Sara Mazzarri

Sentinel lymph node mapping in melanoma: the issue of false-negative findings.

Abstract Management of cutaneous melanoma has changed after introduction in the clinical routine of sentinel lymph node biopsy (SLNB) for nodal staging. By defining the nodal basin status, SLNB provides a powerful prognostic information. Nevertheless, some debate still surrounds the accuracy of this procedure in terms of false-negative rate. Several large-scale studies have reported a relatively high false-negative rate (5.6%–21%), correctly defined as the proportion of false-negative results with respect to the total number of “actual” positive lymph nodes. In this review, we identified all the technical aspects that the nuclear medicine physician, the surgeon, and the pathologist should take into account to improve accuracy of the procedure and minimize the false-negative rate. In particular, SPECT/CT imaging detects more SLNs than those found by planar lymphoscintigraphy. Furthermore, the nuclear medicine community should reach a consensus on the radioactive counting rate threshold to better guide the surgeon in identifying the lymph nodes with the highest likelihood of housing metastases (“true biologic SLNs”). Analysis of the harvested SLNs by conventional techniques is also a further potential source for error. More accurate SLN analysis (eg, molecular analysis by reverse transcriptase–polymerase chain reaction) and more extensive SLN sampling identify more positive nodes, thus reducing the false-negative rate. The clinical factors identifying patients at higher-risk local recurrence after a negative SLNB include older age at diagnosis, deeper lesions, histological ulceration, and head-neck anatomic location of the primary lesion. The clinical impact of a false-negative SLNB on the prognosis of melanoma patients remains controversial, because the majority of studies have failed to demonstrate overall statistically significant disadvantage in melanoma-specific survival for false-negative SLNB patients compared with true-positive SLNB patients. When new more effective drugs will be available in the adjuvant setting for stage III melanoma patients, the implication of an accurate staging procedure for the sentinel lymph nodes will be crucial for both patients and clinicians. Standardization and accuracy of SLN identification, removal, and analysis are required.

Sentinel Lymph Node Biopsy in Breast Cancer: Indications, Contraindications, and Controversies.

Abstract Axillary lymph node status, a major prognostic factor in early-stage breast cancer, provides information important for individualized surgical treatment. Because imaging techniques have limited sensitivity to detect metastasis in axillary lymph nodes, the axilla must be explored surgically. The histology of all resected nodes at the time of axillary lymph node dissection (ALND) has traditionally been regarded as the most accurate method for assessing metastatic spread of disease to the locoregional lymph nodes. However, ALND may result in lymphedema, nerve injury, shoulder dysfunction, and other short-term and long-term complications limiting functionality and reducing quality of life. Sentinel lymph node biopsy (SLNB) is a less invasive method of assessing nodal involvement. The concept of SLNB is based on the notion that tumors drain in an orderly manner through the lymphatic system. Therefore, the SLN is the first to be affected by metastasis if the tumor has spread, and a tumor-free SLN makes it highly unlikely for other nodes to be affected. Sentinel lymph node biopsy has become the standard of care for primary treatment of early breast cancer and has replaced ALND to stage clinically node-negative patients, thus reducing ALND-associated morbidity. More than 20 years after its introduction, there are still aspects concerning SLNB and ALND that are currently debated. Moreover, SLNB remains an unstandardized procedure surrounded by many unresolved controversies concerning the technique itself. In this article, we review the main indications, contraindications, and controversies of SLNB in breast cancer in the light of the most recent publications.

Sentinel Lymph Node Biopsy in Cutaneous Melanoma: Standard and New Technical Procedures and Clinical Advances. A Systematic Review of the Literature.

