The application of SLN biopsy for the surgical staging of the regional lymph node basins during cutaneous malignant melanoma surgery has become widely accepted as a standard of care for cutaneous malignant melanoma of the trunk, extremities, and head and neck region 185. To date, over 1,800 articles have been published which have been sited in PUBMED under the search descriptors of "melanoma" and "sentinel lymph node".

SLN biopsy in cutaneous malignant melanoma was first described in 1992 by Morton et al 186 using a technique of intradermally injected vital blue dye alone. In 1993, Uren et al 187 described a combined technique, consisting of preoperative lymphoscintigraphy (using ^99mTc antimony sulfide colloid) for identification of all sites of location that are simply marked on the skin surface with an indelible marker and of intraoperative intradermally injected vital blue dye (but without use of an intraoperative gamma detection probe), for SLN detection. Shortly thereafter in 1993, the intraoperative use of the gamma detection probe for radioguided SLN biopsy in cutaneous malignant melanoma was first reported by Alex et al 188 at The University of Vermont in ten patients using intradermally injected ^99mTc sulfur colloid (Table 1). Since that time, it has been clearly demonstrated that the use of radioguided SLN biopsy is superior to the vital blue dye alone technique for the surgical evaluation of at-risk nodal basins for cutaneous malignant melanoma 189190191192193194195196197198. The most compelling and well-respected international evidence for this comes from the Multicentric Selective Lymphadenectomy Trial Group results that were published in 1999 by Morton et al 193 on 570 melanoma patients. They demonstrated that the success of SLN identification was significantly improved by a combined radiocolloid and vital blue dye technique (n = 217) as compared to a vital blue dye alone technique (n = 352) (99.1% versus 95.2%, respectively; p = 0.014).

The primary ^99mTc-based agents utilized for radioguided SLN biopsy for cutaneous malignant melanoma are either ^99mTc sulfur colloid or ^99mTc colloidal human albumin (i.e., ^99mTc nanocolloid) 199200201202203204205206. Generally, these radiocolloid agents are most commonly administered one to six hours prior to the planned surgical procedure in a dosing range from 0.4 mCi (14.8 MBq) to 1 mCi (37 MBq). Radiocolloid is exclusively injected intradermally and is administered in one to four sites around the intact primary lesion or around the resultant excisional biopsy scar.

It is clearly evident that preoperative lymphoscintigraphy plays as important of a role as does intraoperative radioguided SLN biopsy for the successful identification of all potential SLN candidates during the surgical management of cutaneous malignant melanoma secondary to the potential for localization to multiple nodal basins 196203207208209210211212213214 and for localization to in-transit (interval) SLNs 215216217218219. For cutaneous malignant melanoma of the truncal region, preoperative lymphoscintigraphy localization to multiple nodal basins has been demonstrated in 17% to 32% of patient undergoing radioguided SLN biopsy 196203207208209210211212213214. Likewise, preoperative lymphoscintigraphy localization to in-transit (interval) SLNs has been demonstrated in 3% to 10% of patient undergoing radioguided SLN biopsy for cutaneous malignant melanoma of the extremities and of the head and neck region 215216217218219. Therefore, unlike other malignancies in which radioguided SLN biopsy can be performed without the antecedent need of preoperative lymphoscintigraphy, the radioguided surgical approach to cutaneous malignant melanoma should include both preoperative lymphoscintigraphy and intraoperative utilization of the gamma detection probe.

The determination of an adequate intraoperative assessment of any given nodal basin with the gamma detection probe during radioguided SLN biopsy for cutaneous malignant melanoma is clearly related to the meticulous intraoperative attention to attempting to identify all potential SLN candidates with counts of at least 10% of the counts of the hottest SLN 220221222223224225. The first compelling argument for the 10% rule for malignant melanoma came from work published by McMasters et al 221 from the Sunbelt Melanoma Trial in which they found that within 13.1% of positive lymph node basins that the most radioactive SLN was negative for tumor while a less radioactive sentinel lymph node was positive for tumor. Additionally, in 50% of such cases, they found that these less radioactive positive SLNs contained 50% or less of the radioactive counts of the hottest non-positive SLN. Similarly, Carlson et al 222 in 2002, Jacob et al 223 in 2003, and Kroon et al 224 in 2007 found in 19.1%, 19.0%, and 11.0% of all positive SLN cases, respectively, that the hottest SLN was negative for tumor. As a result, all these reports have strongly advocated applying the 10% rule to reduce the risk of a missed lymph node metastasis during radioguided SLN biopsy for cutaneous malignant melanoma 220221222223224225.

In addition to the vast body of data in the literature on the application of radioguided SLN biopsy for the surgical staging of conventional sites of cutaneous malignant melanoma (i.e., trunk, extremities, and head and neck region), various case reports and small series reports exist on the potential application of radioguided SLN biopsy for the surgical staging of less conventional sites of malignant melanoma, such as the ocular conjunctiva and periocular skin 226227228229230231232233234, the vulvar region 235236237238239240, the vagina 236238240241242, and the anal canal 243244245246247248. For all these less conventional sites of malignant melanoma, the feasibility of radioguided SLN biopsy has been demonstrated. However, larger scale evaluation of this technology for these less conventional sites of malignant melanoma is obviously necessary in order to better assess its clinical relevance.

The ¹⁸F-FDG avidity of malignant melanoma has made the application of ¹⁸F-FDG PET imaging paramount to the accurate staging and restaging of malignant melanoma 185. Likewise, ¹⁸F-FDG PET imaging and ¹⁸F-FDG PET/CT imaging have been shown to lead to a change in the clinical management of 17% to 39% of malignant melanoma patients, which is far greater than with other conventional imaging techniques alone 249250251252253. While preoperative utilization of ¹⁸F-FDG PET imaging has become a standard of care for the clinical management of selected cases of malignant melanoma, the intraoperative use of ¹⁸F-FDG in combination with gamma detection probe technology has also been proposed and described in the clinical management of selected cases of metastatic malignant melanoma and has received increasing interest within the surgical community 384041434752.

The intraoperative use of ¹⁸F-FDG in combination with gamma detection probe technology for selected cases of metastatic malignant melanoma was first reported in 2001 by Essner et al 38. Six patients were intravenously injected with 7 to 10 mCi (259 to 370 MBq) of ¹⁸F-FDG within three hours of the planned time of surgery. They reported that the tumor to background count ratio varied from 1.16:1 to 4.67:1, with eight of 13 melanoma metastases having a tumor-to-background count ratio of greater than 1.5:1. In 2005, Franc et al 41 reported on 5 patients with recurrent malignant melanoma that were injected with 14.6 ± 3.2 mCi (540 ± 118 MBq) of ¹⁸F-FDG. They found that the use of gamma detection probe technology had a sensitivity of 89% and a specificity of 100% for the detection of tissues containing recurrent malignant melanoma. More recently in 2006, Gulec et al 43 reported on 26 patients with either recurrent or metastatic malignant melanoma that were intravenously injected with 7 to 10 mCi (259 to 370 MBq) of ¹⁸F-FDG within one to four hours of the planned time of surgery. They found that the tumor-to-background ratio ranged from 1.5:1 to 2.5:1, with a mean of 1.8:1, and metastatic lesions as small as 5 mm were detected.

The specific application of a combined approach of preoperative ¹⁸F-FDG PET/CT imaging and intraoperative gamma detection probe technology for recurrent malignant melanoma was first described in 2005 by Carrera et al 40 in a patient intravenously injected with 6.8 mCi (250 MBq) of ¹⁸F-FDG at approximately four hours prior to the planned time of surgery, illustrating the potential advantage to a combination of these technologies. Furthermore, the added benefit to such combination technologies for ¹⁸F-FDG-directed surgery was most recently illustrated by our own group at The Ohio State University in which a multimodality approach of perioperative ¹⁸F-FDG PET/CT imaging (preoperative patient imaging, specimen imaging, and postoperative patient imaging), intraoperative gamma detection probe technology, and intraoperative ultrasound were utilized for tumor localization and resection of all sites of hypermetabolic activity in a case of occult recurrent metastatic malignant melanoma 52. In this case, the patient was intravenously injected with 12.8 mCi (474 MBq) of ¹⁸F-FDG at approximately 80 minutes prior to the planned time of surgery and this multimodality approach allowed for successful identification and resection of all three occult sites of recurrent metastatic malignant melanoma. Such refinements in multimodal ¹⁸F-FDG-directed surgery 4052 may allow this approach to further positively impact upon the established survival advantage of complete surgical resection for malignant melanoma patients with limited metastatic disease 254.

