Claudia Maggi

Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis

BACKGROUND Wild type RAS (RAS-wt) status is predictive of the activities of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (C) and panitumumab (P). We examined the impact of C and P on progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) in advanced colorectal cancer (CRC) patients who have RAS-wt/BRAF-mutant (BRAF-mut) status. METHODS Randomised trials that compared C or P plus chemotherapy (or C or P monotherapy) with standard therapy or best supportive care (BSC) were included. We used published hazard ratios (HRs) if they were available, or we derived treatment estimates from other survival data. Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method. All statistical tests were two-sided. RESULTS Nine phase III trials and one phase II trial (six first-line and two second-line trials, plus two trials involving chemorefractory patients), that included 463 RAS-wt/BRAF-mut CRC patients, were analysed. Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67-1.14; p=0.33), OS (HR, 0.91; 95% CI, 0.62-1.34; p=0.63) and ORR (relative risk, 1.31; 95% CI 0.83-2.08, p=0.25) compared with control regimens. CONCLUSIONS C- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients. These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies.

Evaluation of normal brain development by prenatal MR imaging.

AbstractPurpose.The aim of this study was to describe the normal pattern of development and maturation of the foetal brain with respect to gestational age as assessed with magnetic resonance imaging (MRI) and to provide an overview of the possibilities of the technique.Materials and methods.Foetal cerebral MRI was performed on 56 pregnant women between 19 and 37 weeks of gestation. Half-Fourier single-shot turbo spin-echo (HASTE), true fast imaging with steady precession (FISP), T1-weighted fast low angle shot (FLASH) two-dimensional (2D) and diffusion-weighted (DW) sequences with apparent diffusion coefficient (ADC) were obtained. Biometric parameters and developmental areas of the cerebral cortex were correlated to gestational age by using the Spearman rank correlation test.Results.We found a negative correlation between the germinal matrix/biparietal diameter ratio and gestational age and a positive correlation between the germinal and cortical matrix when expressed as external intraocular diameter ratio (R=0.452, p=0.02). The cortical mantle was correlated with biometric parameters, such as the biparietal diameter and the frontooccipital diameter, and with gestational age. The interhemispheric fissure, the parietooccipital fissure and the sylvian fissure were detectable by the 22nd week. In the grey matter, the mean ADC values varied from 1.76×10-3 mm2/s (at week 19) to 0.89×10-3 mm2/s (at week 37), whereas in the white matter, the values varied from 2.03×10-3 mm2/s (at week 19) to 1.25×10-3 mm2/s (at week 37).Conclusions.MRI provides a reliable valuation of brain maturation during pregnancy.

Role of breast Magnetic Resonance Imaging (MRI) in patients with unilateral nipple discharge: preliminary study

PurposeThis study was performed to assess the role of magnetic resonance imaging (MRI) in patients with unilateral nipple discharge.Materials and methodsForty-four patients with bloody or serosanguineous nipple discharge and negative mammographic findings (35/44 cases) underwent MRI for evaluation of breast ducts. Ultrasonography, negative in 18 patients, identified 26 cases of ductal ectasia (12 simple, nine with solid intraductal echoes and wall thickening, five with inhomogeneous parenchyma). Galactography was negative in three patients and positive in nine. Nineteen patients were followed up by clinical examination, ultrasonography, and cytological evaluation of nipple discharge (6–12 months); three patients underwent excisional biopsy, ten core biopsy and 12 cytological biopsy (followed by excisional biopsy).ResultsMRI identified 25 enhancing lesions Breast Imaging Reporting and Data Systems (BI-RADS) 3 or 4) and confirmed the galactographic findings (ductal ectasia, intraluminal filling defects). Five papillomatoses appeared as patchy, homogeneous enhancing areas, 15 intraductal papillomas as areas with well-defined margins and type II time-intensity curves, and two atypical ductal hyperplasias as diffuse nodular enhancement. One micropapillary ductal carcinoma in situ (DCIS), one papillary carcinoma and one infiltrating ductal carcinoma (IDC) were visualised as two segmental areas of enhancement and one mass-like enhancement with poorly defined margins (BI-RADS 4). The follow-up was negative, showing no pathological enhancement (BI-RADS 1) in 12 patients and benign enhancement (BI-RADS 2) in seven.ConclusionsBreast MRI can be considered a valuable examination in the diagnosis of suspected ductal disease and an alternative to galactography when the latter cannot be used.RiassuntoObiettivoValutare il ruolo della risonanza magnetica (RM) in pazienti con secrezione monorifiziale dal capezzolo.Materiali e metodiQuarantaquattro pazienti con secrezione ematica/sieroematica dal capezzolo, mammografia negativa (35/44 casi) si sottoponevano allo studio dei dotti con RM. L’ecografia negativa in 18 casi, identificava ectasia duttale in 26: semplici in 12, con proliferazione solida intraduttale ed ispessimento parietale in 9 e con disomogeneità ghiandolare in 5; la galattografia negativa in 3 e positiva in 9. Diciannove pazienti effettuavano follow-up clinico, radiologico, citologico della secrezione (6–12 mesi), 3 biopsia chirurgica, 10 core-biopsy e 12 prelievo citologico (seguite da biopsia chirurgica).RisultatiRM identificava 25 aree di potenziamento classificate BI-RADS 3 o 4. Nelle pazienti sottoposte a galattografia, la RM riconosceva i reperti galattografici (ectasia o difetti di riempimento). Cinque papillomatosi duttali si identificavano come potenziamento lineare ed omogeneo; 15 papillomi: enhancement a margini netti e curva intensità-tempo di tipo II, 2 iperplasie duttali atipiche: potenziamento nodulare diffuso. Un carcinoma papillare, 1 CDIS con aspetto micropapillare e 1 CDI si evidenziavano come 2 aree di potenziamento segmentale e un’area di potenziamento nodulare a margini irregolari (BI-RADS4). Follow-up negativo in 12 pazienti senza potenziamento patologico (BI-RADS1) e in 7 con potenziamento benigno (BIRADS2).ConclusioniLa RM può essere considerata valida metodica diagnostica nello studio della sospetta patologia duttale con secrezione, in alternativa alla galattografia quando questa metodica non sia utilizzabile.

Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation

BACKGROUND No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. PATIENTS AND METHODS Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. RESULTS Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P=0.004). TP53 status had no influence on the primary end point. CONCLUSIONS Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.

Chemotherapy or Targeted Therapy as Second-Line Treatment of Advanced Gastric Cancer. A Systematic Review and Meta-Analysis of Published Studies

Chemotherapy is a cornerstone in treatments of gastric cancer, but despite its benefit, less than 60% of patients receive salvage therapy in clinical practice. We performed a systematic review and meta-analysis based on trial data on the role of second-line treatment of advanced gastric cancer. MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared active therapy to best supportive care in advanced gastric cancer. Data extraction was conducted according to the PRISMA statement. Summary HR for OS was calculated using a hierarchical Bayesian model and subgroup analysis was performed based on baseline Eastern Cooperative Oncology Group Performance Status (ECOG) performance status (0 vs. 1 or more). A total of 1,407 patients were evaluable for efficacy, 908 were treated in the experimental arms, with chemotherapy (231 pts) or with targeted therapies (677 pts). The risk of death was decreased by 18% (HR = 0.82; 95% CI, 0.79–0.85; posterior probability HR≥1: <0.00001) with active therapies. Chemotherapy and ramucirumab were able to decrease this risk by 27% and 22%, respectively. No differences were found between chemotherapy and ramucirumab. In patients with ECOG = 0 a greater benefit was found for chemotherapy with a reduction of the risk of death by 43% and no benefits were found for ramucirumab or everolimus. In patients with ECOG = 1 or more a significant reduction of the risk of death by 32% was reported in patients treated with ramucirumab, even if no significant difference was reported between chemotherapy and ramucirumab. This analysis reports that active and available therapies are able to prolong survival in patients with advanced gastric cancer with a different outcome based on initial patient’s performance status. New trials based on a better patient stratification are awaited.

Magnetic resonance imaging versus ultrasonography in fetal pathology.

