Laura Gilardi

Is [18F] fluorodeoxyglucose uptake by the primary tumor a prognostic factor in breast cancer?

BACKGROUND We retrospectively investigated (18)F-FDG uptake by the primary breast tumor as a predictor for relapse and survival. PATIENTS AND METHODS We studied 203 patients with cT1-T3N0 breast cancer. Standardized uptake value (SUVmax), was measured on the primary tumor. After a median follow-up of 68 months (range 22-80), the relation between SUVmax and tumor factors, disease free-survival (DFS) and overall survival (OS) was investigated. RESULTS In the PET-positive patients, the median FDG uptake by the tumor was 4.7. FDG uptake was significantly related to tumor size, number of involved axillary nodes, grade, negative ER, high Ki-67 and HER2 overexpression. No distant metastases or deaths occurred in the PET-negative group. Five-year DFS was 97% and 83%, respectively in the PET-negative and PET-positive groups (P = 0.096). At univariate analysis, DFS was significantly lower in patients with SUVmax >4.7 compared to the patients with negative PET (P = 0.042), but not to the patients with SUVmax ≤4.7 (P = 0.106). At multivariable analysis, among PET-positive patients, SUVmax was not an independent prognostic factor for DFS (HR(>4.7 vs ≤4.7): 1.02 (95% CI 0.45-2.31)). Five-year OS was 100% and 93%, respectively, in the PET-negative and PET-positive groups (P = 0.126). CONCLUSION FDG uptake by the primary lesion was significantly associated with several prognostic variables, but it was not an independent prognostic factor.

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.

Investigation of 18F-FDG PET in the selection of patients with breast cancer as candidates for sentinel node biopsy after neoadjuvant therapy

PurposeThe main objective of this study was to determine the role of [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in the selection of patients with breast cancer as candidates for sentinel node biopsy (SNB) after neoadjuvant therapy.MethodsForty-four patients with primary breast cancer clinically classified as cT2, cT3 or cT4a-c cN0-N2 or cN3 M0 and with a baseline FDG PET scan positive both in the site of primary tumour and axillary lymph nodes underwent neoadjuvant therapy and then a second FDG PET scan. In the case of axillary FDG PET uptake, patients underwent axillary lymph node dissection (ALND). If the second FDG PET scan was negative for axillary involvement, SNB was performed in order to evaluate axillary lymph node status. Only in the case of SN positivity did total ALND follow.ResultsSpecificity and positive predictive value of FDG PET for detection of axillary lymph node metastases after neoadjuvant therapy were as high as 83% (95% confidence interval: 51–97%) and 85% (95% confidence interval: 54–97%), respectively, whereas sensitivity, negative predictive value and diagnostic accuracy were inadequate for a correct staging (34, 32 and 48%, respectively).ConclusionThe poor sensitivity of FDG PET in detecting axillary lymph node metastases makes SNB mandatory in cases of a negative scan. The relatively high positive predictive value seems to suggest a role of FDG PET in selecting patients who, after neoadjuvant therapy, are candidates for ALND, avoiding SNB. However, this issue requires confirmation in a larger series of patients.

PET/CT with Fluorodeoxyglucose during neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Objective The aim of the present study is to evaluate the accuracy of Positron Emission Tomography/Computed Tomography (PET/CT) with Fluorodeoxyglucose ([18F]FDG) to predict treatment response in patients with locally advanced rectal cancer (LARC) during neoadjuvant chemoradiotherapy. Patients and methods Forty-one LARC patients performed [18F]FDG-PET/CT at baseline (PET0). All patients received continuous capecitabine concomitant to radiotherapy on the pelvis, followed by intermittent capecitabine until two weeks before curative surgery. [18F]FDG-PET/CT was also carried out at 40 Gy-time (PET1) and at the end of neoadjuvant therapy (PET2). PET imaging was analysed semi-quantitatively through the measurement of maximal standardised uptake value (SUVmax) and the tumour volume (TV). Histology was expressed through pTNM and Dworak tumor regression grading. Patients were categorised into responder (downstaging or downsizing) and non-responder (stable or progressive disease by comparison pretreatment parameters with clinical/pathological characteristics posttreatment/after surgery). Logistic regression was used to evaluate SUVmax and TV absolute and percent reduction as predictors of response rate using gender, age, and CEA as covariates. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Survivals were compared by the Log-Rank test. Results Twenty-three responders (9 ypCR, 14 with downstaged disease) and 18 non-responders showed differences in terms of both early and posttreatment SUVmax percent reduction (median comparison: responder = 63.2%, non-responder = 44.2%, p = 0.04 and responder = 76.9%, non-responder = 61.6%, p = 0.06 respectively). The best predictive cut-offs of treatment response for early and posttreatment SUVmax percent reduction were ≥57% and ≥66% from baseline (p = 0.02 and p = 0.01 respectively). Conclusions [18F]FDG-PET/CT is a reliable technique for evaluating therapy response during neoadjuvant treatment in LARC, through a categorical classification of the SUV max reduction during treatment.