Abstract Melanoma is an important public health problem, and its incidence is increasing worldwide. The disease status of regional lymph nodes is the most important prognostic factor in early-stage melanoma patients. Sentinel lymph node biopsy (SLNB) was introduced in the early 1990s as a less invasive procedure than complete lymph node dissection to allow histopathologic evaluation of the “sentinel lymph node” (SLN), which is the first node along the lymphatic pathway from a primary tumor. Sentinel lymph node biopsy has minimal complication risks compared with standard complete lymph node dissection. Currently, SLNB is the accepted method for staging patients with clinically node-negative cutaneous melanoma and provides the most powerful prognostic information by evaluating the nodal basin status. The current practice of SLNB consists of the injection of 99mTc-labeled radiopharmaceutical, preoperative lymphoscintigraphy with the possibility of using the SPECT/CT hybrid imaging, and intraoperative SLN localization using a handheld gamma probe with or without the use of blue dye. Recently, the SLN localization and detection have been enhanced with the use of new tracers and new intraoperative devices, which have demonstrated to be particularly useful in melanomas of the head and neck region and in area of complex anatomy. Despite these important advances in the technology and the increasing experience in SLN mapping, major research centers have reported a false-negative rate higher than 15%. This relatively high false-negative rate, greater than those reported in the initial validation studies, points out the importance for the nuclear medicine community to continuously improve their knowledge on the biological behavior of melanoma and to improve the technical aspects that may allow more precise staging. For the SLNB procedure to be accurate, it is of critical importance that all “true” SLNs are identified and removed for examination. The aim of this article is to provide general information about the SLNB procedure in clinical practice highlighting the importance of standardization and accuracy of SLN identification in the light of the most recent technical innovations.

Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer

The role of nuclear medicine physicians in the multidisciplinary team for the management of patients with prostate cancer has been restricted because of a lack of available tools. The only drugs approved to relieve pain related to bone metastases were β-emitting radiopharmaceuticals. These drugs did not prove to prolong survival when used as single agent and resulted associated with important adverse events. This situation has changed with the introduction of radium 223 because of evidence of improved survival in patients, the good safety profile and the opportunity to avoid clonal selection of tumor cells. Cooperation among physicians involved in cancer management will lead to improvements in the treatment of bone metastases due to prostate cancer and is thought to extend to other tumor types.

Safety and antitumor efficacy of 153Sm-EDTMP and docetaxel administered sequentially to patients with metastatic castration-resistant prostate cancer

BackgroundBone metastases are responsible for most of the morbidity associated with metastatic castration-resistant prostate cancer (mCRPC). Bone-seeking radiopharmaceuticals have been approved for palliation of painful skeletal metastases, but their clinical use is limited by concerns of toxicities both when administered alone and especially when combined with chemotherapy agents. ObjectiveWe investigated whether docetaxel administered to mCRPC patients after treatment with samarium-153-labeled ethylene-diamine-tetra-methylene-phosphonic acid (153Sm-EDTMP) has increased toxicity and/or reduced antitumor efficacy. Materials and methodsThirty mCRPC patients with skeletal metastases were enrolled. Patients received standard therapy with docetaxel (75 mg/m2 intravenously every 21 days for at least six cycles) on average 6 weeks after 153Sm-EDTMP (37 MBq/kg). Patients were monitored for the presence of toxicities, and antitumor efficacy was assessed by changes in serum prostate-specific antigen levels. Besides standard descriptive statistical analysis, progression-free survival and overall survival were defined using the Kaplan–Meier method. ResultsOver 80% of the patients showed favorable biochemical responses. Median time to progression was 9.1 months (mean 9.8, 95% confidence interval 7.8–9.9), and median overall survival was 19.9 months (mean 24.5, 95% confidence interval 16.9–22.8); five patients were still alive over 5 years after enrollment. No additional hematological toxicities were observed when docetaxel was administered after 153Sm-EDTMP other than those expected when administering the agent alone. ConclusionPrior administration of 153Sm-EDTMP does not cause additional toxicities for subsequent treatment with docetaxel and does not reduce the antitumor efficacy of the latter. This work justifies further investigations on the possible synergistic effects of combined strategies with the two agents.

Sentinel lymph node biopsy of oral/oropharyngeal squamous cell carcinoma: techniques, indications, advantages, and accuracy.