The concept of RIGS in colorectal cancer 58 was first introduced in 1984 by the work of Aitken and colleagues 289290 at The Ohio State University (Table 1). Using CEA-producing human colonic adenocarcinoma cells (CX-1) grown as tumor xenografts that were subcutaneously implanted on the flank in Swiss nude mice, they demonstrated the feasibility of gamma probe detection of ¹³¹I-labeled anti-CEA polyclonal baboon antibodies within such subcutaneous implants and demonstrated the greater sensitivity of the gamma detection probe as compared to gamma camera imaging for small tumor implants 289290. In addition to these experimental results in mice, they also reported the first clinical application of RIGS in a case study of a 59 year-old male with a rectal carcinoma 290. The handheld gamma probe detected an increased level of the ¹³¹I-labeled anti-CEA polyclonal baboon antibody in the rectal tumor (135 counts/minute) compared to the sigmoid colon (111 counts/minute).

Shortly thereafter, Martin et al. 291 reported the results of the first RIGS clinical series involving 28 patients with primary (n = 12) and recurrent (n = 16) colorectal cancer. Each patient was injected intravenously with 2.2 mCi (81.4 MBq) of ¹³¹I baboon polyclonal anti-CEA antibody at approximately 48 to 72 hours prior to surgery. Twenty-three patients underwent preoperative scintigraphy. In all patients, intraoperative counts (20 seconds per count) of gross tumor and adjacent tissues were obtained using a prototype handheld gamma detection probe and a commercial control unit. Preoperative scintigraphy yielded correct results in 33% and 64% of the patients with primary and recurrent disease, respectively. In comparison, high intraoperative tumor-to-background ratios were achieved in all patients with primary tumors (3.91:1) and recurrent tumors (4.18:1). This clinical feasibility study demonstrated the ability of RIGS technology to provide immediate intraoperative information for the assessment of colorectal cancer. In addition, this study was an early indication of the application of the inverse square law and the advantage of a gamma detection probe 8. The inverse square law states the sensitivity or specificity will increase as the distance from the detector is decreased. Hence, the intraoperative use of the gamma detection probe increased the probability of tumor detection due to its proximity to the source of radioactivity.

In all subsequent RIGS clinical studies, ¹²⁵I was selected to replace ¹³¹I 26101292. ¹²⁵I was selected as the radionuclide of choice for RIGS since the handheld gamma detection probe was more efficient at detecting ¹²⁵I than ¹³¹I secondary to the lower energy level of the primary gamma photon emitter of ¹²⁵I (35 keV) as compared to the primary gamma photon emitter of ¹³¹I (364 keV). Such lower energy gamma photons were more likely to be detected because the radiation was less likely to pass through a small detector without being counted. Likewise, in tumor-bearing mice, higher tumor-to-background ratios were achievable with ¹²⁵I labeled antibodies than with ¹³¹I labeled antibodies 293. This resultant improved tumor-to-background ratio was a function of greater tissue attenuation and lesser scatter that occurs because of the lower energy gamma photon emission of ¹²⁵I 826. Likewise, the majority of clinical trials for RIGS in the detection of colorectal cancer have specifically utilized ¹²⁵I-labeled anti-TAG-72 monoclonal antibodies. As previously discussed, such anti-TAG-72 monoclonal antibodies have evolved from first generation ¹²⁵I-labeled murine B72.3 monoclonal antibodies, to second-generation ¹²⁵I-labeled murine CC49 monoclonal antibodies, and finally to third-generation ¹²⁵I-labeled humanized CC49 (HuCC49) monoclonal antibodies 49.

The availability of the monoclonal antibody 17-1A and its antibody fragment provided preliminary indication of the utility of ¹²⁵I and a gamma detection probe to discriminate between tumor and background tissue and detect occult disease 101. In 1986, O'Dwyer and colleagues 294 at The Ohio State University reported a 75% intraoperative tumor localization rate among patients with primary and recurrent colorectal cancer. Higher tumor-to-background ratios were observed in patients intravenously injected with the ¹²⁵I-17-1A whole monoclonal antibody (3.4:1) compared to its radiolabeled monoclonal antibody fragment F(ab')₂ (2.3:1). Of the 16 evaluable patients (two patients excluded due to a probe malfunction), histologically confirmed occult or subclinical disease was detected in 18% of these patients that would have otherwise not been clinically detected by normal intraoperative inspection and palpation. This early study was useful in shedding light on the optimal timing between injection and surgery for enhancing intraoperative gamma detection.

Petty and colleagues 295 at The Ohio State University continued the investigation of the ¹²⁵I-17-1A monoclonal antibody in thirteen patients with colorectal cancer and optimized the use of the gamma detection probe to determine the clearance of the blood-pool background between the time of injection and surgery. The scheduling of the operative procedure was dependent on external precordial counts of ≤ 10 per second obtained by the gamma detection probe. Intraoperative detection by the gamma detection probe was facilitated by the incorporation of a microprocessor into the control unit. The microprocessor maintained a running average of the count rate and made a synthetic siren sound when the count rate exceeds the background count by a statistically significant amount 8. The squelching feature of the control unit allowed for a siren sound and no sound discrimination between normal tissues and areas of increased radioactivity without interfering with the count rates. Overall tumor localization rate of ¹²⁵I-17-1A monoclonal antibody was 61% 295. Localization was 33% among primary tumor patients and 85% among recurrent tumor patients. Of the 12 tumor sites localized and biopsied, histologically confirmed tumor was identified in 8 (66%) using hematoxylin and eosin (H&E) staining. Additional studies using immunohistochemical staining and autoradiography identified malignant cells in all specimens. In comparison to the study reported by O'Dwyer et al 294, a higher occult disease detection rate was attributed to a lower blood-pool background at operation and improvements in the gamma detecting probe 295. Predictability of ¹²⁵I-17-1A monoclonal antibody blood clearance was feasible using precordial counts. The majority of patients (85%) demonstrated adequate clearance by 10 days post-injection of ¹²⁵I-17-1A monoclonal antibody. Of the seven patients with recurrent disease, occult disease was identified in 43% of these patients. The finding of occult disease altered the surgical management (i.e., extended resection) of six patients. This study demonstrated the ability of the RIGS system to provide immediate intraoperative information regarding the extent and localization of disease by identifying tissues that did not look or feel abnormal but which were worthy of attention due to a siren signal/sound generated by the gamma detection probe.

The first generation of radiolabeled anti-TAG-72 monoclonal antibodies utilized the B72.3 murine monoclonal antibody. From preclinical studies on human colon carcinoma xenografts, significant tumor uptake of ¹³¹I-B72.3 monoclonal antibody was found to occur within 48 hours and subsequently increased over time 296. Although blood-pool background clearance yielded higher tumor-to-background ratios, the activity within the xenograft tumors remained constant over the 19 day period. This prolonged retention of the radiolabeled B72.3 monoclonal antibody and high degree of tumor targeting demonstrated in preclinical studies resulted in the selection of the B72.3 monoclonal antibody for subsequent use in RIGS 296297.

Martin et al 298 reported the use of the ¹²⁵I-B72.3 monoclonal antibody and an improved gamma detection probe in human clinical trials initiated at The Ohio State University in 1986 299 (Table 1). Of the 66 patients with gastrointestinal, breast, and ovarian carcinoma, six and 39 had primary and recurrent colon cancer, respectively 298. Each patient was injected intravenously with 4 to 5 mCi (148 to 185 MBq) of ¹²⁵I-B72.3 monoclonal antibody at approximately 5 to 42 days prior to surgery. Adequate clearance of the blood-pool background yielded a high percentage of tumors identified using RIGS. The mean interval between injection and surgery of 19 days demonstrated long retention of B72.3 monoclonal antibody and adequate amount of the radionuclide for intraoperative gamma probe detection. Tumor localization of ¹²⁵I-B72.3 monoclonal antibody was observed in 83% and 79% of the patients with primary and recurrent colorectal cancer, respectively. Increasing the size of the probe detector crystal and modifications in the crystal mounting improved the counting rate by a factor of approximately 2.5.