PurposeThis paper describes our experience with magnetic resonance imaging (MRI) in the assessment of fetal anatomical structures and major fetal pathologies.Materials and methodsThe retrospective study included 128 pregnant women between the 22nd and 38th week of gestation. We used the following imaging protocol: T2-weighted single-shot fast spin-echo sequences for all foetuses and, in selected cases, gradient echo with steady-state free precession (SSFP), T1-weighted spoiled gradient echo [fast low-angle shot (FLASH)] with and without fat saturation, and T2 thick-slab sequences with multiplanar technique. In 32 cases, we performed diffusion-weighted sequences with apparent diffusion coefficient (ACD) maps on the brain, the kidneys and the lungs.ResultsWe achieved diagnostic-quality images in 125 of 128 patients; MR image quality was unsatisfactory in three cases only. In 16 cases with previous negative ultrasound (US) findings, MRI confirmed the US diagnosis. MRI confirmed the positive US diagnosis in 67 of 109 cases (61.5%); in 11 cases it changed the US diagnosis, and in 31/109 the examination was negative. In addition, MRI identified other anomalies not recognised during US examination.ConclusionsWith its ultrafast sequences, fetal MRI provides good detail of normal fetal anatomy and allows characterisation of suspected anomalies.RiassuntoObiettivoPresentare la nostra esperienza con la risonanza magnetica nella valutazione delle strutture anatomiche e delle patologie principali nel feto.Materiali e metodiLo studio retrospettivo include 128 donne in gravidanza tra la 22a e la 38a settimana di gestazione. Abbiamo utilizzato il seguente protocollo: per tutti i feti sequenze T2 pesate Single Shot Fast Spin Echo e in casi selezionati sequenze Gradient Echo con tecnica steady state free precession (SSFP), sequenze spoiled gradient echo T1 pesate (Fast Low Angle Shot, FLASH) con e senza saturazione del segnale del grasso e sequenze T2 thick slab acquisite con tecnica multiplanare. In 32 casi, abbiamo effettuato sequenze pesate per diffusione con il coefficiente di diffusione apparente (ADC) su cervello, reni e polmoni.RisultatiIn 125 pazienti su 128, l’esame ha mostrato una buona qualità; solo in 3 casi le immagini RM non sono risultate soddisfacenti. Nei 16 casi già negativi all’ecografia, l’RM ha confermato il risultato ecografico. L’RM ha confermato come positive 67 diagnosi ecografiche su 109 casi (61,5%); in 11 casi, invece, l’RM ha modificato la diagnosi ecografica ed in 31 pazienti l’esame è risultato negativo. Inoltre l’RM ha consentito di riconoscere ulteriori anomalie che non sono state diagnosticate durante l’esame ecografico.ConclusioniL’RM fetale, grazie alle sequenze ultra-fast, consente di visualizzare buoni dettagli dell’anatomia fetale e di caratterizzare sospette anomalie.

Role of cMET in the Development and Progression of Colorectal Cancer

Mesenchymal-epithelial transition (MET) is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF). Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC), by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies.

First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis

BACKGROUND The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated. METHODS MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS Seven eligible RCTs were identified. In the overall RAS wild-type population (N=2719), anti-EGFR MoAbs significantly improved OS (HR=0.81; 95%CI, 0.71-0.92; p=0.002), PFS (HR=0.77; 95%CI, 0.60-0.98; p=0.03) and objective response rate (ORR) (RR=1.33; 95%CI, 1.09-1.62; p=0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p<0.001) and ORR (p<0.001) with a trend toward longer OS (p=0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR=0.80; 95%CI, 0.69-0.92; p=0.003), but not PFS (HR=0.94; 95%CI, 0.74-1.19; p=0.59) or ORR (RR=1.10; 95%CI, 0.97-1.25; p=0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based). CONCLUSIONS The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.

AIMS Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. METHODS Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. RESULTS None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C. CONCLUSIONS Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.

Breast MRI: Are T2 IR sequences useful in the evaluation of breast lesions?

AIM To evaluate the potential role of signal intensities calculated in T2 images as an adjunctive parameter in the analysis of mass-like enhancements classified as BIRADS (Breast Imaging Reporting and Data System) assessment categories 2, 3, 4 or 5 with the standard T1 criteria. MATERIALS AND METHODS After a retrospective review of 338-breast Magnetic Resonance Imaging (MRI) performed for the evaluation of a suspicious lesion we selected a group of 65 mass-like enhancements ranging from 5 to 20mm, classified as BIRADS assessment categories 2, 3, 4 or 5, histologically proved. In all cases we calculated the ratio between the signal intensity (SI) of the nodule and the pectoralis major muscle (LMSIR, lesion to muscle signal intensity ratio) with a multiROIs (region of interest) analysis on T2 images. A ROC analysis was performed to test the ability of the two diagnostic parameters separately considered (BIRADS and LMSIR) and combined in a new mono-dimensional variable obtained by a computerized discriminant function. RESULTS Histological examination assessed 34 malignant lesions (52.3%) and 31 benign lesions (47.7%). The evaluation of ROC curves gave the following results: BIRADS area under the curve (AUC) 0.913, S.E. 0.0368, LMSIR AUC 0.854, S.E. 0.0487, combined BIRADS-LMSIR AUC 0.965, S.E. 0.0191 with a definitive increase in the AUC between the overall ROC area and those of the two diagnostic modalities separately considered. DISCUSSION T2-weighted SI assessment with LMSIR measurement improves the diagnostic information content of standard breast MRI and can be considered a promising potential tool in the differential diagnosis of mass-like enhancements judged as borderline lesions (BIRADS 3 and 4).