S quamous cell carcinoma of the upper aerodigestive tract represents 90% of all the malignant tumors that develop in the head and neck. Oral/oropharyngeal squamous cell cancer (OSCC) is one of the most frequent cancers worldwide, with around 300,000 new cases each year. An approximate 75% of cases affect people in the developing world, whereas OSCC is the eighth most prevalent type of tumor in developed countries. The tongue is the most common site of OSCC, followed by the floor of the mouth, lip, gingiva, and retromolar trigone. Prognosis depends on the stage of the disease, and mortality ranges from 10% for stage I to 70% for stage IV tumors. The neck is a crucial point in the management of OSCC. The 5-year survival rate of tongue squamous cell carcinoma is 73% for pN0 cases, 40% for positive nodes without extracapsular spread (pN + ECS−), and 29% for positive nodes with extracapsular spread (pN + ECS+: P < 0.00001). The likelihood of neck nodal metastasis is dependent on the location, size, grading, and infiltration depth of the tumor. Oropharynx and hypopharynx are at highest risk. At diagnosis of the primary lesion, the tonsil, hypopharynx, base of the tongue, and supraglottic larynx have, respectively, 73%, 70%, 65%, and 55% rates of nodal metastases, and neck nodes are often the first sign of OSCC. Neck nodal metastases can be diagnosed preoperatively in more than 90% of patients by palpation combined with either ultrasonography, CT, MR, F-FDG PETwith or without low-dose CT (PET/CT), or fine needle aspiration cytology. The principal clinical problem consists in detecting the micrometastases that are found in up to 50% of OSCC patients (cN0 pN1) undergoing neck dissection. There are currently no clinical staging modalities, biological markers, or imaging diagnostic tools capable of reliably identifying occult nodal micrometastases; therefore, treatment of the N0 neck in OSCC patients is controversial. After removal of the primary lesion, the “wait-and-see” approach (observation with neck dissection only if nodal metastases develop) has been proposed for patients considered at low risk of lymphatic metastases on the basis of small size (<2 cm), minimal depth of invasion (<4 mm), and favorable histological differentiation. Depth of invasion is the pathological feature commonly adopted to select patients for the wait-and-see approach. However, a study involving a large series of OSCC patients showed that tumor thickness was not a statistically significant predictor of nodal metastases, unlike tumor differentiation,

Preoperative and Intraoperative Lymphatic Mapping for Radioguided Sentinel Node Biopsy in Breast Cancer

Axillary lymph node status still is a major prognostic factor in early-stage breast cancer, providing information that is important for tailoring post-surgical treatment [1,2].

223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience

Background: Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. Methods: A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. Results: Patients had a median age of 75 (range 53–89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved (p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. Conclusions: 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases.

Radioguided Occult Lesion Localization: Technical Procedures and Clinical Applications

Purpose Regarding radioguided surgery, the concept of “radioguided occult lesion localization” (ROLL) is based on both preoperative interventional imaging and intraoperative radioguided detection of a clinically occult neoplastic lesion. Methods This methodology consists in the direct administration into the lesion of 99mTc–macroaggregated human albumin formed by relatively large particles retained at the injection site, which direct radioguided excisional biopsy. Results This modality has expanded from the classic application of ROLL for nonpalpable breast lesions to other tumors, such as solitary pulmonary nodules or recurrences from differentiated thyroid carcinoma. In 2011, in order to improve the classification of different radioguided surgical procedures, ROLL applications were included in the more complete concept of GOSTT (Guided intraOperative Scintigraphic Tumor Targeting). This concept was introduced to include the entire range of basic and advanced radioguided procedures necessary to supply a “road map” for the surgeon. Conclusions The terms ROLL and GOSTT have further developed by incorporating novel modalities such as hybrid tracers for simultaneous fluorescence and radioactive signal detection and innovative navigation systems based on mixed-reality protocols.

Disseminated bone metastases from occult thyroid cancer effectively treated with debulking surgery and a single dosimetry-guided administration of radioiodine

In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity.