supine position using a 1.5T MR scanner and a eight-channels phased-array body coil after ingestion of 400 ml of a vanillas pudding mixed with 5 ml of Gd-DTPA. Axial 3D T1w sequence at 0 and 30 min for volume evaluation and cine-steady state acquisition every 5 min for a total time of 30 min for gastric wave speed assessing were acquired. Two blinded observers extrapolated T(1/2) from gastric volume assessment and speed of gastric waves. RESULTS All the patients tolerated the examination. The T(1/2) cut-off was of 115 min with an accuracy in differentiate controls from diabetics of 96% (95% CI 0.766-0.992; p<0.001), while the antral speed cut-off was of 0.15 mm/s with an accuracy of 87% (95% CI 0.628-0.977; p<0.001). The inter-observer agreement for the volumes at time 0 and 30 min was respectively 0.983 (95% CI 0.9628-0.9929; p<0.001) and 0.9933 (95% CI 0.9847-0.9971; p<0.001) with an agreement of 0.9918 (95% CI 0.9853-0.9954; p<0.001), while for antral speed it was of 0.935 (95% CI 0.9097-0.9528; p<0.001). CONCLUSIONS MRI is a reproducible technique for the evaluation of gastric emptying and antral motility.

Diffusion-weighted MR Volumetry for Assessing the Response of Rectal Cancer to Combined Radiation Therapy with Chemotherapy

Editor: In the study by Curvo-Semedo and colleagues (1), which appeared in the September 2011 issue of Radiology, the utility of tumor volumetry derived from diffusion-weighted (DW) magnetic resonance (MR) images was evaluated in the assessment of patients with rectal cancer after preoperative combined radiation therapy with chemotherapy (CRT). They showed that post-CRT DW volumetry and volume shrinkage at both T2-weighted and DW MR imaging were highly accurate in the determination of complete response (areas under the receiver operating characteristic curve [AUC] of 0.93, 0.84, and 0.92, respectively). The apparent diffusion coefficient (ADC) and ADC modification rate were not accurate (AUC, 0.54 and 0.51, respectively). The intraclass correlation coefficient (ICC) between T2-weighted and DW MR volumetry was good for pre-CRT measurements but unsatisfactory for post-CRT measurements. This last observation might be attributable to post-CRT fibrosis, which affects the reliability of segmentation of tumor volume on T2-weighted images with respect to post-CRT DW volumetry based on ADC maps (1). In their study, Curvo-Semedo and colleagues defined complete response as tumor regression grade 1 (2) at pathologic examination or a relapsefree follow-up of 17 months. The preliminary results of our study (3), performed with DW imaging using a b value of 800 sec/mm2, are consistent with those reported by Curvo-Semedo and colleagues. In our study of 21 patients who underwent surgical resection after CRT, the interobserver agreement was good (ICC = 0.948 for T2-weighted MR volumetry and 0.916 for DW MR volumetry), whereas the preand post-CRT DW and T2-weighted volumetry concordance consisted of ICC values of 0.828 and 0.151, respectively. The volume segmented from the DW data set on the basis of hyperintensity of hypercellular tissue on DW images showed a good correlation with tumor regression grade (r = 0.556, P , .05). However, DW MR volumetry has some drawbacks, including the difficulty in detecting small neoplastic residual tumors on the post-CRT ADC maps and T2 shinethrough artifacts, owing to necrosis or mucin, which can produce overestimation of residual tumor at the only qualitative eval uation of DW images. These limitations, in our experience, make it difficult to differentiate between patients with tumor regression grades of 1 or 2 (Mandard five-point scale). The relationship to DW MR volumetry of the nodal stage evaluation could increase its prognostic relevance because good prognosis has been demonstrated for low tumor regression grades ypN2 with respect to ypN+ (4). DW MR volumetry seems to be a promising tool for assessing response after preoperative CRT and deserves further study.