Evaluation of response to immunotherapy: new challenges and opportunities for PET imaging

Cancer immunotherapy focuses on the development of agents that can activate the immune system to recognize and kill tumour cells. It encompasses different strategies, the first of which is the activation of innate and adaptive immune effector mechanisms, such as vaccination with tumour antigens, treatment with cytokines (for example, interleukin 2 or interferon α) and enhancement of antigen presentation. Another important strategy involves neutralizing the inhibitory and suppressive mechanisms and includes the use of antibodies to deplete the regulatory T cells and the use of antibodies against immune-checkpoint molecules, for example cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death (PD1) [1]. Monoclonal antibodies (mAbs) that block the immunoregulatory damping mechanisms of the host response to tumourassociated antigens have recently become a practical reality with the first approval by the US Food and Drug Administration of ipilimumab in patients with unresectable or metastatic melanoma. Ipilimumab is a fully human monoclonal immunoglobulin specific for CTLA-4, a molecule that downregulates T-cell activation via a homeostatic feedback loop. Under normal physiological conditions, this mechanism prevents autoimmunity and allows the body to establish tolerance to self-antigens. Anti-CTLA-4 mAbs block CTLA-4 signalling preventing downregulation of the immune response and increasing the proliferation of Tcells and the interaction of T cells and cancer cells [2]. Ipilimumab has been extensively tested in patients with melanoma. It was found to be the first compound to improve overall survival in a randomized, phase III trial comparing ipilimumab with or without the gp100 peptide vaccine versus gp100 alone in patients with previously treated, unresectable stage III or IV melanoma. Median overall survival in the combination ipilimumab and vaccine arm was similar to that in the ipilimumab-alone arm, but significantly higher than in the gp100 peptide vaccine-alone arm [3]. Another randomized phase III study demonstrated an increase in overall survival in patients with previously untreated stage IV melanoma receiving dacarbazine in combination with ipilimumab compared to dacarbazine alone [4]. Consistent with the mechanism of action of ipilimumab, that does not rely on the direct killing of tumour cells, the changes in tumour burden observed in clinical trials have often been very different from those observed using chemotherapeutic agents. Four distinct patterns of response have been described: (1) response in baseline target lesions, that is a “chemotherapy-like” response; (2) a slow, steady decline in tumour burden; (3) response after an increase in tumour burden, that is after progressive disease (PD) by standard response criteria; and (4) response in target and new lesions accompanied by the appearance of other new lesions. All these patterns are associated with favourable survival, although the last two may be misinterpreted as PD by standard methods [5]. Antibodies that target CTLA-4 have also been associated with several novel adverse effects that have been described as immune-related adverse events (irAEs). They are found in more than 70 % of patients and are typically responsive to interruption or discontinuation of CTLA-4 blockade in combination with immunosuppressive drugs such as corticosteroids [6]. Symptomatic irAEs have been described mainly in four organ systems: gastrointestinal tract, liver, skin and endocrine system. Clinically silent manifestations, in particular benign lymphadenopathy (sarcoid-like syndrome) and L. Gilardi (*) : C. M. Grana Division of Nuclear Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy e-mail: laura.gilardi@ieo.it

Intramedullary spinal cord metastases from breast cancer: detection with 18F-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 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-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.