Prolonged retention of the radiolabeled B72.3 monoclonal antibody and adequate clearance of the blood-pool background at the time of operation was further demonstrated in a study of primary colon cancer 300. Thirty primary colon cancer patients were intravenously injected with 1 to 5 mCi (37 to 185 MBq) of ¹²⁵I-B72.3 monoclonal antibody and then underwent surgery after adequate clearance of the blood-pool background was determined by precordial gamma detection probe counts (mean 22.3 days, range 8 to 34 days). The ¹²⁵I-B72.3 monoclonal antibody localized in histologically confirmed tumor among 23 of the 30 patients (77%). Of the 23 patients, 30% had occult disease in the liver, lymph nodes, and/or invasion in adjacent tissues identified by RIGS. In 23% of these patients, the surgical plan was modified due to the finding of occult disease. RIGS provided adequate information (i.e., gamma detection probe counts comparable to background) regarding tumor margins and histologically confirmed benign lesions of the liver and ovaries. Therefore, the RIGS system provided a more accurate intraoperative staging of disease and immediate confirmation of tumor margins.

In 1991, Martin and Carey 301 reported the relationship between the survival of 86 patients with recurrent colorectal cancer undergoing a second-look procedure and use of the RIGS system. All patients received a preoperative intravenous injection of 2 mCi (74 MBq) of ¹²⁵I-B72.3 monoclonal antibody at approximately 24 days prior to surgery. The abdomen and pelvis were explored using traditional surgical techniques of inspection and palpation. Prior to the use of the gamma detection probe, sites of tumor were noted and the surgeon declared his surgical plan. The surgical field was reexplored using the gamma detection probe to identify areas of increased radioactivity compared to normal adjacent tissues and to determine whether the findings would alter the planned procedure. Fifty-three patients (62%) were deemed resectable by traditional techniques. However, only 40 patients (47%) were determined to be resectable by RIGS. Retroperitoneal disease was a common finding for RIGS nonresectability. Two-, three-, four-, and five-year survival data were reported for three classifications of patients: RIGS resectable (n = 40), traditional nonresectable (n = 33), and RIGS nonresectable (n = 13). Overall survival rate for the RIGS resectable group was 83%, versus 21% and 31% for the traditional nonresectable and RIGS nonresectable groups, respectively. Significant differences in survival were observed in the RIGS resectable versus traditional nonresectable, p < 0.0001; RIGS resectable versus RIGS nonresectable, p < 0.0008; and non-significant differences were noted in the traditional nonresectable versus RIGS nonresectable groups (p = 0.24). A two- and five-year survival comparison is provided in Table 4 for RIGS using ¹²⁵I-B72.3 monoclonal antibody.

The safety and efficacy of ¹²⁵I-B72.3 monoclonal antibody to localize in tumor and detect occult disease was evaluated in a multicenter clinical trial of 104 patients with primary or recurrent colorectal cancer 302. All patients received a preoperative an intravenous injection of 2 mCi (74 MBq) of ¹²⁵I-B72.3 monoclonal antibody at approximately 24 days prior to surgery. Tumor localization occurred in 78% of the patients. A total of 30 occult tumor sites were identified in 26 patients. Of all histologically confirmed tumor sites, 9.2% represented clinically occult sites identified only by the gamma detection probe. Location of occult disease in primary patients included retroperitoneum, pelvis, periportal, and liver. Of the 72 patients with recurrent disease, 37 were deemed unresectable. In 27% of these patients, data provided by the RIGS led to the decision to abandon an attempted resection. In addition, the operative resection was extended in the remaining 35 patients due to RIGS positive findings. One patient developed an acute hypersensitivity reaction to the skin test using unlabeled B72.3 monoclonal antibody. Although 40% of the patients injected with ¹²⁵I-B72.3 monoclonal antibody developed human anti-murine antibodies, the occurrence did not impact upon tumor localization. Serum TAG-72 levels analysis demonstrated no relationship between the circulating antigen and localization of ¹²⁵I-B72.3 monoclonal antibody. The safety analysis of ¹²⁵I-B72.3 monoclonal antibody did reveal statistically significant changes in body temperature, systolic blood pressure, and hemoglobin concentration; however, these changes were clinically insignificant. This multi-institutional study confirmed a relatively low toxicity profile for ¹²⁵I-B72.3 monoclonal antibody and its utility in identifying occult disease and impact on the surgical management of patients with primary and recurrent colorectal cancer.

Additional investigations into RIGS with ¹²⁵I-B72.3 monoclonal antibody were reported in 1998 by the group at The University of Genoa in Italy 303304. They evaluated RIGS in both 16 asymptomatic patients with a history of previously treated colorectal cancer who has a rising CEA 303 and in 64 patients with recurrent or metastatic colorectal cancer 304. In the group of 16 asymptomatic patients with a history of previously treated colorectal cancer who has a rising CEA, they found recurrent disease in only nine of 16 patients (56.2%) by traditional surgical exploration alone, but in 14 of 16 patients (87.5%) using a combined approach of traditional surgical exploration and RIGS, thus demonstrating that RIGS detected over-looked recurrent disease in five of 16 patients (31.3%) 303. In the group of 64 patients with recurrent or metastatic colorectal cancer, they nonrandomly compared ¹²⁵I-B72.3 monoclonal antibody in 30 patients to ¹²⁵I-F023C5 monoclonal antibody fragment that reacts with CEA in 34 patients 304. They determined that the correct RIGS identification of tumor sites occurred in 80.4% of the ¹²⁵I-B72.3 monoclonal antibody group and in 92.6% of the ¹²⁵I-F023C5 monoclonal antibody fragment group, with additional occult sites of tumor identified by RIGS that would modify surgical strategy in 23.3% of the ¹²⁵I-B72.3 monoclonal antibody group and in only 8.8% of the ¹²⁵I-F023C5 monoclonal antibody fragment group. They concluded that ¹²⁵I-B72.3 monoclonal antibody is the first choice for RIGS in recurrent or metastatic colorectal cancer.

The use of ¹¹¹In-B72.3 murine monoclonal antibody 107305306 in radioguided surgery for colorectal cancer has been limitedly investigated. Renda et al 305 investigated the detection of ¹¹¹In-B72.3 monoclonal antibody by RIGS in 8 patients with colorectal cancer, reporting one false-positive and an overall sensitivity of 62.5%. Muxi et al 306 investigated the detection of ¹¹¹In-B72.3 monoclonal antibody by radioimmunoscintigraphy and RIGS in 28 patients with colorectal cancer (18 primary and 10 recurrent) and demonstrated an overall sensitivity of radioimmunoscintigraphy and RIGS of 71.4% and 82.1%, respectively. More recently, Hladik et al 107 investigated the combined use of ¹¹¹In-B72.3 monoclonal antibody and ⁹⁹Tc-anti-CEA monoclonal antibody fragment (⁹⁹Tc-IMMU-4 monoclonal antibody fragment) and compared the findings yielded by preoperative immunoscintigraphy, RIGS, and histology (H & E and immunohistochemistry). Of the 121 patients, 106 and 15 had primary and recurrent colorectal cancer, respectively. A more accurate diagnosis was achieved using preoperative immunoscintigraphy and RIGS. Of the 55 RIGS-positive lymph node patients, 43 cases (78%) were confirmed by histologically, including 9 cases in which RIGS-positivity was recognized by immunohistochemistry alone. Of 66 patients with RIGS-negative results, 62 cases (94%) were confirmed by negative histology. The authors concluded a potential use of RIGS in the surgical management of primary colorectal patients includes better intraoperative assessment of the extent of disease and staging by identifying occult lymph node disease. Nevertheless, the major drawback to the use of ¹¹¹In-B72.3 monoclonal antibody in radioguided surgery for the detection of colorectal cancer has been the nonspecific accumulation of the ¹¹¹In-B72.3 monoclonal antibody conjugate within the liver, thus making it difficult to identify liver metastases and limiting its usefulness to the identification of extrahepatic disease 307.

The second generation of radiolabeled anti-TAG-72 monoclonal antibodies utilized the CC49 murine monoclonal antibody. CC49 murine monoclonal antibody demonstrated a higher affinity constant (K_a 16.18 × 10⁹ m^-1) compared to B72.3 monoclonal antibody (K_a 2.54 × 10⁹ m^-1) 72. In 1992, Arnold et al 74 at The Ohio State University evaluated the efficiency of ¹²⁵I-CC49 monoclonal antibody and its impact on the RIGS system in a clinical trial of colorectal cancer patients, including 24 primary tumors and 30 recurrent tumors. All patients received a preoperative intravenous injection of 2 mCi (74 MBq) of ¹²⁵I-CC49 monoclonal antibody with a varying monoclonal antibody dosage at approximately 14 to 21 days prior to surgery. Tumor localization of the ¹²⁵I-CC49 monoclonal antibody occurred in 86% and 97% of the primary and recurrent tumors, respectively. In comparison to ¹²⁵I-B72.3 monoclonal antibody, ¹²⁵I-CC49 monoclonal antibody tumor localization was superior in targeting primary and recurrent colorectal tumors. The intraoperative findings from RIGS altered the planned surgical procedure in 50% and 47% of the primary and recurrent patients, respectively. Likewise, the intraoperative identification of occult disease by RIGS resulted in upstaging of cancer and abandonment of hepatic resections in three patients undergoing a second-look procedure. In this study, tissue specimens were classified by whether they were detected by RIGS and by the presence or absence of histologically confirmed carcinoma. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and eosin staining: type I, RIGS negative and histologically negative; type II, RIGS negative and histologically positive; type III, RIGS positive and histologically negative; and type IV, RIGS positive and histologically positive. Of interest to the authors were the type III lymph nodes. The intraoperative detection of type III lymph nodes by RIGS was a function of the presence of the TAG-72 within the extracellular environment. At surgery, all RIGS-positive tissue was considered malignant and excised whenever possible. Type III lymph nodes were detected in both primary cases (n = 40 specimens) and recurrent cases (n = 16 specimens). In this regard, Quinlan et al 308 reported a relationship between the presence of CC49 monoclonal antibody in the germinal centers of lymph nodes and early death among patients with colorectal cancer.

The role of RIGS as an intraoperative prognostic indicator of survival in patients with primary colorectal cancer was investigated by Arnold et al 309. Patients were intravenously injected with 2 mCi (74 MBq) of ¹²⁵I-CC49 monoclonal antibody at approximately 21 days prior to surgery. Thirty-one primary colorectal cancer patients with ¹²⁵I-CC49 monoclonal antibody localization were assessed for the presence or absence of residual RIGS-positive tissue at the completion of the operative procedure. Patients were classified as RIGS-positive (i.e., residual RIGS-positive tissue) or RIGS-negative (i.e., no residual RIGS-positive tissue). Tumor localization was observed in 86% of the patients. One-hundred and nine extra-regional sites of RIGS-positivity were identified using RIGS, including but not limited to the gastrohepatic ligament, celiac axis, retroperitoneum, liver, omentum, and sites above the diaphragm. Seventeen and 14 patients were assessed as RIGS-positive and RIGS-negative, respectively, following the completion of the operative procedure. Follow up of patients ranged from 30 to 54 months. Of the 17 patients with residual RIGS-positive tissue, 15 (88%) succumbed to their disease. In comparison, all 14 patients with no residual RIGS-positive tissue were alive at last follow-up (24 to 48 months after surgery) (p < 0.0001). Therefore, the presence or absence of residual RIGS-positive tissue provided immediate and accurate prognostic information regarding the behavior of the tumor and patient outcomes in patients with primary colorectal cancer.

Likewise, in the recurrent colorectal cancer population, Bertsch et al 310 reported an improved survival relative to the use of the RIGS system. One hundred and thirty-one patients with recurrent colorectal cancer were injected with ¹²⁵I-B72.3 monoclonal antibody (n = 86) or ¹²⁵I-CC49 monocloncal antibody (n = 45) and underwent a surgical exploration using traditional inspection and palpation and the RIGS system. Of the 49 patients deemed resectable (i.e., successful removal of all traditionally evident disease and all RIGS-positive tissue), 55% (27 patients) were alive at 2 to 8 years following surgery, with a minimal follow-up of 28 months. In contrast, only 2.4% of all patients (2 of 84 patients) with unresectable disease were alive at the time of this report. None of the patients determined to be traditionally resectable but unresectable by the RIGS system were alive. A significant increase in survival (p < 0.0001) was observed among patients with recurrent colorectal cancer undergoing a resection of all disease found by a combination of both traditional means and by RIGS.

A long-term survival analysis of 97 patients with primary colorectal cancer supports the use of RIGS as an intraoperative prognostic tool 311. Survival was assessed using the traditional staging (TNM) and the presence or absence of RIGS-positive tissue at the end of the operative procedure. The mean follow-up among the 52 evaluable patients was 62 months (range 34 to 89 months). Based on TNM staging 13, 18, and 28 patients were Stage, I, Stage II, and Stage III, respectively. By RIGS status, 24 and 35 were RIGS-negative and RIGS-positive, respectively. The RIGS status was not significantly related to the traditional pathologic staging (p = 0.73). No significant difference in survival was observed using standard pathologic staging (p = 0.12). However, a significant difference in survival was observed by the using the RIGS status (p < 0.0002), with 87% of RIGS-negative patients alive and only 40% of RIGS-positive patients alive at a mean follow-up of 62 months.

The extended survival (i.e., 10-year survival) of 90 colorectal cancer patients undergoing RIGS, based on the presence or absence of residual RIGS-tissue at the time of surgery, was recently analyzed by Sun et al 49. At 10 years after RIGS, survival differences remained significant (p = 0.001), with 49% of the RIGS-negative patients (median survival of 106.5 months) still alive as compared to only 21% of the RIGS-positive patients (median survival of 26 months) still alive. These extended follow-up data support the accuracy of utilizing the RIGS status at the time of surgery as a predictor of long-term survival in colorectal cancer patients.

Additional investigations into RIGS with ¹²⁵I-CC49 murine monoclonal antibody were reported in 2000 and 2001 by the group at Tel-Aviv University in Israel 312313314. Overall, they evaluated a total of 58 patients with recurrent colorectal cancer who were intravenously injected with of 2 mCi (74 MBq) of ¹²⁵I-B72.3 monoclonal antibody at approximately 24 days prior to surgery. Traditional surgical exploration and RIGS were performed. While traditional surgical exploration identified 117 suspected tumor sites, RIGS identified 177 suspected tumor sites. In 17 of 58 patients (29.3%), at least one occult tumor site that was not identified by traditional surgical exploration was identified by RIGS, and was subsequently confirmed by pathology with H&E staining. This resulted in a major change in the surgical plan in 16 cases. RIGS performance was found to vary between lymphoid tissue and non-lymphoid tissue, with a positive predictive value and a negative predictive value of 96% and 90% in non-lymphoid tissue and 40% and 100% in lymphoid tissue, respectively.

A phase I study of ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody conducted at The Ohio State University determined the feasibility of the humanized monoclonal antibody as a component of the RIGS system and evaluated the optimal timing interval between injection and surgery 315. Study eligibility included patients with recurrent colorectal cancer undergoing a surgical exploration and excluded those with prior exposure to murine antibodies. Patients underwent a surgical exploration at variable time intervals following the intravenous administration of 2 mCi (74 MBq) of ¹²⁵I-HuCC49 ΔC_H2 monoclonal antibody or after the precordial counts measured by a handheld gamma detecting probe were less than 30 counts per two seconds. HAMA determinations were obtained at baseline, as well as at 4 to 6 weeks and 12 weeks post-injection of the ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody. At surgery, traditional exploration (i.e., inspection and palpation) and subsequent RIGS exploration were performed. Suspicious tissues were biopsied or excised to determine the presence of absence of carcinoma. The findings were analyzed to determine the sensitivity and positive predictive value for each modality. Of the twenty recurrent colorectal cancer patients evaluated, the first 15 operative procedures were performed at various time intervals (3, 5, 7, 9, 11, and 13 days) after the injection of ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody and independent of the precordial counts. In the five remaining patients, the timing of surgery was determined by the demonstration of precordial counts of less than 30 counts per two seconds, indicating optimal clearance of ¹²⁵I-HuCC49 ΔC_H2 monoclonal antibody from the blood-pool background. This occurred at 10 to 24 days after the injection of ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody. The adequate clearance of the blood-pool background in these five patients allowed for intraoperative differentiation of RIGS-positive tissue compared to normal adjacent tissue. Among those five patients with optimized clearance conditions based on precordial counts of less than 30 counts per two seconds, 17 and 21 sites were identified using traditional techniques (i.e., inspection and palpation) and RIGS system, respectively. Approximately 90% of the excised tissues identified by traditional techniques and by RIGS were histologically positive for tumor. Of the six sites identified exclusively by RIGS, five were excised and all contained tumor. Table 5 provides the sensitivity of traditional exploration and RIGS exploration using ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody for identifying recurrent colorectal cancer and the positive-predictive value. No significant HAMA response was detected in these patients. Despite the small number of evaluable patients, the study demonstrated the safety and utility of ¹²⁵I-HuCC49ΔC_H2 monoclonal antibody in RIGS. The rate of tumor localization and detection of occult disease was comparable to murine CC49 previously reported by Arnold et al 74, but without a detectable HAMA response. The use of HuCC49ΔC_H2 monoclonal antibody as a component of RIGS technology suggests that it is worthy of continued investigations in colorectal cancer patients.

Limited information is available on use radiolabeled anti-CEA monoclonal antibody in RIGS for colorectal cancer 9091107316. Dawson et al 91 evaluated 43 patients undergoing surgery with primary colorectal cancer and 9 patients undergoing second look laparotomy for recurrent colorectal cancer who were intravenously injected with 2 mCi (74 MBq) of ¹²⁵I-anti-CEA monoclonal antibody (¹²⁵I-A₅B₇) three to ten days before surgery. They determined that RIGS assessment of ¹²⁵I-A₅B₇localized in 97.8% of primary tumors and in 88.8% of most principle tumor sites found at the time of the second look procedure. Likewise, they determined that the use of RIGS influenced the overall surgical procedure performed in 2 of 43 cases (4.6%) of primary colorectal cancer and in three of nine cases (33%) of recurrent colorectal cancer. Lechner et al 316 evaluated 20 patients with primary colorectal cancer who were intravenously injected with 25 mCi (925 MBq) of ⁹⁹Tc-anti-CEA monoclonal antibody fragment (⁹⁹Tc-IMMU-4) on the day before RIGS. They determined that RIGS assessment of ⁹⁹Tc-IMMU-4 led to up-staging of disease in 7 of 20 patients (35%). Hladik et al 107 evaluated 65 patients with either primary or recurrent colorectal cancer who were intravenously injected with ⁹⁹Tc-IMMU-4 in a dose range of 18.9 to 24.3 mCi (700 to 900 MBq) on the day before RIGS. They determined that RIGS assessment of ⁹⁹Tc-IMMU-4 led to a sensitivity and accuracy for the detection of tumor or local recurrence of 92% and 92%, for the detection of hepatic metastases of 75% and 92%, and for the detection of extrahepatic metastases of 57% and 78%, respectively. Finally, Gu et al 90 evaluated 29 patients with primary colorectal cancer who were injected with 0.5 mCi (18.5 MBq) of ¹²⁵I-anti-CEA monoclonal antibody (¹²⁵I-CL58) into the colonic submucosa at the tumor-surrounding areas (at 2, 4, 6, 8,10, and 12 o'clock locations) via colonoscopy at a time of approximately three to 14 days before RIGS. The sensitivity of RIGS in detecting primary lesions was 93.1%, and the specificity of RIGS to correctly identify negative surgical margins was 95.5%. For detection of lymph node metastases, the sensitivity and specificity of RIGS was 92.0% and 87.8%, respectively.

The application of SLN biopsy technology to colorectal cancer has been thoroughly studied. While the vast majority of the information available for SLN biopsy for colorectal cancer is on the application of the blue dye alone technique, the radioguided application of ^99mTc sulfur colloid technique with intraoperative gamma probe detection has been limitedly investigated 317318319320321322323324. The results of the two largest reported series are strikingly divergent 319323. In 2003, Bilchik et al 319 evaluated 120 patients using a combined blue dye and ^99mTc sulfur colloid (dose not reported) technique in 32 such patients. They reported successfully identifying a SLN in 115 of 120 (96%) patients, with a false-negative SLN biopsy results identified in only 5 of 115 (4%) patients. In contrast, in 2007, Lim et al 323 evaluated 120 patients using a combined blue dye and ^99mTc sulfur colloid (0.5 mCi; 19 MBq) technique in all patients. They reported successfully identifying a SLN in 119 of 120 (99%) patients, with a falsely negative SLN biopsy results identified in 20 of 119 (17%) patients. As a consequence of these strikingly different results with regards to the false-negative rate, we can realistically say that at the current time we are no closer to elucidating the clinical relevance of SLN biopsy technology for colorectal cancer surgery.

The most recent application of the gamma detection probe for radioguided surgery in colorectal cancer has been directed towards to identification of ¹⁸F-FDG-avid tumors 35363738394550. This technique was first described by Desai et al 3536 at The Ohio State University (Table 1). Fourteen colorectal cancer patients received an intravenous injection of 4.0 to 5.7 mCi (148 to 211 MBq) of ¹⁸F-FDG at a time of 58 to 110 minutes prior to intraoperative evaluation with the gamma detection probe. Single or multiple tumor foci were correctly identified in 13 of 14 patients with the gamma detection probe as ¹⁸F-FDG-avid tissue and this correlated to hypermetabolic activity on prior preoperative diagnostic ¹⁸F-FDG PET imaging. These results have been further corroborated since that time in several other clinic reports 3738394550. Most recently, a combined approach of preoperative diagnostic ¹⁸F-FDG PET imaging and intraoperative gamma probe detection has been advocated to potentially provide the surgeon with a real-time, intraoperative roadmap for accurately locating and determining the extent of tumor recurrence in patients with colorectal cancer 50. In this series, patients received an average dose of 10 to 15 mCi (370 to 555 MBq) of ¹⁸F-FDG at a time of 30 to 60 minutes prior to intraoperative evaluation with the gamma detection probe. It was determined that intraoperative evaluation with the gamma detection probe appeared to be more sensitive in detecting the extent of abdominal and pelvic recurrence, while preoperative ¹⁸F-FDG PET imaging was more sensitive in detecting liver metastases and other distant metastases 50.

The necessary extent of lymphadenectomy during gastric cancer surgery remains a controversial issue, with two randomized trials demonstrating no survival advantage for patients treated with D2 lymphadenectomy as compared to a D1 lymphadenectomy 353354 compared with other retrospective reviews showing a survival benefit for patients treated with D2 lymphadenectomy 355356. In this regard, the potential application of SLN biopsy for gastric cancer remains an active avenue of clinical research and debate amongst surgeons who treat gastric cancer. This is most relevant for those clinicians in eastern Asia that primarily treat early stage gastric cancers, which by definition should have a less than 10% chance of nodal involvement 357.

Multiple reports exist in the literature on the feasibility of radioguided SLN biopsy for gastric cancer 338344345358359360361362363364365366367368369370371372373374375376377378379380381382383. Many of these reports from eastern Asia specifically target a purely laparoscopic approach to radioguided SLN biopsy in the treatment of cases of early stage gastric cancer 338361367371377378380381382.

Most frequently, ^99mTc tin colloid 338344345346359360361363364365366367369371375376377378380382 has been used as the radiocolloid, especially in eastern Asia. However, ^99mTc colloidal rhenium sulfide 362368374379, ^99mTc sulfur colloid 352358370372, and ^99mTc colloidal human albumin 381 have also been utilized. The dosing of these radiocolloid agents vary from as low as 0.5 mCi (18.5 MBq) 374 to as high as 6.0 mCi (222 MBq) 364369. These radiocolloid agents are generally injected endoscopically in up to four submucosal sites around the tumor at a time period from two to 24 hours before surgery.

