Cost-effectiveness analysis of imaging strategy for an intensive follow-up of patients with American Joint Committee on Cancer stage IIB, IIC and III malignant melanoma.

BACKGROUND: Many follow-up guidelines for patients with high-risk melanoma include expensive imaging studies, serum biomarkers and regular visits to the dermatologist, with little attention to cost-effectiveness. OBJECTIVES: To establish the cost-effectiveness of chest-abdomen-pelvis computed tomography (CT) and brain magnetic resonance imaging (MRI) in a follow-up protocol for patients at high risk of relapse. METHODS: This was a prospective single-centre cohort study of 290 patients with clinicopathological American Joint Committee on Cancer (AJCC) stage IIB, IIC and III melanoma. Patients had a body CT scan and brain MRI every 6 months and were withdrawn from the study after completing a 5-year follow-up or when metastases were detected. A cost-effectiveness analysis for each follow-up radiological procedure was performed. RESULTS: Patients underwent 1805 body CT scans and 1683 brain MRIs. Seventy-six metastases (26·2%) were identified by CT or MRI. CT scan was cost-effective in the first 4 years (cost-effectiveness ratio €4710·70-€14 437·10/patient with metastasis); brain MRI was cost-effective during the first year (cost-effectiveness ratio €14 090·60/patient with metastasis). Limitations included lack of survival analysis and comparisons with willingness-to-pay thresholds. CONCLUSIONS: Six-monthly CT scan of the chest, abdomen and pelvis is a cost-effective technique for the early detection of metastases in the first 4 years of follow-up in patients with AJCC stage IIC and III melanoma, and in the first 3 years in patients with AJCC stage IIB melanoma. In addition, brain MRI has been shown to be cost-effective only in the first year of follow-up in patients with AJCC stage IIC and III melanoma.

Dermoscopy structures as predictors of sentinel lymph node positivity in cutaneous melanoma.

BACKGROUND: Histological features such as Breslow thickness, ulceration and mitosis are the main criteria to guide sentinel lymph node biopsy (SLNB) in melanoma. Dermoscopy may add complementary information to these criteria. OBJECTIVES: To evaluate the correlation between dermoscopy structures and SLNB positivity. METHODS: Retrospective analysis of 123 consecutive melanomas with Breslow thickness > 0·75 mm, SLNB performed during follow-up and dermoscopic images. RESULTS: Men were more likely to have a positive SLNB. The presence of ulceration and blotch and the absence of a pigmented network in dermoscopy correlated with positive SLNB. Histological ulceration also correlated with positive SLNB. A dermoscopy SCORE predicted SLN status with a sensitivity of 96·3% and a specificity of 30·2%. When sex and Breslow thickness were added (SCOREBRESEX), the sensitivity remained at 96·3% but the specificity increased to 52·1%. This study is limited by the number of patients and was performed in only one institution. CONCLUSIONS: Dermoscopy allowed a more precise prediction of SLN status. If a combined SCOREBRESEX was used to select patients for SLNB, 41·5% of procedures might be avoided.

Multidisciplinary radio-guided surgery team: Alternative to change the current paradigm.

INTRODUCTION: Given the constant increase in the healthcare demand for examinations related to radio-guided surgery (RGS), our hospital adopted new professional profiles in the RGS team, in order to partially reduce the time spent by nuclear medicine physicians on this task. AIM: To analyze the process of incorporating the profiles of Diagnostic Imaging Technician (DIT) and Sentinel Node Referent Nurse (SNRN), evaluating their deployment in the procedures linked to the technique. MATERIAL AND METHODS: Analysis of RGS activity during the period 2018-2022, focusing on pre-surgical and surgical procedures related to breast cancer (BC) and malignant melanoma (MM), as they are those pathologies on which the transfer of care competencies was concentrated. Chronological evolution of the competencies assumed by the different profiles during their integration into the RGS team. RESULTS: RGS's healthcare activity during the analyzed period experienced an increase of 109%. BC and MM were the pathologies that accounted for by far the greatest demand for care. The transfer of competencies in these two pathologies occurred in a progressive and staggered manner, with 74% (460/622) of the administration phase being carried out by the SNRN and 64% (333/519) of the surgeries by the DIT in 2022. CONCLUSIONS: The creation of a multidisciplinary RGS team that includes different professional profiles (nuclear medicine physician [MN], ERGC and TSID) is an effective strategy to respond to the increase in the complexity and number of all procedures related to RGS.

Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.

BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Use of SPECT/CT for improved sentinel lymph node localization in endometrial cancer.

OBJECTIVE: To assess the usefulness of adding SPECT/CT to planar images for pre-surgical sentinel lymph node (SLN) identification in endometrial cancer (EC), a technique that could have an important clinical impact on the staging, treatment, and prognosis of EC patients. METHODS: We compared the planar and SPECT/CT lymphoscintigraphic images of 44 patients with high-risk EC who underwent sentinel lymph node procedure (SLN) using an injection technique recently developed at our center known as TUMIR (Transvaginal Ultrasound Myometrial Injection of Radiotracer). 148 MBq (4 mCi) of 99mTc-nanocolloid were injected, guided by transvaginal ultrasound imaging. Planar and SPECT/CT images were performed in all 44 patients. RESULTS: SLNs were seen on planar images in 32 cases (73%) and in 34 cases (77%) using SPECT/CT. A total of 88 SLNs were depicted by planar lymphoscintigraphy while SPECT/CT visualized a total of 110 SLNs. SPECT/CT changed the assessment of the SLNs visualized in planar lymphoscintigraphy in 26 cases, either by modifying the number and/or the location of the SLNs detected. External iliac chain was the most frequent location of SLN detection (71%) in the 34 cases. Fifteen of these patients (44%) showed para-aortic SLNs. One case had exclusive para-aortic drainage (3%) that was only visualized by SPECT/CT. In another case, SPECT/CT was able to localize the only pelvic metastatic lymph node not visualized by planar images. CONCLUSIONS: SPECT/CT combined with planar imaging improves preoperative SLN detection and provides valuable anatomic information that enhances the presurgical stage of the SLN technique in endometrial cancer.

Interventional nuclear medicine's contribution to molecularly targeted precision surgery.

The surgical approach to different pathologies, not only oncological, has evolved. As Veronesi's group has coined very graphically, we are moving from "maximum tolerable treatments to minimum effective treatments" and this journey cannot be carried out in any other way than through a multidisciplinary and multimodality approach. Multidisciplinary, because collaboration between surgeons, oncologists, radiologists, nuclear physicians, pathologists, and all those involved in patient follow-up is necessary, and multimodality, because we must move towards precision surgery tailored to each patient in which, on the part of Nuclear Medicine, hybrid imaging (SPECT/CT and PET/CT), bimodal tracers, the use of new allies such as ultrasound or our own adaptation to robotic surgery have a great deal to say. A wide range of possibilities is built on the solid foundation of preoperative scintigraphy, which makes it possible to identify the target tissues and whose knowledge prior to surgery allows the necessary surgical approach to be considered for each patient.

Sentinel node referent nurse: Description, validation and application in clinical practice.