Diffusion-Weighted Magnetic Resonance Diagnosis of Local Recurrences of Prostate Cancer after Radical Prostatectomy: Preliminary Evaluation on Twenty-Seven Cases

Objectives. To assess the diagnostic performance of diffusion-weighted MR imaging (DWI) in patients affected by prostatic fossa (PF) relapse after radical prostatectomy (RP) for prostatic carcinoma (PC). Methods. Twenty-seven patients showing a nodular lesion in the PF at T2-weighted MR imaging after RP, with diagnosis of PC relapse established by biopsy or PSA determinations, were investigated by DWI. Two readers evaluated the DWI results in consensus and the apparent diffusion coefficient (ADC) of the nodules, separately; a mean value was obtained (ADCm). Results. Relapses did not significantly differ in size in respect of postsurgical benign nodules. The DWI qualitative evaluation showed sensitivity, specificity, accuracy, ppv, and npv values, respectively, of 83.3%, 88.9%, 85.2%, 93.7%, and 72.7% (100%, 87.5%, 95.6%, 93.7%, and 100%, for nodules >6 mm). The intraclass correlation coefficient (ICC) for ADC evaluation between the two readers was 0.852 (95% CI 0.661–0.935; P = 0.0001). The ADCm values for relapses and benign nodules were, respectively, 0.98 ± 0.21 × 10−3 mm2/sec and 1.24 ± 0.32 × 10−3 mm2/sec (P = 0.006). Sensitivity, specificity, accuracy, ppv and npv of ADCm were, respectively, 77.8%, 88.9%, 81.8%, 93.3%, and 66.7% (93.3%, 87.5%, 85.4%, 93.3%, and 87.5% for nodules >6 mm). Conclusions. Diffusion-weighted MR imaging is a promising tool in the management of a hyperintense nodule detected by T2-weighted sequences. This might have a relevant importance in contouring radiotherapy treatment volumes.

Radiotherapy prolongs the survival of advanced non-small-cell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev)

Radiotherapy (RT), together with a direct cytolytic effect on tumor tissue, also elicits systemic immunological events, which sometimes result in the regression of distant metastases (abscopal effect). We have shown the safety and anti-tumor activity of a novel metronomic chemotherapy (mCH) regimen with dose-fractioned cisplatin, oral etoposide and bevacizumab, a mAb against the vasculo-endothelial-growth-factor (mPEBev regimen), in metastatic non-small-cell-lung cancer (mNSCLC). This regimen, designed on the results of translational studies, showed immune-modulating effects that could trigger and empower the immunological effects associated with tumor irradiation. In order to assess this, we carried out a retrospective analysis in a subset of 69 consecutive patients who received the mPEBev regimen within the BEVA2007 trial. Forty-five of these patients, also received palliative RT of one or more metastatic sites. Statistical analysis (a Log-rank test) revealed a much longer median survival in the group of patients who received RT [mCH vs mCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6) vs 22.12 +/-4.3 (95%CI 11.9-26.087) months; P=0.015] with no difference in progression-free survival. In particular, their survival correlated with the mPEBev regimen ability to induce the percentage of activated dendritic cells (DCs) (CD3-CD11b+CD15-CD83+CD80+) [Fold to baseline value (FBV) ≤1 vs >1: 4+/-5.389 (95%CI,0- 14.56) vs 56+/-23.05 (95%CI,10.8-101.2) months; P:0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV ≤ 1 vs >1: 8+/-5.96 (95%CI,0-19.68) vs 31+/-12.3 (95%CI,6.94-55.1) months; P:0.045]. These results suggest that tumor irradiation may prolong the survival of NSCLC patients undergone mPEBev regimen presumably by eliciting an immune-mediated effect and provide the rationale for further perspective clinical studies.

