Matteo Salgarello

Small-animal radionuclide luminescence imaging of thyroid and salivary glands with Tc99m-pertechnetate

Abstract. The in vitro and in vivo detection of visible photons from radioisotopes using optical techniques is a fast-growing field in molecular imaging. Tc99m-pertechnetate is used as an alternative to I123 in imaging of the thyroid and is generally imaged with gamma cameras or single photon emission tomography instruments. The uptake in the thyroid tissue is mediated by the sodium-iodide symporter (NIS), a glycoprotein that actively mediates iodide transport into the thyroid follicular cells and several extrathyroidal tissues. The luminescence of the gamma emitter Tc99m-pertechnetate in order to visualize its biodistribution in healthy small living animals by using a commercial optical imaging system is investigated. Here we show that in Nu/Nu mice, the uptake of Tc99m-pertechnetate in the thyroid gland and in salivary glands is very detectable by using radionuclide luminescence imaging. We also found light emission from the stomach in accordance with the literature. The localization of the light signals in the anatomical regions where the radiopharmaceutical is expected, confirmed by resections, shows that it is possible to image NIS-expressing tissues.

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

UNLABELLED : Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline- and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. IMPLICATIONS FOR PRACTICE Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

The role of 18fluoro-deoxyglucose positron emission tomography/computed tomography in resectable pancreatic cancer

BACKGROUND The role of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in pancreatic ductal adenocarcinoma is debated. We retrospectively assessed the value of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in addition to conventional imaging as a staging modality in pancreatic cancer. METHODS (18)Fluoro-deoxyglucose positron emission tomography/computed tomography was performed in 72 patients with resectable pancreatic carcinoma after multi-detector computed tomography positron emission tomography was considered positive for a maximum standardized uptake value >3. RESULTS Overall, 21% of patients had a maximum standardized uptake value ≤ 3, and 60% of those had undergone neoadjuvant treatment (P=0.0001). Furthermore, 11% of patients were spared unwarranted surgery since positron emission tomography/computed tomography detected metastatic disease. All liver metastases were subsequently identified with contrast-enhanced ultrasound. Sensitivity and specificity of positron emission tomography/computed tomography for distant metastases were 78% and 100%. The median CA19.9 concentration was 48.8 U/mL for the entire cohort and 292 U/mL for metastatic patients (P=0.112). CONCLUSIONS The widespread application of (18)fluoro-deoxyglucose positron emission tomography/computed tomography in patients with resectable pancreatic carcinoma seems not justified. It should be considered in selected patients at higher risk of metastatic disease (i.e. CA19.9>200 U/mL) after undergoing other imaging tests. Neoadjuvant treatment is significantly associated with low metabolic activity, limiting the value of positron emission tomography in this setting.

PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability

Immunotherapy with checkpoint inhibitors, allowing recovery of effector cells function, has demonstrated to be highly effective in many tumor types and represents a true revolution in oncology. Recently, the anti-PD1 agent pembrolizumab was granted FDA approval for the first line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors show PD-L1 expression in ≥ 50% of neoplastic cells and as a second line treatment for patients with NSCLC expressing PD-L1 in ≥1% of neoplastic cells, evaluated with a validated assay. For the large majority of patients such evaluation is made on small biopsies. However, small tissue samples such as core biopsies might not be representative of tumors and may show divergent results given the possible heterogeneous immunoexpression of the biomarker. We therefore sought to evaluate PD-L1 expression concordance in a cohort of 239 patients using tissue microarrays (TMA) as surrogates of biopsies stained with a validated PD-L1 immunohistochemical assay (SP263) and report the degree of discordance among tissue cores in order to understand how such heterogeneity could affect decisions regarding therapy. We observed a discordance rate of 20% and 7.9% and a Cohens κ value of 0.53 (moderate) and 0,48 (moderate) for ≥ 1% and ≥ 50% cutoffs, respectively. Our results suggest that caution must be taken when evaluating single biopsies from patients with advanced NSCLC eligible for immunotherapy; moreover, at least 4 biopsies are necessary in order to minimize the risk of tumor misclassification.

Stereotactic Ablative Radiation Therapy for Lung Oligometastases: Predictive Parameters of Early Response by (18)FDG-PET/CT

Objectives: The objective of this study was to investigate fludeoxyglucose F 18 positron emission tomography/computed tomography (18FDG‐PET/CT) parameters as predictive of response after stereotactic ablative radiotherapy (SABR) for lung oligometastases. Methods: The inclusion criteria of the current retrospective study were as follows: (1) lung oligometastases treated by SABR, (2) presence of 18FDG‐PET/CT before and after SABR for at least two subsequent evaluations, (3) Karnofsky performance status higher than 80, and (4) life expectancy longer than 6 months. All patients were treated with a biologically equivalent dose of at least 100 Gy with an alpha/beta ratio of 10. The following metabolic parameters were semiquantitatively defined: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume, and total lesion glycolysis. Results: A total of 50 patients met the inclusion criteria, for a total of 70 lung metastases. The pre‐SABR median SUVmax was 6.5 (range 4–17), the median SUVmean was 3.7 (range 2.5–6.5), and the median metabolic tumor volume was 2.3 cm3 (0.2–31 cm3). The following metabolic parameters were significantly related to complete response at 6 months: SUVmax less than 5 (p < 0.001) and SUVmean less than 3.5 (p = 0.03). &Dgr;SUVmax at 3 to 6 months was +126% for lesions with in‐field progression versus –26% for the remaining lesions (p = 0.002). &Dgr;SUVmean at 3 to 6 months was +15% for lesions with in‐field progression versus –26% for the remaining metastases (p = 0.008). Conclusions: In the current analysis, complete response from lung metastasis at 6 months after stereotactic body radiation therapy was significantly associated with both the maximum and mean values of pre‐SABR 18FDG‐PET/CT SUV. Longer‐term trials are strongly advocated to improve the personalization of the monitoring of tumor response in patients with lung oligometastases and, consequently, monitoring of the cost‐effectiveness of the health care.