INTRODUCTION: In 2019 the opportunity to add a nurse within the radioguided surgery (RGS) team was generated. The referent nurse model was adapted to, the sentinel node (SN) preoperative approaches. OBJECTIVES: To describe the process performed to define the sentinel node referent nurse (SNRN) profile, to validate its practical application and to establish its clinical implementation. MATERIAL AND METHODS: Methodology of analysis and continuous improvement in the management of processes (cycle PDCA): definition and planning of the SNRN functions in the breast cancer protocol, performance of a pilot test with 20 patients and analysis of the data in order to validate the circuit and establish its final clinical implementation. RESULTS: New procedure flows-charts were elaborated, adding the figure of the SNRN, its function and nursing interventions during the process. In the pilot test a 58.3% reduction in subjective anxiety, a 75% decrease of the overall anxiety level, a 100% knowledge of the test and an acceptable patient perception of pain's level during the radiotracer administration were obtained. Regarding technical quality, 8/10 items assessed reached the level previously established by the RGS team. CONCLUSIONS: The increasing complexity of the SN biopsy technique has created the opportunity to implement nursing care in the presurgical SN localization process. The profile of the SNRN is ideal for carrying it out and has led to improvements in the nursing diagnoses and assessed items.

Radioguided surgery in primary hyperparathyroidism: a review of the different available techniques. / Cirugía radioguiada en el hiperparatiroidismo primario: revisión de las diferentes técnicas disponibles.

Parathyroidectomy has evolved over the years from bilateral neck exploration to a single gland approach using minimally invasive surgery. The precise presurgical localization of the problem gland, using functional techniques, such as double-phase scintigraphy with [99mTc] Tc-MIBI including SPECT-CT and PET-CT with [18F]-Choline and morphological ones, such as ultrasound have played a crucial role in this paradigm's shift. Radioguided surgery techniques have also adapted and grown with new contributions known for their indication in other fields. Thus, we currently have a wide range of techniques that have been added to the minimally invasive radioguided parathyroidectomy with [99mTc] Tc-MIBI, which was the first on the stage and for which more experience exists. Among them, in this update, we will discuss parathyroidectomy using ultrasound-guided ROLL technique as well as with the use of 125I seeds and finally, hybrid techniques that use radiotracer and fluorescence.

[Added value of prone position technique for PET-TAC in breast cancer patients]. / Valor añadido de la técnica en decúbito prono para el estudio con tomografía por emisión de positrones-tomografía computarizada en las pacientes con cáncer de mama.

AIM: This study has aimed to assess if the prone position shows significant differences in regards to the supine position in PET/CT studies in breast cancer patients and to determine which modality offers better evaluation of the images. METHOD: A total of 30 patients were included from October 2009 to February 2010 prior to beginning neoadjuvant chemotherapy. An intravenous (18)F-FDG dose ranging from 180 to 240 MBq was administered. Image acquisition was begun 60 ± 10 min after injection. First of all, a thorax scan was performed with the patient in prone position, followed by a whole body study with the patient in supine position. RESULTS: Uptake in tumor lesions was observed in all of the patients. Twenty-four patients (80%) had the same number of lesions with both techniques. Five patients (17%) had a different amount of axillary lymph nodes. One patient (3.3%) had a different number of lesions. The prone position lesions had a mean SUVmax 8.89 ± 4.18 compared to 7.67 ± 4.34 in supine position. The areas of the primary breast lesions were higher in the prone position (8.59 ± 7.80 compared with 7.81 ± 7.39). Mean SUVmax of axillary nodes was 5.97 ± 4.02 in prone and 4.41 ± 3.10 in supine. CONCLUSION: The hanging breast technique can achieve higher lesion visualization as well as higher semiquantitative values in comparison with standard procedure. This supports its inclusion in acquisition guidelines of PET/CT imaging in breast cancer patients.

Prognostic value of tyrosinase reverse transcriptase PCR analysis in melanoma sentinel lymph nodes: long-term follow-up analysis.

