[18 F]-FDG PET radiomic model as prognostic biomarker in diffuse large B-cell lymphoma.

To evaluate the association between radiomic features (RFs) extracted from 18 F-FDG PET/CT (18 F-FDG-PET) with progression-free survival (PFS) and overall survival (OS) in diffuse large-B-cell lymphoma (DLBCL) patients eligible to first-line chemotherapy. DLBCL patients who underwent 18 F-FDG-PET prior to first-line chemotherapy were retrospectively analyzed. RFs were extracted from the lesion showing the highest uptake. A radiomic score to predict PFS and OS was obtained by multivariable Elastic Net Cox model. Radiomic univariate model, clinical and combined clinical-radiomic multivariable models to predict PFS and OS were obtained. 112 patients were analyzed. Median follow-up was 34.7 months (Inter-Quartile Range (IQR) 11.3-66.3 months) for PFS and 41.1 (IQR 18.4-68.9) for OS. Radiomic score resulted associated with PFS and OS (p < 0.001), outperforming conventional PET parameters. C-index (95% CI) for PFS prediction were 0.67 (0.58-0.76), 0.81 (0.75-0.88) and 0.84 (0.77-0.91) for clinical, radiomic and combined clinical-radiomic model, respectively. C-index for OS were 0.77 (0.66-0.89), 0.84 (0.76-0.91) and 0.90 (0.81-0.98). In the Kaplan-Meier analysis (low-IPI vs. high-IPI), the radiomic score was significant predictor of PFS (p < 0.001). The radiomic score was an independent prognostic biomarker of survival in DLBCL patients. The extraction of RFs from baseline 18 F-FDG-PET might be proposed in DLBCL to stratify high-risk versus low-risk patients of relapse after first-line therapy, especially in low-IPI patients.

First Live-Experience Session with PET/CT Specimen Imager: A Pilot Analysis in Prostate Cancer and Neuroendocrine Tumor.

OBJECTIVE: to evaluate the feasibility of the intra-operative application of a specimen PET/CT imager in a clinical setting. MATERIALS AND METHODS: this is a pilot analysis performed in three patients who received an intra-operative administration of 68Ga-PSMA-11 (n = 2) and 68Ga-DOTA-TOC (n = 1), respectively. Patients were administrated with PET radiopharmaceuticals to perform radio-guided surgery with a beta-probe detector during radical prostatectomy for prostate cancer (PCa) and salvage lymphadenectomy for recurrent neuroendocrine tumor (NET) of the ileum, respectively. All procedures have been performed within two ongoing clinical trials in our Institute (NCT05596851 and NCT05448157). Pathologic assessment with immunohistochemistry (PSMA-staining and SSA immunoreactivity) was considered as standard of truth. Specimen images were compared with baseline PET/CT images and histopathological analysis. RESULTS: Patients received 1 MBq/Kg of 68Ga-PSMA-11 (PCa) or 1.2 MBq/Kg of 68Ga-DOTA-TOC (NET) prior to surgery. Specimens were collected, positioned in the dedicated specimen container, and scanned to obtain high-resolution PET/CT images. In all cases, a perfect match was observed between the findings detected by the specimen imager and histopathology. Overall, the PET spatial resolution was sensibly higher for the specimen images compared to the baseline whole-body PET/CT images. Furthermore, the use of the PET/CT specimen imager did not significantly interfere with any procedures, and the overall length of the surgery was not affected using the PET/CT specimen imager. Finally, the radiation exposure of the operating theater staff was lower than 40 µSv per procedure (range 26-40 µSv). CONCLUSIONS: the image acquisition of specimens obtained by patients who received intra-surgery injections of 68Ga-PSMA-11 and 68Ga-DOTA-TOC was feasible and reliable also in a live-experience session and has been easily adapted to surgery daily practice. The high sensitivity, together with the evaluation of intra-lesion tumor heterogeneity, were the most relevant results since the data derived from specimen PET/CT imaging matched perfectly with the histopathological analysis.