Interim 18F-FDG-PET/CT during chemo-radiotherapy in the management of oesophageal cancer patients. A systematic review

Oesophageal cancer is an aggressive disease. The possibility to early stratify patients as responsive and non-responsive with a non-invasive method is extremely appealing. The uptake of 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). In the last years, efforts have been focused on the possibility to use ad interim 18F-FDG-PET/CT (PETint) to evaluate response during radiation therapy. However, controversial findings have been reported, although some relevant results would support its use for individual therapeutic decision. The present review assembles the comprehensive literature of the last decade to evaluate whether and in which cases PETint may offer predictive potential in oesophageal cancer. All the analysed studies (13 studies, 697 patients) denoted PETint as a challenging examination for early assessment of outcomes during CRT. In particular, 8 studies advocated the predictivity of PETint, whilst 5 did not find any correlation between the interim variation of PET parameters and the pathological complete response and/or the clinical outcome. The reasons that possibly have caused contradictions among the studies demand further research with prospective and uniform protocols and methods of analysis to assess the predictive and prognostic value of PETint in oesophageal cancer.

Breast Cancer Incidentally Detected by 18F-Choline PET/CT in a Patient With Recurrent Prostate Carcinoma

A 79-year-old man underwent F-choline PET/CT for biochemical recurrence of prostate cancer. PET/CT images showed an area of elevated radiopharmaceutical uptake in a left pelvic node. In addition, a small focus of increased radiolabeled choline accumulation was seen in a small nodule of the right breast, which was later histologically characterized as an infiltrating ductal carcinoma. In this patient, choline PET/CT was critical in localizing prostate cancer recurrence and identifying a second unsuspected malignancy.

68Ga- DOTA0-Tyr3octreotide (DOTATOC) positron emission tomography (PET)/CT in five cases of ectopic adrenocorticotropin-secreting tumours

Cushing’s syndrome results from autonomous and/or excessive glucocorticoid secretion. In most cases, it is adrenocorticotropin (ACTH)-dependent, originating either from a pituitary ACTHsecreting tumour (Cushing’s disease) or, less frequently, from nonpituitary tumours secreting ACTH (ectopic ACTH-secreting [EAS] tumours). About one-half of patients with EAS tumours have lung cancer, such as small-cell lung carcinoma and bronchial carcinoid tumours. However, the source of ACTH remains unidentified in about 8–19% of cases. Despite recent advances in endocrine investigations, no single test is accurate enough to distinguish between ectopic and pituitary sources of ACTH. Similarly, no single imaging modality is capable of identifying and localizing tumours responsible for ectopic ACTH secretion. The diagnostic utility of somatostatin receptor scintigraphy (SRS) with [In-DTPA]-octreotide (In-pentetreotide – Octreoscan) for the localization of EAS tumours has been evaluated in several studies with conflicting results. The development of novel positron emission tomography (PET) tracers which specifically bind to somatostatin receptors (SSTR2-5) permits the visualization of neuroendocrine tumours with higher sensitivity than other imaging procedures, such as CT or SRS. Several different DOTA-peptides such as [DOTA-Tyr]octreotide (DOTA-TOC), [DOTA1NaI]octreotide (DOTA-NOC) and [DOTA-Tyr]octreotate (DOTA-TATE) are used in the clinical setting, the main difference between these compounds being a slightly different affinity for SSTR subtypes. Ga-DOTA-peptides PET/CT is increasingly being used for diagnosis, therapy monitoring and follow-up of neuroendocrine tumours. To the best of our knowledge, however, only two ‘case reports’ have been published on the use of Ga-DOTA-peptides PET/CT in patients with EAS tumours. In particular, Gani and co-workers failed to localize a lung ACTH-secreting carcinoid tumour with Ga-DOTATOC PET/CT. Subsequent thoracotomy and removal of the nodule allowed the diagnosis eighteen months after the onset of symptoms. Conversely, Willhauck and co-workers detected an ACTH-positive neuroendocrine tumour of the right sphenoidal sinus using Ga-DOTATATE PET/CT. Previous extensive imaging procedures, including CT scan of chest and abdomen, SRS and magnetic resonance imaging of the chest and pituitary gland, had not succeeded in finding the source of ACTH secretion. We report our experience with Ga-DOTATOC PET/CT in five patients with clinical and biochemical evidence of EAS tumours of unknown origin. Among patients submitted to Ga-DOTATOC PET/CT at the European Institute of Oncology between 2008 and 2012, we retrospectively identified five (four females and one male, aged 37–67 years) who underwent the examination to identify the source of ectopic ACTH secretion. Patients 1 and 2 had repeated investigations over a period of four and 7 years, respectively, which failed to locate an ACTH ectopic source. Patient 3 had a newly diagnosed EAS tumour that was not detected by SRS and conventional imaging. Patients 4 and 5 had suspected lesions in the right lung and right pulmonary hilar region, respectively. Diagnosis of ACTH-dependent Cushing’s syndrome was based on standard biochemical criteria, and the suspicion of EAS originated from the absence of a central/ peripheral ACTH gradient during bilateral inferior petrosal sinus sampling in the two patients with pituitary adenomas (cases 3 and 5). PET/CT scans were carried out with a hybrid PET/CT scanner (Discovery; GE Medical System, Waukesha, WI, USA) 50 min after the intravenous administration of 3MBq/kg of Ga-DOTATOC. Neither the isotope nor the radiopharmaceutical gave adverse events. Visual analysis was performed on digital transaxial PET, CT and fused images; any focal uptake higher than the surrounding normal tissue (target to nontarget ratio – T/nT) was considered as a positive result. Lesions expressing somatostatin receptors were found in all patients. Patients 2 and 3 had a lung nodule smaller than one centimetre characterized by a modest uptake of the tracer (larger diameter 5 8 and 7 4 mm; T/NT equal to 6 1 and 2 9, respectively, – Fig. 1 a–b). A high uptake of tracer (T/NT equal to 9 7) confirmed the right pulmonary hilar lesion in patient 5 Correspondence: Giovanni Paganelli, Division of Nuclear Medicine, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. Tel.: 390257489043; Fax: 390294379223; E-mail: divisione.medicinanucleare@ieo.it