OBJECTIVE: To determine the prognostic value of detecting tyrosinase transcripts in melanoma sentinel lymph nodes (SLNs). METHODS: Reverse transcription (RT) PCR for tyrosinase mRNA was performed on negative SLNs of 76 patients with melanoma. RESULTS: Tyrosinase mRNA was found in 39 patients (51.3%). After a median follow-up period of 51 months, significant differences were found in overall survival (OS) but not in disease-free survival (DFS). The 5-year OS and DFS rates were 97.2% and 80%, respectively, for RT-PCR tyrosinase-negative (TN) patients vs. 78.67% and 66.24% for RT-PCR tyrosinase-positive (TP) patients (P = 0.019 and P = 0.38, respectively). Of four progressing patients in the TN group, three relapsed with subcutaneous, soft-tissue or lymph-node metastases, while seven out of nine progressing patients in the TP group relapsed at visceral sites. CONCLUSIONS: No significant differences in DFS were found by RT-PCR tyrosinase expression analysis at melanoma SLNs. Significant differences in OS could be related to a different pattern of relapse and must be confirmed after a longer follow-up time.

Monitoring system for isolated limb perfusion based on a portable gamma camera.

BACKGROUND: The treatment of malignant melanoma or sarcomas on a limb using extremity perfusion with tumour necrosis factor (TNF-alpha) and melphalan can result in a high degree of systemic toxicity if there is any leakage from the isolated blood territory of the limb into the systemic vascular territory. Leakage is currently controlled by using radiotracers and heavy external probes in a procedure that requires continuous manual calculations. The aim of this work was to develop a light, easily transportable system to monitor limb perfusion leakage by controlling systemic blood pool radioactivity with a portable gamma camera adapted for intraoperative use as an external probe, and to initiate its application in the treatment of MM patients. METHODS: A special collimator was built for maximal sensitivity. Software for acquisition and data processing in real time was developed. After testing the adequacy of the system, it was used to monitor limb perfusion leakage in 16 patients with malignant melanoma to be treated with perfusion of TNF-alpha and melphalan. RESULTS: The field of view of the detector system was 13.8 cm, which is appropriate for the monitoring, since the area to be controlled was the precordial zone. The sensitivity of the system was 257 cps/MBq. When the percentage of leakage reaches 10% the associated absolute error is +/-1%. After a mean follow-up period of 12 months, no patients have shown any significant or lasting side-effects. Partial or complete remission of lesions was seen in 9 out of 16 patients (56%) after HILP with TNF-alpha and melphalan. CONCLUSION: The detector system together with specially developed software provides a suitable automatic continuous monitoring system of any leakage that may occur during limb perfusion. This technique has been successfully implemented in patients for whom perfusion with TNF-alpha and melphalan has been indicated.

[Sentinel node in gynaecological cancers. Our experience]. / Ganglio centinela en cánceres ginecológicos. Nuestra experiencia.

UNLABELLED: Although sentinel lymph node (SLN) identification is widespread used in melanoma and breast cancer some concerns exist in other malignancies, such gynaecologic cancers, and this staging method has not been adopted in many centers due to lack or large validation studies. AIM: To evaluate the applicability and results of SLN technique in gynaecological malignancies referred to our institution. METHOD: We studied 155 patients with different malignancies (70 vulvar, 50 cervical and 35 endometrial cancers). The day before surgery a lymphoscintigraphy was performed by injecting 111 MBq of (99m)Tc-nanocolloid in several ways depending on the type of cancer studied. Intraoperative detection of the SLN was always performed by using a hand-held gammaprobe and, in 100 cases with the aid of blue dye injection (70 vulvar and 30 in cervical cancer) few minutes before surgical intervention. Pathological study of SLN was performed in all cases. Lymphadenectomy was done in all cervix and endometrial cancer patients and in the first 35 vulvar cancer patients. RESULTS: Pre-surgical lymphoscintigraphy demonstrated one, at least, SLN in 97% of vulvar cancer patients, 92% in the cervical malignancy and 64% in the endometrial cancer patients. During surgery, SLN was harvested in 97%, 90% and 62% of patients, respectively. The pathological study showed metastases in 24.2%, 8.8 and 4.5% of patients with vulvar, cervical and endometrial cancer, respectively. The false negative percentage was 5.5% in vulvar cancer patients, with 2 cases in the endometrial cancer and without any case in the cervical cancer patients. CONCLUSION: Lymphoscintigraphy is a relatively simple and useful technique to identify the SLN in this kind of tumours. However, in endometrial cancer more effort has to be made to reach a suitable result. Sentinel lymph node biopsy seems to be a reliable technique in vulvar and cervical malignancies.