[18F]FDG PET/CT: Lung Nodule Evaluation in Patients Affected by Renal Cell Carcinoma.

Renal Cell Carcinoma (RCC) is generally characterized by low-FDG avidity, and [18F]FDG-PET/CT is not recommended to stage the primary tumor. However, its role to assess metastases is still unclear. The aim of this study was to evaluate the diagnostic accuracy of [18F]FDG-PET/CT in correctly identifying RCC lung metastases using histology as the standard of truth. The records of 350 patients affected by RCC were retrospectively analyzed. The inclusion criteria were: (a) biopsy- or histologically proven RCC; (b) Computed Tomography (CT) evidence of at least one lung nodule; (c) [18F]FDG-PET/CT performed prior to lung surgery; (d) lung surgery with histological analysis of surgical specimens; (e) complete follow-up available. A per-lesion analysis was performed, and diagnostic accuracy was reported as sensitivity and specificity, using histology as the standard of truth. [18F]FDG-PET/CT semiquantitative parameters (Standardized Uptake Value [SUVmax], Metabolic Tumor Volume [MTV] and Total Lesion Glycolysis [TLG]) were collected for each lesion. Sixty-seven patients with a total of 107 lesions were included: lung metastases from RCC were detected in 57 cases (53.3%), while 50 lesions (46.7%) were related to other lung malignancies. Applying a cut-off of SUVmax ≥ 2, the sensitivity and the specificity of [18F]FDG-PET/CT in detecting RCC lung metastases were 33.3% (95% CI: 21.4-47.1%) and 26% (95%CI: 14.6-40.3%), respectively. Although the analysis demonstrated a suboptimal diagnostic accuracy of [18F]FDG-PET/CT in discriminating between lung metastases from RCC and other malignancies, a semiquantitative analysis that also includes volumetric parameters (MTV and TLG) could support the correct interpretation of [18F]FDG-PET/CT images.

Predictors of positive axillary non-sentinel lymph nodes in breast cancer patients with positive sentinel lymph node biopsy after neoadjuvant systemic therapy.

AIM: To assess the rate of positive non-sentinel lymph nodes (non-SLNs) after neoadjuvant systemic therapy (NAST) in breast cancer (BC) following positive sentinel lymph node biopsy (SLNB). MATERIALS AND METHODS: From institutional database, 265 consecutive patients receiving NAST for cT1-3, any N, M0 BC between 2001 and 2018 were identified. Patients presented clinically negative axilla before surgery and were candidate for SLNB. Following metastatic SLNB, completion axillary lymph node dissection (AxLND) was performed. Non-SLNs rate was investigated using multivariate (MV) logistic regression models. The distribution of non-SLNs across the axilla was observed. RESULTS: Positive non-SLNs were found in 62.3% of cases and showed no correlation with SLN metastasis size. At MV, statistically significant variables associated with non-SLNs were older age (p = 0.025), clinically positive lymph nodes (p = 0.002), SLN extracapsular extension (ECE, p = 0.001), and higher ratio of positive SLNs/total SLNs (p = 0.016). ECE and higher nodal ratio were independent predictors of III axillary level positivity. By categorizing patients in intermediate- and high-risk groups using the study variables, positive non-SLNs were found in the range of 23-56% across the three axillary levels, rates which did not support radiotherapy volume de-escalation. The III axillary level lower involvement (6.3%) was better identified with the RAPCHEM trial criteria based on the ypN status after AxLND. CONCLUSIONS: Involved non-SLNs rate following positive SLNB after NAST is nearly double the rate observed after primary surgery, supporting some intervention on the axilla. If AxLND is limited to I and II level, the involvement of the III level up to 31% of the cases seems to require some additional treatment, while the omission in selected cases needs further investigation.

From the Magic Bullet to Theragnostics: Certitudes and Hypotheses, Trying to Optimize the Somatostatin Model.

The first "theragnostic model", that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the "DOTA-Ga-68/Lu-177", used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted.

Role of interim 18F-FDG-PET/CT for the early prediction of clinical outcomes of Non-Small Cell Lung Cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review.

