Advancements in Neuroendocrine Neoplasms: Imaging and Future Frontiers.

Neuroendocrine neoplasms (NENs) are a diverse group of tumors with varying clinical behaviors. Their incidence has risen due to increased awareness, improved diagnostics, and aging populations. The 2019 World Health Organization classification emphasizes integrating radiology and histopathology to characterize NENs and create personalized treatment plans. Imaging methods like CT, MRI, and PET/CT are crucial for detection, staging, treatment planning, and monitoring, but each of them poses different interpretative challenges and none are immune to pitfalls. Treatment options include surgery, targeted therapies, and chemotherapy, based on the tumor type, stage, and patient-specific factors. This review aims to provide insights into the latest developments and challenges in NEN imaging, diagnosis, and management.

Dual-energy CT applications on liver imaging: what radiologists and radiographers should know? A systematic review.

PURPOSE: This review aims to provide a comprehensive summary of DECT techniques, acquisition workflows, and post-processing methods. By doing so, we aim to elucidate the advantages and disadvantages of DECT compared to conventional single-energy CT imaging. METHODS: A systematic search was conducted on MEDLINE/EMBASE for DECT studies in liver imaging published between 1980 and 2024. Information regarding study design and endpoints, patient characteristics, DECT technical parameters, radiation dose, iodinated contrast agent (ICA) administration and postprocessing methods were extracted. Technical parameters, including DECT phase, field of view, pitch, collimation, rotation time, arterial phase timing (from injection), and venous timing (from injection) from the included studies were reported, along with formal narrative synthesis of main DECT applications for liver imaging. RESULTS: Out of the initially identified 234 articles, 153 met the inclusion criteria. Extensive variability in acquisition parameters was observed, except for tube voltage (80/140 kVp combination reported in 50% of articles) and ICA administration (1.5 mL/kg at 3-4 mL/s, reported in 91% of articles). Radiation dose information was provided in only 40% of articles (range: 6-80 mGy), and virtual non-contrast imaging (VNC) emerged as a common strategy to reduce the radiation dose. The primary application of DECT post-processed images was in detecting focal liver lesions (47% of articles), with predominance of study focusing on hepatocellular carcinoma (HCC) (27%). Furthermore, a significant proportion of the articles (16%) focused on enhancing DECT protocols, while 15% explored metastasis detection. CONCLUSION: Our review recommends using 80/140 kVp tube voltage with 1.5 mL/kg ICA at 3-4 mL/s flow rate. Post-processing should include low keV-VMI for enhanced lesion detection, IMs for tumor iodine content evaluation, and VNC for dose reduction. However, heterogeneous literature hinders protocol standardization.

Focal Liver Lesions in Budd-Chiari Syndrome: Spectrum of Imaging Findings.

Budd-Chiari syndrome (BCS) is a rare clinical entity characterized by hepatic venous outflow obstruction, resulting in liver congestion and subsequent chronic parenchymal damage. This condition often leads to the development of focal liver lesions, including benign focal nodular hyperplasia-like regenerative nodules, hepatocellular carcinoma, and perfusion-related pseudo-lesions. Computed tomography, ultrasound, and magnetic resonance are the commonly employed imaging modalities for the follow-up of BCS patients and for the detection and characterization of new-onset lesions. The accurate differentiation between benign and malignant nodules is crucial for optimal patient management and treatment planning. However, it can be challenging due to the variable and overlapping characteristics observed. This review aims to provide a comprehensive overview of the imaging features and differential diagnosis of focal liver lesions in BCS, emphasizing the key findings and discussing the challenges associated with their interpretation, with the purpose of facilitating the subsequent clinical decision-making.

Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report.

BACKGROUND: Cancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent. CASE PRESENTATION: A 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy. CONCLUSIONS: Even considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

Ability of Delta Radiomics to Predict a Complete Pathological Response in Patients with Loco-Regional Rectal Cancer Addressed to Neoadjuvant Chemo-Radiation and Surgery.

We performed a pilot study to evaluate the use of MRI delta texture analysis (D-TA) as a methodological item able to predict the frequency of complete pathological responses and, consequently, the outcome of patients with locally advanced rectal cancer addressed to neoadjuvant chemoradiotherapy (C-RT) and subsequently, to radical surgery. In particular, we carried out a retrospective analysis including 100 patients with locally advanced rectal adenocarcinoma who received C-RT and then radical surgery in three different oncological institutions between January 2013 and December 2019. Our experimental design was focused on the evaluation of the gross tumor volume (GTV) at baseline and after C-RT by means of MRI, which was contoured on T2, DWI, and ADC sequences. Multiple texture parameters were extracted by using a LifeX Software, while D-TA was calculated as percentage of variations in the two time points. Both univariate and multivariate analysis (logistic regression) were, therefore, carried out in order to correlate the above-mentioned TA parameters with the frequency of pathological responses in the examined patients' population focusing on the detection of complete pathological response (pCR, with no viable cancer cells: TRG 1) as main statistical endpoint. ROC curves were performed on three different datasets considering that on the 21 patients, only 21% achieved an actual pCR. In our training dataset series, pCR frequency significantly correlated with ADC GLCM-Entropy only, when univariate and binary logistic analysis were performed (AUC for pCR was 0.87). A confirmative binary logistic regression analysis was then repeated in the two remaining validation datasets (AUC for pCR was 0.92 and 0.88, respectively). Overall, these results support the hypothesis that D-TA may have a significant predictive value in detecting the occurrence of pCR in our patient series. If confirmed in prospective and multicenter trials, these results may have a critical role in the selection of patients with locally advanced rectal cancer who may benefit form radical surgery after neoadjuvant chemoradiotherapy.

Is routine CT scan after pancreaticoduodenectomy a useful tool in the early detection of complications? A single center retrospective analysis.

PURPOSE: The clinical impact of routine CT imaging after pancreaticoduodenectomy (PD) has not been properly investigated. The aim of this study was to investigate the role of routine CT scan after PD for the detection of postoperative complications. METHODS: Prospectively collected data of consecutive patients undergoing PD and receiving routine postoperative CT imaging were retrospectively analyzed. The primary endpoint was accuracy of CT imaging in identifying major complications. The secondary endpoint was identification of preoperative and intraoperative factors associated with severe complications. A subgroup analysis of CT scan accuracy in identifying severe complications in patients stratified by fistula risk score (FRS) and presence of early clinical alterations was also performed. RESULTS: A total of 145 patients were included. Routine CT scan had low specificity (Sp = 0.36) and high sensitivity (Sn = 0.98) for predicting major complications, with an accuracy of 0.57. At multivariate logistic regression analysis, only fistula moderate-high FRS (p = 0.029) was independently associated with severe complications. In patients with negligible-low FRS, CT scan showed a Sp of 0.63 and a Sn of 1.0 with an accuracy of 0.69. In patients with moderate-high FRS, CT scan had a Sp of 0.19, a Sn of 0.97 and an accuracy of 0.5. In the 20 (14%) patients with negligible-low FRS and no clinical alterations, no deaths or readmissions occurred regardless of CT findings, while one severe complication occurred in the positive CT scan group. In all other groups, no deaths or readmissions occurred in case of negative CT, with only one severe complication in the moderate-high FRS group with clinical alterations. In case of positive CT, the rate of severe complications was 47% in case of negligible-low FRS and clinical alterations, 40% in case of moderate-high FRS with no clinical alterations, and 45% in case of moderate-high FRS and clinical alterations. CONCLUSIONS: Routine postoperative CT scan after PD should not be performed in patients with negligible-low FRS and no clinical alterations. In all other patients, a negative CT scan appears to be highly accurate in identifying patients who will have an uneventful course and who could benefit from early discharge.

Retzius-sparing Robot-assisted Radical Prostatectomy in High-risk Prostate Cancer Patients: Results from a Large Single-institution Series.

Background: Retzius-sparing (RS) robot-assisted radical prostatectomy represents a valid surgical treatment option for prostate cancer (PCa) patients. However, the available evidence on the role of RS in high-risk (HR) PCa setting is sparse. Objective: To describe our RS technique for HR-PCa patients and to evaluate intra-, peri-, and postoperative oncological and functional outcomes. Design setting and participants: A total of 340 D'Amico HR-PCa patients underwent RS at a single high-volume centre between 2011 and 2020. Surgical procedure: Surgical procedures were performed by five experienced robotic surgeons. Measurements: Complications were collected according to the standardised methodology proposed by the European Association of Urology guidelines. Postoperative outcomes were evaluated in patients with complete follow-up data (n = 320). Biochemical recurrence (BCR) was defined as two consecutive prostate-specific antigen values of ≥0.2 ng/ml. Urinary continence (UC) recovery was defined as the use of zero or one safety pad. Kaplan-Meier and multivariable logistic and Cox regression models were performed. Results and limitations: Fourteen patients (4%) experienced intraoperative complications and 52 90-d complications occurred in 44 patients (14%), of whom 24 had Clavien-Dindo 3a/b. Final pathology reported 49% International Society of Urological Pathology (ISUP) grade 4-5, 55% ≥pT3a, and 28.8% positive surgical margins (PSMs; 9.4% focal and 19.4% extended PSMs). The median follow-up was 47 mo. Overall, 35.3% and 1.3% harboured BCR and died from PCa. At 4 yr of follow-up, BCR-free survival and additional treatment-free survival were 63.6% and 56.6%, respectively. ISUP 4-5 at biopsy (odds ratio [OR]: 2.6), prostate volume (OR: 1.03), partial or full nerve sparing (OR: 1.9), and full bladder neck preservation (OR: 2.2) were independent predictors of PSMs. Pathological ISUP 4-5 (hazard ratio [HR]: 1.5) and PSMs (HR: 2.3) were independent predictors of BCR. Pathological ISUP 4-5 (HR: 1.5), PSMs (HR: 2.4), pT ≥3b (HR: 1.8), and pN ≥1 (HR: 1.8) were independent predictors of additional treatment. Immediate UC recovery was recorded in 53% patients. The 1- and 2-yr UC recovery and erectile function recovery were, respectively, 84% and 85%, and 43% and 50%. Conclusions: RS in HR-PCa patients allows optimal intra-, peri-, and postoperative outcomes. The RS approach should be considered a valid surgical treatment option for HR-PCa patients in expert hands. Patient summary: Relying on the largest cohort of high-risk prostate cancer patients treated with Retzius sparing (RS), we observed that the RS approach is safe and allows optimal cancer control, without significantly compromising functional outcomes.

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases.

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R-) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R- lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies.

From LI-RADS Classification to HCC Pathology: A Retrospective Single-Institution Analysis of Clinico-Pathological Features Affecting Oncological Outcomes after Curative Surgery.