Update on radioguided surgery: from international consensus on sentinel node in head and neck cancer to the advances on gynaecological tumors and localization of non-palpable lesions. / Actualización en cirugía radioguiada: del consenso internacional en ganglio centinela de cabeza y cuello a los avances en tumores ginecológicos y localización de lesiones no palpables.

The aim of this review is to provide an updated perspective on different fields of radioguided surgery. With reference to the sentinel lymph node biopsy in oral squamous cell carcinoma, we present the results of the interactive debate held at the recent Congress of our specialty about the more relevant aspects of the London Consensus. Drainage peculiarities and indications according to the current guidelines on gynaecological tumours, endometrial and cervical cancer, are detailed and new scenarios for nuclear medicine physicians are presented; robotic surgery and hybrid tracers, for instance. Moreover, the notable growth in radioguided surgery indications for non-palpable lesions, widely used in mammary pathology, make it advisable to update two procedures which have shown satisfying results, such as the solitary pulmonary nodule and the osteoid osteoma.

[Application of the ROLL technique in a case of bilateral multifocal breast cancer]. / Aplicación de la técnica ROLL en un caso de cáncer de mama multifocal bilateral.

The increasing number of non-palpable breast lesions and the trend to perform less aggressive surgical procedures have prompted the development of radioguided surgery in breast lesions, alone (ROLL) or with sentinel node detection. We present a 55-year-old woman with four mammary lesions diagnosed by magnetic resonance. The ROLL technique allowed not only their characterisation but also the study of the lymphatic drainage of malignant lesions. Moreover, it was useful as a guide for surgical biopsy of the benign lesions. The combination of different colloid size allowed an accurate study of each lesion and avoided radical surgery. The applications of radioguided surgery are ever increasing. Individualisation of each indication will benefit a greater number of patients.

[In-transit sentinel lymph nodes in malignant melanoma. What is their importance?]. / Ganglios centinela ''en tránsito'' en el melanoma maligno. Cuál es su importancia?

UNLABELLED: The sentinel lymph node (SLN) is the first node in a lymph node basin to receive direct drainage from the primary tumour. However, in some cases, lymphoscintigraphy images demonstrate the presence of lymph nodes located in the area between the primary tumour and the first regional lymph node basin. These nodes are called in-transit nodes and have to be considered SLNs as well. AIM: It was to determine the incidence and location of in-transit SLNs in patients with malignant melanoma and to evaluate whether it is necessary to harvest them. METHOD. Nine hundred patients with malignant melanoma were included. Lymphoscintigraphy was performed on the day before surgery following intradermal injection of 74-111 MBq of 99mTc-Nanocolloid in four doses around the primary lesion or the biopsy scar. RESULTS: The presence of in-transit SLNs was revealed in 80 patients. During surgery, in-transit SLNs were identified and excised in all but 3 patients (96.2 %). Metastatic cell deposits were identified in these in-transit SLNs in 15 patients (19.4 %), with 4 patients with no tumour involvement of the regional lymph node basin. CONCLUSIONS: Lymphoscintigraphy is mandatory in the location of in-transit SLNs. Moreover, although the incidence of these nodes is relatively low in malignant melanoma, the presence of metastatic cells in these in-transit SLNs reaches a significant percentage. Therefore, excision of in-transit SLNs is necessary in all cases.

Next generation of radiotracers for sentinel lymph node biopsy: What is still necessary to establish new imaging paradigms? / Nueva generación de radiotrazadores para la biopsia del ganglio centinela: ¿qué es necesario para establecer nuevos paradigmas de imagen?