Anti-cancer activity of dose-fractioned mPE +/− bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients

Background Results from the BEVA2007 trial, suggest that the metronomic chemotherapy regimen with dose-fractioned cisplatin and oral etoposide (mPE) +/- bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), shows anti-angiogenic and immunological effects and is a safe and active treatment for metastatic non-small cell lung cancer (mNSCLC) patients. We carried out a retrospective analysis aimed to evaluate the antitumor effects of this treatment in a subset of patients with squamous histology. Methods Retrospective analysis was carried out in a subset of 31 patients with squamous histology enrolled in the study between September 2007 and September 2015. All of the patients received chemotherapy with cisplatin (30 mg/sqm, days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE) and 14 of them also received bevacizumab 5 mg/kg on the day 3q21 (mPEBev regimen). Results This treatment showed a disease control rate of 71% with a mean progression free survival (PFS) and overall survival (OS) of 13.6 and 17 months respectively. After 4 treatment courses, 6 patients showing a remarkable tumor shrinkage, underwent to radical surgery, attaining a significant advantage in term of survival (P=0.048). Kaplan-Meier and log-rank test identified the longest survival in patients presenting low baseline levels in neutrophil-to-lymphocyte ratio (NLR) (P=0.05), interleukin (IL) 17A (P=0.036), regulatory-T-cells (Tregs) (P=0.020), and activated CD83+ dendritic cells (DCs) (P=0.03). Conclusions These results suggest that the mPE +/- bevacizumab regimen is feasible and should be tested in comparative trials in advanced squamous-NSCLC (sqNSCLC). Moreover, its immune-biological effects strongly suggest the investigation in sequential combinations with immune check-point inhibitors.

La volumetria con risonanza magnetica pesata in diffusione nella valutazione della risposta alla chemio-radioterapia nel tumore del retto: studio preliminare

PurposeThis study evaluated the feasibility of magnetic resonance (MR) volumetry using a diffusion-weighted data set (VDWI) and compared it with conventional T2-weighted volumetry (VC) in patients affected by rectal cancer treated with chemoradiation therapy (CHRT).Materials and methodsFourteen patients with a biopsy diagnosis of rectal cancer underwent MR examination before and after CHRT. T2-weighted images were used to extrapolate VC. A diffusion-weighted (DW) sequence was acquired [spin-echo diffusion-weighted echo-planar imaging (SE-DW-EPI)] with a b-value of 800 s/mm2 and volume (VDWI) was calculated by semiautomatic segmentation of tumour hyperintensity. Two radiologists independently assessed volumes and analysed data in order to establish interobserver agreement and compare and correlate volumes to tumour regression grade (TRG), as evaluable at pathological examination of the surgical specimen.ResultsInterobserver agreement was 0.977 [(95% confidence interval (CI) 0.954–0.989) and 0.956 (95% CI 0.905–0.980) for VC and VDWI and 0.964 (95% CI 0.896–0.988) and 0.271 (95% CI-0.267 to 0.686) between VC and VDWI before and after CHRT. The correlation between TRG and VC and VDWI was, respectively, rho = 0.597 (p<0.05) and r2=0.156 (p=0.162) and rho=0.847 (p<0.001).ConclusionsVDWI seems to be a promising tool for assessing response to CHRT in rectal cancer. Further studies on large series of patients are needed to refine the technique and evaluate its potential predictive value.RiassuntoObiettivoScopo del nostro lavoro è stato valutare la fattibilità della volumetria in risonanza magnetica (RM) con immagini pesate in diffusione (VDWI) e confrontare tale metodo con la volumetria convenzionale (VC) basata su immagini T2-pesate in pazienti affetti da neoplasia rettale trattati con chemio-radioterapia (CHRT).Materiali e metodiQuattordici pazienti affetti da neoplasia rettale documentata istologicamente sono stati esaminati con RM prima e dopo chemio-radioterapia. Due osservatori hanno estrapolato indipendentemente il VC dalle immagini T2-pesate e il VDWI dall’acquisizione spin echo (SE)-echo-planar imaging (EPI)-diffusion-weighted (DW) (b-value 800 s/mm2) mediante segmentazione semiautomatica dell’iperintensità patologica. Le due volumetrie sono state comparate e correlate al grado di regressione tumorale sul pezzo operatorio (tumor regression grade, TRG).RisultatiL’accordo inter-osservatore per VC e VDWI è stato di 0,977 (95% intervallo di confidenza 0,954–0,989) e 0,956 (95% intervallo di confidenza 0,905–0,980) e tra VC e VDWI pre- e post-CHRT di 0,964 (95% intervallo di confidenza 0,896–0,988) e 0,271 (95% intervallo di confidenza −0,267–0,686). La correlazione tra TRG e VC e VDWI è stata rispettivamente di rho=0,597 (p<0,05) e rho=0,847 (p<0,001).ConclusioniLa VDWI sembra essere promettente per valutare la risposta alla CHRT nelle neoplasie rettali, tuttavia sono necessari ulteriori studi su casistiche più ampie al fine di migliorare la qualità di tale metodo e per valutarne il reale valore predittivo.