The two largest series reported are by Kitagawa et al 359 and Uenosono et al 369. In 2002, Kitagawa et al 359 identified a SLN in 138 of 145 patients (95.2%) with presumed cT1N0 or cT2N0 gastric cancer. A SLN was positive in 22 of 24 patients who had lymph node metastases and this demonstrated a diagnostic accuracy of assessment of the regional lymph node status on the basis of the SLN status of 98.6%. In 2005, Uenosono et al 369 identified a SLN in 99 of 104 patients (95.2%) with presumed cT1 or cT2 gastric cancer. Excluding three technical failures in radiocolloid injection, identification rates were 99% (78 of 79) and 95% (21 of 22) for cT1 and cT2 lesions, respectively. Lymph node metastases and/or micrometastases were found in 28 patients (15 cT1 and 13 cT2) and the resultant false-negative rate, sensitivity, and accuracy were significantly better for cT1 tumors than for cT2 tumors (P < 0.001, P = 0.004, and P < 0.001, respectively). While the possibility exists for radioguided SLN biopsy to help individualize the surgical therapy for patients with early stage gastric cancer, additional studies are needed to determine its utility.

The feasibility of RIGS for gastric cancer has been evaluated by several groups of investigators 149383384385386387. In 1988, Martin et al 149 evaluated ¹²⁵I-B72.3 murine monoclonal antibody in five patients with gastric cancer, finding positive gamma detection probe counts in four patients. In 1994, Xu et al 383 and Lui et al 384 evaluated ¹³¹I-3H11 murine monoclonal antibody, a mouse antibody raised against human gastric cancer cells, in 25 patients with gastric cancer. They reported detection of metastatic lymph nodes with a sensitivity of 99.2%, a specificity of 97.7%, and an accuracy of 98.8%, and reported the detection of tumor infiltration of the gastric wall with a sensitivity of 94.6%, a specificity of 96.7%, and an accuracy of 95.9%. In 1998, Lucisano et al 385 evaluated ¹²⁵I-B72.3 murine monoclonal antibody in 7 patients with gastric cancer. The correct RIGS identification of the primary tumor was seen in four of seven patients (57.1%) and of metastatic lymph nodes in two of four patients (50%). Also, in 1998, Mussa et al 386 evaluated ¹¹¹In-B72.3 murine monoclonal antibody in 3 patients with gastric cancer, confirming intraoperative tumor-to-background counts of greater than 2 in all three cases and demonstrating a sensitivity of 100%, a specificity of 72%, and no false-negative findings with RIGS. Finally, in 2000, Wang et al 387 evaluated ¹²⁵I-3H11 murine monoclonal antibody in 35 patients with gastric cancer. For the detection of lymphatic metastases, they demonstrated a sensitivity of 83.6%, a specificity of 95.0%, and an accuracy of 91.3%. The existence of lymphatic micrometastatic disease was verified immunohistochemically in 10 of 19 patients (52.6%) that were RIGS-positive but that had H&E histologically negative lymph nodes. Despite these early promising results, no further investigations into RIGS for gastric cancer have been published since that last report.

The use of ¹⁸F-FDG-directed surgery has been very limitedly reported in the literature for the surgical management of gastric cancer 4547. Gulec et al 45 reported on a single case of gastric cancer in which ¹⁸F-FDG-directed surgery was utilized for the identification and resection of a hypermetabolic metastatic lymph node during a gastectomy and extended node dissection. Piert et al 47 reported on the use of ¹⁸F-FDG-directed surgery in three gastric adenocarcinomas and two adenocarcinomas of the gastroesophageal junction.

While SLN biopsy had become a widely accepted diagnostic technique in the evaluation of the lymph node status in breast cancer and melanoma, it has been met with much more limited enthusiasm for squamous cell cancers of the head and neck region, including the oral cavity, oropharynx, hypopharynx, and laryngeal region, secondary to the complicated lymphatic drainage pathways of the head and neck region 389. In 1996, Alex and Krag 390 first described successful radiolocalization of SLNs with ^99mTc sulfur colloid in the aerodigestive system in a patient with supraglottic squamous cell cancer. Since the time of this initial report, the sensitivity and specificity of radioguided SLN biopsy has become greater than that of physical exam, computed tomography, magnetic resonance imaging, or positron emission tomography for assessing the N0 neck 391. Additionally, the overall feasibility of radioguided SLN biopsy has gradually improved, with most recently reported success of localization of 99.3% in 137 patients by American College Of Surgeons Oncology Group Z0360 392 and 100% in 79 patients by Stoeckli 393 for early (T1/T2) squamous cell cancers of the oral cavity and oropharynx.

The overall methodology for performing radioguided SLN biopsy for squamous cell cancers of the head and neck region, including the oral cavity, oropharynx, hypopharynx, and laryngeal region is not that dissimilar as to that for breast cancer and melanoma. However, there are some unique features that are worth further discussing 392393394395396397.

Recently, Vigili et al 396 have outlined one such protocol for performing radioguided SLN biopsy for squamous cell cancers of the oral cavity and oropharynx. Topical anesthetic (10% lidocaine spray) was administered to the oral cavity. Then, 0.8 mCi (30 MBq) to 1.4 mCi (50 MBq) of ^99mTc human nanocolloidal albumin within 0.3 ml of normal saline solution was injected superficially into the subepithelial stroma in four points around the tumor. Injection into deeper tissues resulted in a poorer image quality, increased blood accumulation of the tracer, and a lower success rate for SLN localization. The mouth was immediately washed out in order to prevent pooling and swallowing of any residual ^99mTc human nanocolloidal albumin. Immediate dynamic lymphoscintigraphy imaging and 30 minute static images were performed with lateral and/or anterior views. The skin overlying the area of the identifiable SLNs seen on lymphoscintigraphy were marked with a permanent marking pen. Subsequent appropriate surgery and radioguided SLN biopsy with the gamma detection probe were performed approximately three hours after completion of lymphoscintigraphy. They defined a SLN as any lymph node containing activity counts of at least three times that of the background count activity.

Likewise, recently, Tomifuji et al 397 have outlined one such protocol for performing radioguided SLN biopsy for squamous cell cancers of the hypopharynx and laryngeal region. On the day before surgery, topical anesthetic (4% lidocaine spray) was administered to the oral cavity. Then, a 2.0 mCi/mL (74 MBq/mL) solution of ^99mTc phytate was submucosally injected in 0.2 mL quantities into three to four sites adjacent to the tumor using a 23-gauge endoscopic puncture needle that was passed through the channel of a flexible laryngohypopharyngeal endoscope with a transparent hood. Three hours after the injection, static lymphoscintigraphy images were obtained from lateral and anterior views. The skin overlying the area of the identifiable SLNs seen on lymphoscintigraphy were marked with a permanent marking pen. The following day, appropriate surgery and radioguided SLN biopsy with the gamma detection probe were performed. They defined a SLN as any lymph node containing activity counts of at least ten times that of the background count activity.

The determination of the adequacy of the intraoperative assessment of the neck with the gamma probe during radioguided SLN biopsy for squamous cell cancers of the oral cavity and oropharynx has been recently assessed. In a recent study of 31 patients undergoing radioguided SLN biopsy, resection of the primary tumor, and a concomitant neck dissection, Atula et al 398 reported that all patients could be accurately staged based upon the findings within the hottest three SLNs removed.

Despite encouraging results, controversy still exists as to whether SLN biopsy will ultimately replace the standard clinical practice of selective neck dissection for squamous cell cancers of the head and neck region, as previously described 399400. Potential disadvantages of SLN biopsy include a limited exposure and the potential injury to neural structures, such as cranial nerve XI and the mandibular branch of cranial nerve VII 401. Additionally, if neck nodal metastases are not identified with frozen section, then a subsequent operation within a recently open and inflamed surgical field could increase morbidity 393. Furthermore, it has been observed that lymph nodes predominately replaced by metastatic disease do not accumulate radiotracer and may result in altered lymphatic pathways, thereby increasing false negatives 402. Finally, the proximity of the primary tumor and the SLN can be problematic. Kovács et 401 al reported that 6 of 104 known sites of radiotracer localization seen on preoperative lymphoscintigraphy were intraoperatively missed using the gamma detection probe secondary to shine-through radioactivity from a nearby injection site. This proximity issue likely explains why the radioguided SLN identification frequency is less for carcinomas of the floor of mouth as compared to other sites of carcinomas within the oral cavity, oropharynx, hypopharynx, and laryngeal region 392395396397.