BACKGROUND: Non-Small Cell Lung Cancer (NSCLC) is characterized by aggressiveness and includes the majority of thorax malignancies. The possibility of early stratification of patients as responsive and non-responsive to radiotherapy with a non-invasive method is extremely appealing. The distribution of the Fluorodeoxyglucose (18F-FDG) in tumours, provided by Positron-Emission-Tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT). OBJECTIVES: In the last years, particular efforts have been focused on the possibility of using ad interim 18F-FDG PET (FDGint) to evaluate response already in the course of radiotherapy. However, controversial findings have been reported for various malignancies, although several results would support the use of FDGint for individual therapeutic decisions, at least in some pathologies. The objective of the present review is to assemble comprehensively the literature concerning NSCLC, to evaluate where and whether FDGint may offer predictive potential. METHODS: Several searches were completed on Medline and the Embase database, combining different keywords. Original papers published in the English language from 2005 to 2016 with studies involving FDGint in patients affected by NSCLC and treated with radiation therapy or chemo-radiotherapy only were chosen. RESULTS: Twenty-one studies out of 970 in Pubmed and 1256 in Embase were selected, reporting on 627 patients. CONCLUSION: Certainly, the lack of univocal PET parameters was identified as a major drawback, while standardization would be required for best practice. In any case, all these papers denoted FDGint as promising and a challenging examination for early assessment of outcomes during CRT, sustaining its predictivity in lung cancer.

Interim 18FDG PET/CT during radiochemotherapy in the management of pelvic malignancies: A systematic review.

18F-fluorodeoxyglucose PET/CT (18F-FDG-PET/CT) is widely applied in oncology for disease staging, assessment of therapy response, relapse diagnosis, follow-up and target volume delineation. In particular, it can detect early response during chemoradiotherapy (interim) because functional modifications usually precede morphological ones. This ability is crucial to the radiation oncologist for the management of patients, to avoid persisting with ineffective therapy - often leading toxicity - and to shift to potentially more effective alternatives. Interim 18F FDG-PET imaging in rectal and cervical cancer, the main malignancies of the pelvic district, has been applied and a broad literature is available, although some results are discordant. This systematic review summarizes the application of 18F FDG-PET/CT during the chemoradiotherapy of locally advanced pelvic malignancies in order to clarify its capability to predict response and prognosis and its potential role to tailor therapy, which seems to be validated in rectal cancer, whilst less conclusive in cervical cancer.

The role of [(18)F]FDG-PET/CT in staging and treatment planning for volumetric modulated Rapidarc radiotherapy in cervical cancer: experience of the European Institute of Oncology, Milan, Italy.

RATIONALE: to evaluate the role of 18F-fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) integrated with computer tomography (CT) scan [(18)F]FDG-PET/CT in the staging and target volume definition in Intensity Modulated RapidarcTM Delivery (RA-IMRT) in cervical cancer. METHODS: From June 2010 to December 2011, 66 patients affected by cervical cancer, candidates for definitive or adjuvant radiochemotherapy, underwent standard staging with CT and magnetic resonance imaging (MRI). All patients underwent [(18)F]FDG-PET/CT in order to exclude distant metastases and to define gross tumor volume (GTV). 40 and 26 patients received exclusive and adjuvant radiotherapy, respectively. RA-IMRT with simultaneous integrated boost (SIB) to the positive disease technique was employed. RESULTS: [(18)F]FDG-PET/CT has changed the stage, and radiotherapy treatment planning was modified in 25% and 7.7 % of patients that received definitive and adjuvant radiotherapy, respectively. Particularly [(18)F]FDG-PET/CT imaging showed metabolically active tumor in lymph nodes area, therefore the stage and the treatment planning changed for these patients. CONCLUSIONS: [(18)F]FDG-PET/CT leads to a better staging and definition of disease and has the potential of showing lymph-node metastasis not only within the pelvis but also in the para-aortic area. In addition, [(18)F]FDG-PET/CT is useful for better definition of the target volume and to produce a 'dose painted' treatment. This might also open the field for escalation dose regimens.