Assessment of response to chemoradiation therapy in rectal cancer using MR volumetry based on diffusion-weighted data sets: a preliminary report@@@La volumetria con risonanza magnetica pesata in diffusione nella valutazione della risposta alla chemio-radioterapia nel tumore del retto: studio preliminare

PurposeThis study evaluated the feasibility of magnetic resonance (MR) volumetry using a diffusion-weighted data set (VDWI) and compared it with conventional T2-weighted volumetry (VC) in patients affected by rectal cancer treated with chemoradiation therapy (CHRT).Materials and methodsFourteen patients with a biopsy diagnosis of rectal cancer underwent MR examination before and after CHRT. T2-weighted images were used to extrapolate VC. A diffusion-weighted (DW) sequence was acquired [spin-echo diffusion-weighted echo-planar imaging (SE-DW-EPI)] with a b-value of 800 s/mm2 and volume (VDWI) was calculated by semiautomatic segmentation of tumour hyperintensity. Two radiologists independently assessed volumes and analysed data in order to establish interobserver agreement and compare and correlate volumes to tumour regression grade (TRG), as evaluable at pathological examination of the surgical specimen.ResultsInterobserver agreement was 0.977 [(95% confidence interval (CI) 0.954–0.989) and 0.956 (95% CI 0.905–0.980) for VC and VDWI and 0.964 (95% CI 0.896–0.988) and 0.271 (95% CI-0.267 to 0.686) between VC and VDWI before and after CHRT. The correlation between TRG and VC and VDWI was, respectively, rho = 0.597 (p<0.05) and r2=0.156 (p=0.162) and rho=0.847 (p<0.001).ConclusionsVDWI seems to be a promising tool for assessing response to CHRT in rectal cancer. Further studies on large series of patients are needed to refine the technique and evaluate its potential predictive value.RiassuntoObiettivoScopo del nostro lavoro è stato valutare la fattibilità della volumetria in risonanza magnetica (RM) con immagini pesate in diffusione (VDWI) e confrontare tale metodo con la volumetria convenzionale (VC) basata su immagini T2-pesate in pazienti affetti da neoplasia rettale trattati con chemio-radioterapia (CHRT).Materiali e metodiQuattordici pazienti affetti da neoplasia rettale documentata istologicamente sono stati esaminati con RM prima e dopo chemio-radioterapia. Due osservatori hanno estrapolato indipendentemente il VC dalle immagini T2-pesate e il VDWI dall’acquisizione spin echo (SE)-echo-planar imaging (EPI)-diffusion-weighted (DW) (b-value 800 s/mm2) mediante segmentazione semiautomatica dell’iperintensità patologica. Le due volumetrie sono state comparate e correlate al grado di regressione tumorale sul pezzo operatorio (tumor regression grade, TRG).RisultatiL’accordo inter-osservatore per VC e VDWI è stato di 0,977 (95% intervallo di confidenza 0,954–0,989) e 0,956 (95% intervallo di confidenza 0,905–0,980) e tra VC e VDWI pre- e post-CHRT di 0,964 (95% intervallo di confidenza 0,896–0,988) e 0,271 (95% intervallo di confidenza −0,267–0,686). La correlazione tra TRG e VC e VDWI è stata rispettivamente di rho=0,597 (p<0,05) e rho=0,847 (p<0,001).ConclusioniLa VDWI sembra essere promettente per valutare la risposta alla CHRT nelle neoplasie rettali, tuttavia sono necessari ulteriori studi su casistiche più ampie al fine di migliorare la qualità di tale metodo e per valutarne il reale valore predittivo.