Regardless of these potential disadvantages, radioguided SLN biopsy has proven value especially in management of the N0 neck in squamous cell cancers of the head and neck region 278392395396. One advantage of radioguided SLN biopsy is for guiding selective nodal harvesting in carcinomas situated at or adjacent to the midline, since in such situations the lymphatic drainage may be bilateral in up to 10% of cases 403. In this setting, lymphoscintigraphy and intraoperative gamma probe detection of SLNs may provide a suitable alternative in these patients, in whom the management of the contralateral neck is debatable. Another advantage of SLN biopsy is the allowance of a concentrated and extensive pathologic examination of a limited number of lymph nodes versus that of a limited pathologic examination of numerous lymph nodes from selective neck dissections where finding a metastasis is similar to the proverbial needle in a haystack 392. Because of this required meticulous histopathologic examination, Kovács 404 has discouraged the use of frozen section, but admits its intraoperative availability and diagnostic accuracy are important in shortening the time to deciding on a therapeutic neck dissection. SLN biopsy has been reported to aid in the identification of skip metastases, defined by Byers et al 405 as metastases that bypass level I and II lymph nodes and go directly to levels III through V. They demonstrated that skip metastases were the only manifestation of disease in the neck after selective neck dissection in approximately 16% of 277 patients evaluated. Such a finding can clearly explain disease relapse after surgeries which do not include all five levels. A final potential benefit of radioguided SLN biopsy is the upstaging of early tumors from N0 to N1 which occurs in 16% to 34% 392395 of patients with early squamous cell carcinomas (T1/2) of the oral cavity and oropharynx. This finding has led to appropriate therapy of the neck (i.e., neck dissection or radiation), and unlike in melanoma where lymphatic metastases portend an extremely poor prognosis, squamous cell carcinomas of the head and neck region with lymphatic metastases remain potentially curable.

Only one available report can be found in the literature on the application of RIGS to squamous cell cancers of the head and neck region 406. In this report, Argenzio et al described the intravenous administration of 15 mCi (555 MBq) of ^99mTc-labeled anti-CEA monoclonal antibody fragments in two cases with squamous cell cancer of the head and neck, with one to the cheek and one to the scalp 406. Diagnostic gamma camera imaging was performed 4 and 12 hours after intravenous administration of ^99mTc-labeled anti-CEA monoclonal antibody fragments and then intraoperative gamma probe detection was used to assist in the resection of the primary tumor and the assessment of surgical margins at a time approximately 36 hours after the initial intravenous dosage of this radiopharmaceutical. They defined tumor to healthy tissue background ratio of greater than two as a discriminate value for defining diseased tissue.

Only one report is currently available in the literature on the application of gamma probe detection during ¹⁸F-FDG-directed surgery to squamous cell cancer of the head and neck region 45. In this report, Gulec et al 45 describe a single case in which ¹⁸F-FDG-directed surgery was used the localize a nonpalpable target from a head and neck cancer at approximately 4 hours after intravenous injection of a unknown dose of ¹⁸F-FDG. In an additional report by Meller et al 44, they describe the use of a high energy gamma detection probe to preoperatively identify metastatic lymph nodes in 36 patients with cancers of the oral cavity and oropharynx which was performed within a two week period prior to their definitive surgery and specifically at the time of their diagnostic whole body PET scan. Patients were intravenously injected with 6.8 mCi (250 MBq) to 9.5 mCi (350 MBq) of ¹⁸F-FDG for the purpose of the preoperative diagnostic whole body PET scan and for the formalized preoperative survey of the lymph node levels within the bilateral neck with a high energy gamma detection probe. Nevertheless, this high energy gamma detection probe was not utilized within the intraoperative setting during their definitive surgical procedure.

In 1984, Ubhi et al 408 first described the use of the gamma detection probe for intraoperative identification of ²⁰¹Tl-thallous chloride in a case of mediastinal parathyroid adenoma (Table 1). Then, in 1995, Martinez et al 409 first described the use of the gamma detection probe for intraoperative identification of ^99mTc-MIBI in patients with parathyroid gland pathology (Table 1). Later in 1997, the University of South Florida group 410411 popularized this technique of using ^99mTc-MIBI for the surgical management of primary hyperparathyroidism (Table 1). Since that time, multiple other groups of investigators have published reports describing their experience with minimally-invasive radioguided parathyroidectomy for primary hyperparathyroidism 412413414415416417418419420421422423424425426427428429430431.

In their initial report, Norman and Chheda from The University of South Florida 410 described their technique of minimally-invasive radioguided parathyroidectomy in 15 patients and utilized an approach of same-day MIBI imaging and radioguided parathyroid surgery. Patients were intravenously injected with 20 to 25 mCi (740 to 925 MBq) of ^99mTc-MIBI 411. After completion of preoperative scintigraphic localization of the presumed parathyroid adenoma (at approximately 3 hours after the MIBI injection), patients underwent radioguided parathyroid surgery. A gamma detection probe was then used to systematically assess radioactivity in all four quadrants of the neck. An initial 2 cm skin incision was then made overlying the location of the radioactive parathyroid gland, the platysma muscle and strap muscles were retracted, and dissection proceeded with guidance from the gamma detection probe for identification of the radioactive parathyroid gland representing the presumed parathyroid adenoma. After resection of the radioactive gland, counts were recorded of the four quadrants of the neck, along with excised radioactive parathyroid gland, excised fat, and excised lymph nodes. Parathyroid adenomas were consistently found to have counts exceeding the postexcisional background counts by more than 20%, whereas the counts of fat and lymph nodes never exceeded 3% of the postexcision background counts 411. This finding has subsequently led to the abandonment of frozen section pathology for confirmation of the presence of parathyroid tissue 411. In their initial report 410, a single parathyroid adenoma was located by this technique in 14 of 15 patients, with an average time of approximately 19 minutes to find the radioactive parathyroid gland and an average total operating time of approximately 48 minutes. The one failed patient was intraoperatively found to have four-gland hyperplasia as diagnosed by increased background counts after successful excision of the first targeted radioactive parathyroid gland. The first 5 procedures were done under general anesthesia, with all subsequent procedures being done under local anesthetic.

Instead of utilizing a same-day protocol for MIBI imaging and radioguided parathyroid surgery, other investigators have described and recommended utilizing separate days for MIBI imaging and radioguided parathyroid surgery in order to allow for more efficient use of operative time by preselecting those individuals with confirmed localization to a solitary parathyroid adenoma on MIBI imaging for determination of the appropriateness of minimally-invasive radioguided parathyroidectomy 412419. Flynn et al 412 previously described performing preoperative MIBI imaging electively before the day of surgery and subsequent intravenous injection of 20 mCi (740 MBq) of ^99mTc-MIBI on the day of surgery at a time approximately 60 to 90 minutes preoperatively. In order to decrease the radiation dose at the time of surgery, Rubello and colleagues have developed a low dose ^99mTc-MIBI technique 418419420421422423424. As originally described, Rubello et al 419 reported performing preoperative double-tracer (^99mTc-pertechnetate and ^99mTc-MIBI) subtraction scanning at a time several days before the proposed surgery to identify those individuals with a presumed solitary parathyroid adenoma and then, on the day of surgery, those individuals who preoperatively localized were subsequently intravenously injected with a low dose of 1 mCi (37 MBq) of ^99mTc-MIBI just a few minutes prior to the start of surgery. Both the Flynn et al series 412 and the Rubello et al series 419 reported excellent intraoperative localization rates with the gamma detection probe for demonstrating an abnormal parathyroid gland. Additionally, with the low dose ^99mTc-MIBI technique that was administered just a few minutes prior to the start of surgery, Rubello et al 419 demonstrated that all excised parathyroid adenomas had ex vivo radioactivity that was more than 40% of the postexcision background counts, further confirming completeness of surgical excision beyond that of the 20% rule previously established by Murphy and Norman 411. Finally, both the Flynn et al series 412 and the Rubello et al series 419 used an intraoperative quick parathyroid hormone assay to aid in the surgical decision-making process. While Rubello and colleagues 419420421422424 and Chen et al 428 have strongly advocated the routine use of the intraoperative quick parathyroid hormone assay for further confirming completeness of removal of all hyperfunctioning parathyroid tissue (especially to aid in the recognition of previously unrecognized double adenomas or multiple-gland hyperplasia), Flynn et al 412, Goldstein et al 427, Caudle et al 429, and Norman and Politz 430 have not. In their series of 112 patients with preoperative localization on an MIBI scan, Goldstein et al 427 reported a 98% success rate for identification of a radioactive parathyroid gland based upon the intraoperative use of the gamma detection probe alone during minimally-invasive radioguided parathyroid surgery.