Ipilimumab-induced immunomediated adverse events: possible pitfalls in (18)F-FDG PET/CT interpretation.

A 42-year-old woman underwent resection of a high-risk melanoma of the right thigh. Adjuvant treatment with ipilimumab was then started within a phase III randomised, double-blind clinical trial. F-FDG PET/CT scan showed intense uptake in mediastinal hilar lymph nodes, bilaterally, and in rectus abdominis muscle. Biopsy at the abdominal wall revealed a chronic granulomatous inflammation. After oral steroid treatment, all the areas of abnormal tracer uptake disappeared. Ipilimumab can induce inflammatory immunomediated reactions that should be taken into account to avoid misinterpretation.

Intramedullary spinal cord metastases from breast cancer: detection with (18)F-FDG PET/CT.

A 35-year-old woman, already treated with surgery, chemotherapy, and radiotherapy for a ductal carcinoma of the left breast, underwent an (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) scan for an increase of the serum markers carcinoembryonic antigen (CEA) and cancer antigen 15.3 (CA15.3). The scan showed multiple FDG-avid lesions in the liver and bone. The images also detected two areas of uptake in the dorsal and lumbar spinal cord, which were suspicious for metastases; magnetic resonance imaging (MRI) confirmed these lesions.

Extrapulmonary malignancies detected at lung cancer screening.

PURPOSE: To retrospectively assess the detection rate, histologic characteristics, and clinical stage of screening-detected extrapulmonary malignancies in a population at high risk for lung cancer. MATERIALS AND METHODS: In this institutional review board-approved study, 5201 asymptomatic heavy smokers aged 50 years or older underwent annual low-dose computed tomography (CT) for 5 consecutive years. The 5-year cumulative effective dose was 5 mSv. Subjects with at least one "potentially significant extrapulmonary incidental finding" (PS-IF) were extracted from the study database. An extrapulmonary finding was classified as potentially significant if it required further diagnostic and/or clinical evaluation. In retrospect all clinically relevant information, including findings from diagnostic work-up and final diagnosis of the PS-IF, was collected. On the basis of the information collected, only histologically proved screening-detected extrapulmonary malignancies were eventually included in this study. The percentages of volunteers with extrapulmonary malignancies were calculated, along with 95% confidence intervals (CIs), on the basis of a binomial distribution. RESULTS: After 5 years of CT screening, 27 unsuspected extrapulmonary malignancies were diagnosed, representing 0.5% (27 of 5201 subjects; 95% CI: 0.34%, 0.75%) of volunteers enrolled and 6.2% (27 of 436 findings; 95% CI: 4.12%, 8.88%) of PS-IFs. Eight malignancies were diagnosed at the 1st year of screening, nine at the 2nd year, four at the 3rd year, two at the 4th year, and four at the 5th year. Twelve of the 27 extrapulmonary tumors (44%) were renal carcinomas (n = 7) or lymphomas (n = 5). Twenty-four of the 27 subjects with a malignancy were alive at the most recent follow-up. CONCLUSION: A considerable number of unsuspected extrapulmonary malignancies can be detected in lung cancer screening trials. A careful evaluation of extrapulmonary structures, with particular attention to the kidneys and lymph nodes, is recommended.

A multiple points method for 4D CT image sorting.