Background: The latest Liver Imaging Reporting and Data System (LI-RADS) classification by the American College of Radiology has been recently endorsed in the American Association for the Study of Liver Disease (AASLD) guidelines for Hepatocellular carcinoma (HCC) management. Although the LI-RADS protocol has been developed as a diagnostic algorithm, there is some evidence concerning a possible correlation between different LI-RADS classes and specific pathological features of HCC. We aimed to investigate such radiological/pathological correlation and the possible prognostic implication of LI-RADS on a retrospective cohort of HCC patients undergoing surgical resection. Methods: We performed a retrospective analysis of the pathological characteristics of resected HCC, exploring their distribution among different LI-RADS classes and analyzing the risk factors for recurrence-free, overall and cancer-specific survival Results: LI-RADS-5 (LR-5) nodules showed a higher prevalence of microvascular invasion (MVI), satellitosis and capsule infiltration, as well as higher median values of alpha-fetoprotein (αFP) compared to LI-RADS-3/4 (LR-3/4) nodules. MVI, αFP, satellitosis and margin-positive (R1) resection resulted as independent risk factors for recurrence-free survival, while LI-RADS class did not exert any significant impact. Focusing on overall survival, we identified patient age, Eastern Cooperative Oncology Group performance status (ECOG-PS), Model for End Stage Liver Disease (MELD) score, αFP, MVI, satellitosis and R1 resection as independent risk factors for survival, without any impact of LI-RADS classification. Last, MELD score, log10αFP, satellitosis and R1 resection resulted as independent risk factors for cancer-specific survival, while LI-RADS class did not exert any significant impact. Conclusions: Our results suggest an association of LR-5 class with unfavorable pathological characteristics of resected HCC; tumor histology and underlying patient characteristics such as age, ECOG-PS and liver disease severity exert a significant impact on postoperative oncological outcomes.

Avoiding immediate whole-body trauma CT: a prospective observational study in stable trauma patients.

High energy blunt trauma patients with normal vital signs are usually investigated with a Contrast Enhanced Computed Tomography (CECT) for torso injuries. CECT involves high levels of radiations, often showing no injuries in patients over-triaged to the trauma center. The aim of our study was to suggest an alternative diagnostic protocol based on Emergency Room (ER) tests (physical exam, blood tests, extended FAST, Chest and Pelvis X-ray) to avoid CECT in selected patients. A prospective cohort study was conducted from September 2018 to September 2019. Five hundred patients fulfilled the inclusion criteria. Patients received torso-CECT scan only if they had at least one positive ER test. The validity of the single component of the protocol and the global validity of the ER tests to detect torso injuries was assessed through sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, positive (+ LR) and negative (- LR) likelihood ratio. Multivariate analysis was performed to identify independent predictors of torso injuries. One hundred and seventy patients received a torso-CECT scan because of positive ER tests. ER tests showed a global sensitivity for torso injuries of 86.96% (95% CI 80.17-92.08) specificity of 83.98%(95% CI 79.79-87.60), PPV of 67.42% (95% CI 61.83-72.54), NPV of 94.41% (95% CI 91.63-96.30) + LR of 5.43 (95% CI 4.25-6.93), - LR of 0.16 (95% CI 0.10-0.24). ER tests in an experienced center seem to be able to identify more severe blunt trauma patients needing CECT. Further studies are advisable to confirm these results.

A retrospective single-centre analysis of the oncological impact of LI-RADS classification applied to Metroticket 2.0 calculator in liver transplantation: every nodule matters.

Although the diagnostic value of Liver Imaging Reporting and Data System (LI-RADS) protocol is well recognized in clinical practice, its role in liver transplant (LT) setting is under-explored. We sought to evaluate the oncological impact of LI-RADS classification applied to Metroticket 2.0 calculator in a single-centre retrospective cohort of transplanted hepatocellular carcinoma (HCC) patients, exploring which LI-RADS subclasses need to be considered in order to grant the best Metroticket 2.0 performance. The most recent pre-LT imaging of 245 patients undergoing LT for HCC between 2005 and 2015 was retrospectively and blindly reviewed, classifying all nodules according to LI-RADS protocol. Metroticket 2.0 accuracy was subsequently tested incorporating all vital nodules identified during multi-disciplinary team (MDT) meetings attended before LI-RADS reclassification of the latest pre-LT imaging, LR-5 and LR-treatment-viable (LR-TR-V), LR-4/5 and LR-TR-V, and LR-3/4/5 and LR-TR-V nodules respectively. Considering their extremely low probability for harbouring HCC, LR-1 and LR-2 nodules were not considered in this analysis. Incorporation of all HCCs identified during MDT meetings attended before LI-RADS reclassification of the latest pre-LT imaging resulted in a Metroticket 2.0 c-index of 0.72, [95% confidence interval (CI) 0.64-0.80]. Metroticket 2.0 c-index dropped to 0.60 [95% CI: 0.48-0.72] when LI-RADS-5 and LI-RADS-TR-V (P = 0.0089) or LI-RADS-5, LI-RADS-4 and LI-RADS-TR-V (P = 0.0068) nodules were entered in the calculator. Conversely, addition of LI-RADS-3 HCCs raised the Metroticket 2.0 c-index to 0.65 [95% CI: 0.54-0.86], resulting in a not statistically significant diversion from the original performance (0.72 vs. 0.65; P = 0.08). Exclusion of LR-3 and LR-4 nodules from Metroticket 2.0 calculator resulted in a significant drop in its accuracy. Every nodule with an intermediate-to-high probability of harbouring HCC according to LI-RADS protocol seems to contribute to tumour burden and should be entered in the Metroticket 2.0 calculator in order to grant appropriate performance.