Clinical Usefulness of 18F‐Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero‐Pancreatic Neuroendocrine Neoplasms

BACKGROUND The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. RESULTS A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F-FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F-FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). CONCLUSION 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. IMPLICATIONS FOR PRACTICE The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

18F-NaF PET/CT Imaging of Brain Metastases.

F-NaF is a radiopharmaceutical widely used in PET imaging to detect bone metastases. Several cases of F-NaF uptake from brain metastases have been described, but a specific protocol for the evaluation of brain metastases with F-NaF has not been developed yet. Here we report images of F-NaF PET/CT, standard CT, and MRI of a brain metastasis in a patient with non-small lung cancer. Through a dynamic acquisition procedure, we have identified the first minutes after injection as the preferable time point of imaging acquisition for the study of brain metastases with F-NaF.

Laparoscopy for primary cytoreduction with multivisceral resections in advanced ovarian cancer: prospective validation. “The times they are a-changin”?

AbstractBackgroundPrimary cytoreduction is the mainstay of treatment for advanced ovarian cancer (AOC). We developed and prospectively evaluated an algorithm to investigate the possible role of laparoscopic primary cytoreduction (LPC) in carefully selected patients, with AOC.MethodsFrom June 2007 to July 2015, all patients with stage III–IV ovarian cancer and clinical conditions allowing aggressive surgery were candidate to primary cytoreduction with the aim of achieving residual tumor (RT) = 0. The possibility of attempting laparoscopic cytoreduction was carefully evaluated using strict selection criteria. The other patients were approached by abdominal primary cytoreduction (APC). At the end of LPC, an ultra-low pubic mini-laparotomy was performed to extract surgical specimens and to accomplish a laparoscopic hand-assisted exploration of the abdominal organs, in order to confirm complete excision of the disease.ResultsOf the included 66 patients, 21 were considered eligible for LPC; the remaining 45 underwent APC. Optimal cytoreduction (i.e., RT = 0) was obtained in 95 and 88.4% in the LPC and APC groups, respectively. No intra-operative complication and 4 (19%) early post-operative complications were observed among patients who received LPC. Patients who underwent APC had 17.8 and 46.7% intra- and early post-operative complications, respectively. Median time to initiation of chemotherapy was 15 (range, 10–30) days in the LPC group and 28 (20–35) days in the APC group. After a median follow-up of 51 months, 2-year disease-free survival was 76.2% in the LPC group and 73.4% in the APC group.ConclusionsAfter strict selection, a group of patients with AOC may undergo LPC with extremely high rates of optimal cytoreduction, satisfactory perioperative morbidity, a short interval to chemotherapy, and encouraging survival outcomes. Clinical trial registration NCT02980185

The role of combined Ga-DOTANOC and 18FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors

Purpose: The aim of this study was to evaluate the effect of combined ⁶⁸Ga and ¹⁸F-FDG PET/CT on treatment management for patients with pancreatic neuroendocrine tumor (PNET). Methods: Between January 2012 and April 2014, 49 consecutive patients with a cytologically and/or histologically proven diagnosis of PNET underwent combined ⁶⁸Ga and ¹⁸FDG PET/CT on the same day. Results: The study group consisted of 21 males and 28 females with a median age of 59 years. Disease detection was achieved in 48 out of the 49 cases with ⁶⁸Ga imaging, and in 36 of the 49 cases with ¹⁸FDG PET/CT. These results corresponded to sensitivities of 98% for ⁶⁸Ga versus 73% for ¹⁸FDG PET/CT. Patients with NET-G1/NET-G2 had a positive⁶⁸Ga and negative¹⁸FDG PET/CT in 13 cases, whereas both ⁶⁸Ga and ¹⁸FDG PET/CT were positive in 27 cases. Patients with NEC-G3 were positive by both ⁶⁸Ga and ¹⁸FDG PET/CT in 7 cases and positive only by ¹⁸FDG in 1 case. Another NEC-G3 patient was only positive by ⁶⁸Ga PET/CT. The median Ki67 was 7% for ⁶⁸Ga PET/CT-positive tumors and 10% for tumors with both ⁶⁸Ga and ¹⁸FDG PET/CT positivity (p = 0.130). Half of the patients with a prevalent uptake of ¹⁸FDG (n = 7) had an NEC-G3 compared with 12% of patients with a prevalent uptake of ⁶⁸Ga (p = 0.012). There were no significant differences between patients with positive ⁶⁸Ga and those with positive ¹⁸FDG with regards to treatment choice. Conclusions: The association of ¹⁸FDG slightly increases sensitivity of ⁶⁸Ga PET/CT alone in the diagnosis of PNET. A combined dual tracer PET/CT does not influence the choice of treatment strategy.

The evolving landscape of criteria for evaluating tumor response in the era of cancer immunotherapy: From Karnofsky to iRECIST

The objective response is an important endpoint to evaluate clinical activity of new anticancer drugs. Standardized criteria for evaluating response are needed for comparing results of different trials and represent the basis for advances in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 are the most used in clinical practice and in clinical trials; however, they are not able to capture atypical responses seen with immunotherapy drugs. We describe the evolution of response criteria with a special focus on the immune-related criteria.