PURPOSE: Artifacts affect 4D CT images due to breathing irregularities or incorrect breathing phase identification. The purpose of this study is the reduction of artifacts in sorted 4D CT images. The assumption is that the use of multiple respiratory related signals may reduce uncertainties and increase robustness in breathing phase identification. METHODS: Multiple respiratory related signals were provided by infrared 3D localization of a configuration of markers placed on the thoracoabdominal surface. Multidimensional K-means clustering was used for retrospective 4D CT image sorting, which was based on multiple marker variables, in order to identify clusters representing different breathing phases. The proposed technique was tested on computational simulations, phantom experimental acquisitions, and clinical data coming from two patients. Computational simulations provided a controlled and noise-free condition for testing the clustering technique on regular and irregular breathing signals, including baseline drift, time variant amplitude, time variant frequency, and end-expiration plateau. Specific attention was given to cluster initialization. Phantom experiments involved two moving phantoms fitted with multiple markers. Phantoms underwent 4D CT acquisition while performing controlled rigid motion patterns and featuring end-expiration plateau. Breathing cycle period and plateau duration were controlled by means of weights leaned upon the phantom during repeated 4D CT scans. The implemented sorting technique was applied to clinical 4D CT scans acquired on two patients and results were compared to conventional sorting methods. RESULTS: For computational simulations and phantom studies, the performance of the multidimensional clustering technique was evaluated by measuring the repeatability in identifying the breathing phase among adjacent couch positions and the uniformity in sampling the breathing cycle. When breathing irregularities were present, the clustering technique consistently improved breathing phase identification with respect to conventional sorting methods based on monodimensional signals. In patient studies, a qualitative comparison was performed between corresponding breathing phases of 4D CT images obtained by conventional sorting methods and by the described clustering technique. Artifact reduction was clearly observable on both data set especially in the lower lung region. CONCLUSIONS: The implemented multiple point method demonstrated the ability to reduce artifacts in 4D CT imaging. Further optimization and development are needed to make the most of the availability of multiple respiratory related variables and to extend the method to 4D CT-PET hybrid scan.

Radio-guided ultrasound lymph node localization: feasibility of a new technique for localizing and excising nonpalpable lymph nodes ultrasound suspicious for melanoma metastases.

Identification of lymph nodes suspicious for metastases is crucial in melanoma patients during the follow-up. We propose a procedure called radio-guided ultrasound lymph node localization (RULL) for melanoma patients with ultrasound (US) suspicious, not palpable, lymph nodes. The aim of this study was to evaluate the feasibility of this technique, and to assess the efficacy of this new method. RULL was applied in 12 consecutive melanoma patients with non-palpable lymph nodes found suspicious for metastases during US follow-up. Macro-aggregates of human serum albumin labelled with diluted technetium-99m were injected into the suspected lymph node under US guidance and followed by a scintigraphy. The surgical treatment was carried out with the support of hand-held gamma-probe used for sentinel node biopsy. The tracer was correctly positioned in all 12 patients. Pathological examination revealed seven patients with metastatic lymph nodes, four with no metastatic lymph node, one patient with Hodgkin disease. No surgical complications were described. In conclusion, RULL may integrate the standard ultrasound-guided fine-needle aspiration to improve the diagnostic accuracy on US suspicious nodes and might replace the more logistically complicated wire identification or less accurate cutaneous marker identification of these nodes. Sensibility and specificity of this approach should be defined through a large multicentric study.

Imaging as a surveillance tool in rectal cancer.

Despite advances in diagnosis and treatment, half of patients with treated rectal cancer will die owing to recurrent disease. There is no evidence of benefit on survival from an intensive surveillance program, even if presymptomatic recurrent disease is detected. The aim of this article is to review the results described for the different imaging techniques in diagnosing rectal cancer recurrence in different sites and to discuss their relative clinical impact. The sensitivity of imaging techniques is related to the performance of the machines and the site being examined. Computed tomography is the most used technique owing to its availability, speed, panoramic images and ease of use, while MRI of the pelvis and the liver produces the highest resolution, sensitivity and specificity in these anatomical areas. Owing to its high cost, [(18)F] fluorodeoxyglucose-PET should be used as a third-level examination, a 'problem-solving' method when the site of recurrence is unknown or to rule out other possible sites of recurrence before a second surgery, and, finally, because it offers the possibility to investigate the whole body. The follow-up must be designed for individual patients, taking into account a number of factors. In the near future, whole-body imaging, probably by MRI, that is free from radiation will become the method of choice for screening for recurrent disease.

Intraoperative avidination for radionuclide therapy: a prospective new development to accelerate radiotherapy in breast cancer.