Sentinel lymph node (SLN) biopsy is now the standard of care for regional staging in several solid tumors. The interstitial administration of a radiotracer around the primary tumor provide the possibility to sequentially obtain images with a gamma camera and visualize lymphatic mapping and the SLN. There is, however, a large geographical variability in those radiotracers and nanocolloids ranging from 15-100nm which are most widely employed in Europe, while filtered and unfiltered 99mTc-sulfur colloid (range 20-1000nm) is usually used in the USA with different drawbacks in its use. The new radiotracer 99mTc-Tilmanocept, designed specifically for the identification of SLNs and recently becoming commercially available in USA and Europe, appears to have the potency to overcome the shortcomings described for the conventional radiotracers used until now for SLN biopsy and at the same time to transform current imaging paradigms. After delineating the challenges for the next generation of radiotracers, this paper discusses the properties of 99mTc-Tilmanocept, its validation process for SLN biopsy and its emerging clinical applications in various malignancies.

Multimodal approach in radioguided surgery in a case of multiple paraganglioma. / Abordaje multimodal en la cirugía radioguiada de un caso de paraganglioma múltiple.

The case involves a 34-year-old woman who underwent surgical removal of a retroperitoneal paraganglioma adjacent to the left kidney's lower pole, previously visualized by CT and MRI. The 123I-MIBG scan was positive for this lesion and, in addition, another uptake was observed located caudally at the level of L5 and of smaller size and less intensity. The second lesion was not considered for surgical removal, due to its lack of morphological definition. One week after surgical intervention, the patient presented difficult-to-control high blood pressure. A second 123I-MIBG scan was performed. The previously described second image was more intense in this study, and surgery was planned to remove it. A combination of techniques including freehand-SPECT and a portable hybrid gamma camera (with optical camera) were used pre-operatively to identify the location of the lesion. The combination of intra-operative laparoscopic gamma probe and portable hybrid gamma camera enabled the tumor to be located, excised, and its complete removal to be monitored. The histopathology analysis confirmed a second paraganglioma.

Review of the role of the sentinel node biopsy in neoadjuvant chemotherapy in women with breast cancer and negative or positive axillary node at diagnosis. / Actualización de la biopsia del ganglio centinela tras quimioterapia neoadyuvante en el cáncer de mama sin y con afectación ganglionar al diagnóstico.

The role of the selective sentinel node biopsy (SNB) is increasing in relevance in breast cancer women with indication of neoadjuvant chemotherapy (NAC). The Radiosurgery Working Group of the SEMNIM is aware of the necessity of establishing the need for SNB before or after NAC, and also how to manage patients with axillary node-negative or node-positive. There is sufficient data to assess that the SNB with radioisotope techniques are feasible and safe in all these scenarios. An adequate axilla evaluation prior to surgery and the possibility of marking prior to NAC the nodes infiltrated must be the two main pillars to guarantee the success of the SNB. It has been shown that to incorporate the SNB in breast cancer women with indication of NAC increases the rate of a conservative treatment of the axilla that will be a clear benefit for these patients.

From interventionist imaging to intraoperative guidance: New perspectives by combining advanced tools and navigation with radio-guided surgery. / De la imagen intervencionista a la guía intraoperatoria: nuevas perspectivas combinando herramientas avanzadas y navegación con la cirugía radioguiada.

The integration of medical imaging technologies into diagnostic and therapeutic approaches can provide a preoperative insight into both anatomical (e.g. using computed tomography, magnetic resonance imaging, or ultrasound), as well as functional aspects (e.g. using single photon emission computed tomography, positron emission tomography, lymphoscintigraphy, or optical imaging). Moreover, some imaging modalities are also used in an interventional setting (e.g. computed tomography, ultrasound, gamma or optical imaging) where they provide the surgeon with real-time information during the procedure. Various tools and approaches for image-guided navigation in cancer surgery are becoming feasible today. With the development of new tracers and portable imaging devices, these advances will reinforce the role of interventional molecular imaging.