Inter-center agreement of mRECIST in transplanted patients for hepatocellular carcinoma.

OBJECTIVES: To evaluate the inter-observer reliability of modified Response Evaluation Criteria In Solid Tumours (mRECIST) of patients with hepatocellular carcinoma (HCC) undergoing neo-adjuvant treatments before liver transplant (LT). The agreement of tumor number, size, transplant criteria, and the radiological-pathological concordance were also assessed. METHODS: A total of 180 radiological studies before/after neo-adjuvant therapies performed on 90 patients prior to LT were reviewed from three expert centers. Kappa-statistic and intraclass correlation (ICC) were evaluated on mRECIST and on tumoral features. Complete radiological response (CR) was compared with complete pathological response (CPR). RESULTS: Before neo-adjuvant therapies, the agreement on tumor number, size, and transplant criteria ranged from moderate (defined as ICC of 0.41-0.60) to almost perfect (ICC of 0.81-0.99), being higher with magnetic resonance imaging (MRI) than CT (0.657-0.899 and 0.422-0.776, respectively). After neo-adjuvant therapies, the agreement decreased, as ICCs ranged between 0.518 and 0.663 with MRI and between 0.508 and 0.677 with CT. Concordant mRECIST pairs were 201 of 270 reviews (76.3%) with a kappa of 0.648 indicating substantial agreement. When the three observers completely agreed on CR, the positive predictive value for CPR was 51.6%. The negative predictive value was 94.2% with a kappa of 0.512 indicating fair agreement between radiology and pathology. CONCLUSIONS: mRECIST agreement was substantial among the three observers involved. The agreement on tumor number, size, and transplant criteria ranged from moderate to almost perfect, with the highest ICCs obtained with MRI before neo-adjuvant therapies. Finally, the predictive value of mRECIST in the diagnosis of CPR was only fair. KEY POINTS: • The review of 180 radiological exams of patients with hepatocellular carcinoma before and after neo-adjuvant therapies showed that the concordance among three different raters on mRECIST diagnosis was substantial. • The inter-observer reliability on fulfilment of transplant criteria slightly decreased when evaluated through CT and after loco-regional therapies. • The radiological diagnosis of complete response after neo-adjuvant therapies was predictive of complete pathological response in only 51.6% of cases.

Surgical Resection vs. Percutaneous Ablation for Single Hepatocellular Carcinoma: Exploring the Impact of Li-RADS Classification on Oncological Outcomes.