PURPOSE: In a continuous effort to seek for anticancer treatments with minimal side effects, we aim at proving the feasibility of the Intraoperative Avidination for Radionuclide Therapy, a new procedure for partial breast irradiation. EXPERIMENTAL DESIGN: To assess doses of 90Y-DOTA-biotin to target (i.e., breast tumor bed) and nontarget organs, we did simulation studies with 111In-DOTA-biotin in 10 candidates for conservative breast surgery. Immediately after quadrantectomy, patients were injected with 100-mg avidin in the tumor bed. On the following day, patients were given 111In-DOTA-biotin (approximately 111 MBq) i.v. after appropriate chase of biotinylated albumin (20 mg) to remove circulating avidin. Biokinetic studies were done by measuring radioactivity in scheduled blood samples, 48-h urine collection, and through scintigraphic images. The medical internal radiation dose formalism (OLINDA code) enabled dosimetry assessment in target and nontarget organs. RESULTS: Images showed early and long-lasting radioactive biotin uptake in the operated breast. Rapid blood clearance (<1% at 12 h) and urine excretion (>75% at 24 h) were observed. Absorbed doses, expressed as mean+/-SD in Gy/GBq, were as low as 0.15+/-0.05 in lungs, 0.10+/-0.02 in heart, 0.06+/-0.02 in red marrow, 1.30+/-0.50 in kidneys, 1.50+/-0.30 in urinary bladder, and 0.06+/-0.02 in total body, whereas in the targeted area, they increased to 5.5+/-1.1 Gy/GBq (50% ISOROI) and 4.8+/-1.0 Gy/GBq (30% ISOROI). CONCLUSION: Our preliminary results suggest that Intraoperative Avidination for Radionuclide Therapy is a simple and feasible procedure that may improve breast cancer patients' postsurgical management by shortening radiotherapy duration.

Neoadjuvant therapy in locally advanced breast cancer: 99mTc-MIBI mammoscintigraphy is not a reliable technique to predict therapy response.

Mammoscintigraphy (MMS) has been indicated as a useful tool in predicting response to therapy in cancer. However, contrasting results have been reported in the literature for breast cancer patients. The aim of this study was to explore the role of MMS in locally advanced breast cancer (LABC) patients. Fifty-one patients affected by LABC and scheduled for neoadjuvant therapy were enrolled. Breast tumor status was evaluated at baseline, during therapy and at the completion of therapy by radiological techniques and by MMS. Pre-therapy (MMS1) and post-therapy MIBI (2-methoxyisobutilysonitrile) images (MMS2-3) were analyzed. MMS1 was performed in all pts, 41 carried out MMS2 and 27 had MMS3. Tumor uptake and washout in MMS1 did not show any correlation with the therapy response. The absence of any association between tumor uptake and washout with respect to therapy response suggests that MMS is not a reliable technique to predict therapy response in LABC.

Sentinel node detection in pre-operative axillary staging.

The concept of sentinel lymph node biopsy in breast cancer surgery is based on the fact that the tumour drains in a logical way via the lymphatic system, from the first to upper levels. Since axillary node dissection does not improve the prognosis of patients with breast cancer, sentinel lymph node biopsy might replace complete axillary dissection for staging of the axilla in clinically N0 patients. Sentinel lymph node biopsy would represent a significant advantage as a minimally invasive procedure, considering that about 70% of patients are found to be free from metastatic disease, yet axillary node dissection can lead to significant morbidity. Subdermal or peritumoural injection of small aliquots (and very low activity) of radiotracer is preferred to intratumoural administration, and (99m)Tc-labelled colloids with most of the particles in the 100-200 nm size range would be ideal for radioguided sentinel node biopsy in breast cancer. The success rate of radioguidance in localising the sentinel lymph node in breast cancer surgery is about 97% in institutions where a high number of procedures are performed, and the success rate of lymphoscintigraphy in sentinel node detection is about 100%. The sentinel lymph node should be processed for intraoperative frozen section examination in its entirety, based on conventional histopathology and, when necessary, immune staining with anti-cytokeratin antibody. Nowadays, lymphoscintigraphy is a useful procedure in patients with different clinical evidence of breast cancer.