Improper use of “radioguided occult lesion localization” (ROLL) technique leads to misleading conclusions

Postma et al. [1] have compared radioguided occult lesion localization (ROLL) with wire-guided localization (WGL) in patients with non-palpable invasive breast carcinoma requiring surgery with sentinel node biopsy in a multicenter randomized controlled trial. Three hundred and fourteen patients were enrolled; 162 were allocated to ROLL and 152 to WGL. Primary outcome measures were the proportion of complete tumor excisions, the proportion of patients requiring re-excision and the volume of tissue removed. They concluded that the two procedures are comparable in terms of complete tumor excision and re-excision rates, but ROLL leads to the excision of larger tissue volumes and cannot replace WGL as the standard of care. In our opinion, the authors committed at least three mistakes that make their work less reliable . First of all they used Tc-nanocolloid (Tc-NC) as radiotracer for ROLL procedure. This is a comprehensible choice, as a single injection allowed the localization of non-palpable breast lesion and the identification of sentinel lymph node, but not the most effective one. The ROLL technique was introduced in 1997 at the European Institute of Oncology in Milan [2]. After the first experience, which proved that this procedure allowed rapid, easy, and accurate removal of occult breast lesions [3–6], the optimal lymphoscintigraphic method to detect both occult lesions and sentinel node (that was called SNOLL: sentinel node and occult lesion localization) was evaluated [7]. Two hundred and twenty-seven patients with non-palpable breast lesions were enrolled in the study. One hundred and forty-eight patients were submitted to the ROLL procedure using macroaggregates of Tc-labelled human serum albumin (Tc-MAA) injected directly into the lesion and also to lymphoscintigraphy with Tc-NC injected in peritumoral (62 patients) and subdermal site (86 patients). Seventy-nine patients received only an intratumoral injection of Tc-NC to perform both ROLL and sentinel node localization. The results showed that ROLL has a high rate of success (94.7 %), without significant differences among the groups. These findings demonstrated that NC may be used for lesion localization, but in some cases the surgeons had difficulties in delimiting the exact edge of the hot spot. This was probably due to the NC migration to the lymphatic vessels in the patients submitted to the single injection. On the contrary, MAA do not move from the injection site: consequently they do not adversely affect the radioguided tumor excision and do not determine an increase of the quantity of healthy tissue removed, as probably occurred in Postma et al. patients. Other two factors that we believe may have affected the results are the excessive volume and amount of injected radiotracer. Indeed, the authors performed an intratumoral injection of 120 MBq of Tc-NC in a volume of max 0.5 ml of saline and this could have contributed to the excision of a larger volume of tissue. In our previous papers, we used an amount of radiotracer 12–30 times as small as Postma’s one (from 3.7 to 7–10 MBq) in only 0.2 ml of saline [3–7], obtaining excellent results (that were reconfirmed on more than nine hundred patients submitted to the SNOLL procedure from 1997 to 2004 [8]) and implying negligible radiation risk for patients and medical staff [9]. G. Paganelli (&) L. Gilardi Division of Nuclear Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy e-mail: divisione.medicinanucleare@ieo.it