Background: Single hepatocellular carcinoma (HCC) benefits from surgical resection (SR) or US-guided percutaneous ablation (PA), although the best approach is still debated. We evaluated the impact of Li-RADS classification on the oncological outcomes of SR vs. PA as single HCC first-line treatment. Methods: We retrospectively and blindly classified treatment-naïve single HCC that underwent SR or PA between 2010 and 2016 according to Li-RADS protocol. Overall survival (OS), recurrence free survival (RFS) and local recurrence after SR and PA were compared for each Li-RADS subclass before and after propensity-score matching (PS-M). Results: Considering the general population, SR showed better 5-year OS (68.3% vs. 52.2%; p = 0.049) and RFS (42.5% vs. 29.8%; p = 0.002), with lower incidence of local recurrence (8.2% vs. 44.4%; p < 0.001), despite a significantly higher frequency of clinically-relevant complications (12.8% vs. 1.9%; p = 0.002) and a higher Comprehensive Complication Index (12.1 vs. 2.2; p < 0.001). Focusing on different Li-RADS subclasses, we highlighted better 5-year OS (67.1% vs. 46.2%; p = 0.035), RFS (45.0% vs. 27.0% RFS; p < 0.001) and lower incidence of local recurrence (9.7% vs. 48.6%; p < 0.001) after SR for Li-RADS-5 HCCs, while these outcomes did not differ for Li-RADS-3/4 subclasses; such results were confirmed after PS-M. Conclusions: Our analysis suggests a potential prognostic role of Li-RADS classification, supporting SR over PA especially for Li-RADS-5 single HCC.

MRI only in a patient with prostate cancer with bilateral metal hip prostheses: case study.

OBJECTIVE: To outline a practical method of performing prostate cancer radiotherapy in patients with bilateral metal hip prostheses with the standard resources available in a modern general hospital. The proposed workflow is based exclusively on magnetic resonance imaging (MRI) to avoid computed tomography (CT) artifacts. CASE DESCRIPTION: This study concerns a 73-year-old man with bilateral hip prostheses with an elevated risk prostate cancer. Magnetic resonance images with assigned electron densities were used for planning purposes, generating a synthetic CT (sCT). Imaging acquisition was performed with an optimized Dixon sequence on a 1.5T MRI scanner. The images were contoured by autosegmentation software, based on an MRI database of 20 patients. The sCT was generated assigning averaged electron densities to each contour. Two volumetric modulated arc therapy plans, a complete arc and a partial one, where the beam entrances through the prostheses were avoided for about 50° on both sides, were compared. The feasibility of matching daily cone beam CT (CBCT) with MRI reference images was also tested by visual evaluations of different radiation oncologists. CONCLUSIONS: The use of magnetic resonance images improved accuracy in targets and organs at risk (OARs) contouring. The complete arc plan was chosen because of 10% lower mean and maximum doses to prostheses with the same planning target volume coverage and OAR sparing. The image quality of the match between performed CBCTs and MRI was considered acceptable. The proposed method seems promising to improve radiotherapy treatments for this complex category of patients.

Impact of inter-reader contouring variability on textural radiomics of colorectal liver metastases.

BACKGROUND: Radiomics is expected to improve the management of metastatic colorectal cancer (CRC). We aimed at evaluating the impact of liver lesion contouring as a source of variability on radiomic features (RFs). METHODS: After Ethics Committee approval, 70 liver metastases in 17 CRC patients were segmented on contrast-enhanced computed tomography scans by two residents and checked by experienced radiologists. RFs from grey level co-occurrence and run length matrices were extracted from three-dimensional (3D) regions of interest (ROIs) and the largest two-dimensional (2D) ROIs. Inter-reader variability was evaluated with Dice coefficient and Hausdorff distance, whilst its impact on RFs was assessed using mean relative change (MRC) and intraclass correlation coefficient (ICC). For the main lesion of each patient, one reader also segmented a circular ROI on the same image used for the 2D ROI. RESULTS: The best inter-reader contouring agreement was observed for 2D ROIs according to both Dice coefficient (median 0.85, interquartile range 0.78-0.89) and Hausdorff distance (0.21 mm, 0.14-0.31 mm). Comparing RF values, MRC ranged 0-752% for 2D and 0-1567% for 3D. For 24/32 RFs (75%), MRC was lower for 2D than for 3D. An ICC > 0.90 was observed for more RFs for 2D (53%) than for 3D (34%). Only 2/32 RFs (6%) showed a variability between 2D and circular ROIs higher than inter-reader variability. CONCLUSIONS: A 2D contouring approach may help mitigate overall inter-reader variability, albeit stable RFs can be extracted from both 3D and 2D segmentations of CRC liver metastases.

Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial.

BACKGROUND: HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting. METHODS: HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1). RESULTS: Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue. CONCLUSIONS: HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource. TRIAL REGISTRATION NUMBER: 2012-002128-33 and NCT03225937.

Long-term Clinical Outcome of Trastuzumab and Lapatinib for HER2-positive Metastatic Colorectal Cancer.

BACKGROUND: ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences. PATIENTS AND METHODS: Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging. RESULTS: A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval [CI] 3.7-6.1). Median overall survival was 10.0 months (95% CI 7.9-15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients. CONCLUSIONS: Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies. Clinicaltrials. Gov identifier: NCT 03225937.

Radiomics predicts response of individual HER2-amplified colorectal cancer liver metastases in patients treated with HER2-targeted therapy.

The aim of our study was to develop and validate a machine learning algorithm to predict response of individual HER2-amplified colorectal cancer liver metastases (lmCRC) undergoing dual HER2-targeted therapy. Twenty-four radiomics features were extracted after 3D manual segmentation of 141 lmCRC on pretreatment portal CT scans of a cohort including 38 HER2-amplified patients; feature selection was then performed using genetic algorithms. lmCRC were classified as nonresponders (R-), if their largest diameter increased more than 10% at a CT scan performed after 3 months of treatment, responders (R+) otherwise. Sensitivity, specificity, negative (NPV) and positive (PPV) predictive values in correctly classifying individual lesion and overall patient response were assessed on a training dataset and then validated on a second dataset using a Gaussian naïve Bayesian classifier. Per-lesion sensitivity, specificity, NPV and PPV were 89%, 85%, 93%, 78% and 90%, 42%, 73%, 71% respectively in the testing and validation datasets. Per-patient sensitivity and specificity were 92% and 86%. Heterogeneous response was observed in 9 of 38 patients (24%). Five of nine patients were carriers of nonresponder lesions correctly classified as such by our radiomics signature, including four of seven harboring only one nonresponder lesion. The developed method has been proven effective in predicting behavior of individual metastases to targeted treatment in a cohort of HER2 amplified patients. The model accurately detects responder lesions and identifies nonresponder lesions in patients with heterogeneous response, potentially paving the way to multimodal treatment in selected patients. Further validation will be needed to confirm our findings.

Standardization of CT radiomics features for multi-center analysis: impact of software settings and parameters.

The aim of this multicentric study is an inter-center benchmarking, to assess how different set tools applied to the same radiomics workflow affected the radiomics features (RFs) values. This topic is of key importance to start collaboration between different centers and to bring radiomic studies from benchmark to bedside. A per-lesion analysis was performed on 56 metastases (mts) selected from 14 patients. A single radiologist performed the segmentation of all mts, and RFs were extracted from the same segmentation of each mts, using two different software and file formats. Potential sources of discrepancies were evaluated. The intraclass correlation coefficient was used to describe how strongly the same radiomic measurements calculated in the two different centers resemble each other. Moreover, means of the relative changes of each RF were calculated, compared and gradually reduced. We showed that, after matching all formulas, discrepancies in RFs calculation between two centers ranged from 1% to 277%. Therefore, we evaluated other sources of variability using a stepwise approach, which led us to reduce the inter-center discrepancies to 0% for 22/25 RFs and below 2% for 3 RFs out of 25. In this study we demonstrated that different radiomic applications and masks formats might strongly impact the computation of some RFs. Therefore, when dealing with multi-center studies it is mandatory to adopt all strategies that can help in limiting the differences, thus keeping in mind the feasibility of these strategies in large cohort studies.