Several authors have discussed the potential advantages of a minimally-invasive radioguided parathyroid surgical approach as compared to standard bilateral neck exploration for the surgical management of primary hyperparathyroidism. Rubello and colleagues 418419420421422423424 have emphasized several potential advantages of a minimally-invasive radioguided parathyroid surgical approach for the surgical management of primary hyperparathyroidism. This includes minimizing the invasiveness of the surgical approach for identifying and resecting solitary parathyroid adenomas (thus allowing for maximal cosmetic outcome and the ability to perform such cases without the need of general anesthesia), as well as enhancing the accuracy of the surgeon to specifically locate ectopic parathyroid adenomas and ensure complete operative success by intraoperatively evaluating the postresectional field for residual radioactivity. Additionally, Flynn et al 412 has emphasized a modest cost savings of almost one thousand dollars per patient, particularly due to shorter operative time, avoidance of general anesthesia, elimination of the need for both frozen section pathology and intraoperative quick parathyroid hormone assays, and earlier hospital discharge. A similar effect on cost was reported by Goldstein et al. 413 in which they described a reduction in hospital charges by nearly 50% for the minimally-invasive radioguided parathyroid surgical approach as compared to that of standard neck exploration. Furthermore, a potential benefit of a minimally-invasive radioguided parathyroid surgical approach for reoperative parathyroid surgery has been reported in cases where a failed initial surgical exploration without the use of the gamma detection probe resulted from what was labeled as a "false-positive" MIBI scan 414. In this series of 17 patients in which a minimally-invasive radioguided parathyroid surgical approach was utilized for reoperative parathyroid surgery, Norman et al 414 reported that a repeat MIBI scan again demonstrated the same focus of radioactivity and intraoperative use of the gamma detection probe correctly identified and aided in the excision of a radioactive parathyroid gland in all 17 patients who were previously presumed to have an initial "false-positive" MIBI scan.

Throughout the development of minimally-invasive radioguided parathyroid surgery, identification of an adenoma on preoperative MIBI scintigraphic imaging has been the most important criteria for the determination of the appropriateness of this surgical approach. However, if an initial negative MIBI scan is encountered in a patient with primary hyperparathyroidism, there may still be a viable role for consideration of MIBI-directed intraoperative gamma probe detection at the time of minimally-invasive radioguided parathyroid surgery. Lal and Chen 431 recently described an algorithm for patients with primary hyperparathyroidism in whom an initial negative MIBI scan is encountered. In a group of 90 such patients, this algorithm involved the use of further preoperative testing with thallium subtraction scanning and neck ultrasound, as well as intraoperative bilateral internal jugular sampling of parathyroid hormone, along with intraoperative quick parathyroid hormone assay, and/or intraoperative MIBI-directed gamma probe detection. Their results indicated that despite an initial negative MIBI scan, that 67% of such patients had a single adenoma as the cause of their primary hyperparathyroidism, and 23% of such patients had successful utilization of intraoperative MIBI-directed gamma probe detection at the time of minimally-invasive radioguided parathyroid surgery.

While the role of utilizing intraoperative gamma probe detection during radioguided parathyroid surgery is well established for parathyroid adenomas, few reports have focused on its effectiveness for hyperplastic parathyroid glands demonstrated in either primary or secondary/tertiary hyperparathyroidism 432433434435436437438439440. This approach was first successfully reported in 2000 by Rossi et al 432 in 11 patients with persistent hyperparathyroidism undergoing reoperative neck exploration for localizing residual hyperfunctioning parathyroid tissue and by Navarra et al 433 in a single patient with recurrent secondary renal hyperparathyroidism. The largest series to date has been reported by Chen et al 436, in which they compared the results of minimally-invasive radioguided parathyroid surgery in 25 patients with secondary/tertiary hyperparathyroidism with that of 77 patients with primary hyperparathyroidism. Their results demonstrated in vivo counts of parathyroid adenomas and hyperplastic parathyroid glands did not significantly differ; however, ex vivo counts were highest in single gland adenomas and lowest in hyperplastic parathyroid glands. Nevertheless, all hyperplastic parathyroid glands still registered ex vivo counts > 20% of postexcision background counts in a setting where each patient received an intravenous dosage of 10 mCi (370 MBq) of ^99mTc-MIBI at approximately 30 to 60 minutes before surgery. Despite this, Rubello et al 424 still recommend use of the intraoperative quick parathyroid hormone assay at the time of radioguided parathyroidectomy by the low dose ^99mTc-MIBI technique in order to establish the completeness of removal of additional foci of hyperfunctioning parathyroid tissue secondary to the persistence of previously unrecognized hyperplastic parathyroid glands.

Parathyroid cancer is an extremely rare entity that has been reported to occur in 0.1% to 0.4% of patients with primary hyperparathyroidism 441. The incidental finding of parathyroid cancer at the time of minimally-invasive radioguided surgery for primary hyperparathyroidism presumed secondary to a parathyroid adenoma is well-described in the literature 424. Nevertheless, only one report in the literature exists which describes the use of an intraoperative gamma probe detection of ^99mTc-MIBI-avid tissue during radioguided surgery that is specifically directed toward parathyroid cancer 442. In this report, they describe a case of recurrent parathyroid carcinoma in which the patient was intravenously injected with 10 mCi (370 MBq) of ^99mTc-MIBI at one hour prior to surgery and an intraoperative gamma detection probe was used to localize and aid in the resection of the area of recurrent disease. In this case, successful resection was verified by normalization of the postresection parathyroid hormone level on intraoperative quick parathyroid hormone assay and for which they report that the patient remains asymptomatic at 17 months after surgery.

The experience of treating differentiated thyroid cancers with ¹³¹I remnant ablative therapy following total thyroidectomy has made ¹³¹I the most logical radionuclide for localization of iodine-avid recurrent tumors during radioguided surgery. Due to the fact that ¹³¹I has a relatively long physical half-life (approximately 8 days), as well as the fact that it is readily available, highly affordable 26, and can be used to distinguish tumor from that of background with a collimated gamma detection probe, it is an ideal radionuclide for detecting iodine-avid recurrent disease. This approach for using ¹³¹I is well reported in the literature. The first description of radioguided surgery for thyroid cancer was published in 1956 by Harris et al 3 and was later refined in 1971 by Morris et al 452, in which they described using a CsI [Tl] gamma detection probe to localize thyroid tissue or recurrent thyroid cancer in patients undergoing neck exploration.

Recently, Rubello et al 446 reported an eight-day protocol for radioguided surgery for iodine-avid recurrent disease, which was modified from the first original protocol reported by Travagli et al 453. In this protocol, a therapeutic dosage of 100 mCi (3700 MBq) of ¹³¹I was orally administered to hypothyroid patients (serum thyroid stimulating hormone level > 30 μU/ml) on day 0, with a whole-body gamma camera imaging (¹³¹I scan) performed on day 3. Then on day 5, radioguided neck surgery was performed with the assistance of a 15-mm collimated handheld gamma detection probe, and all sites of elevated activity were resected. A subsequent postoperative neck ¹³¹I scan was obtained on day 7 to evaluate the success of the surgery, utilizing the remaining radioactivity from the initial oral dosage of ¹³¹I given on day 0. Of the 184 metastatic foci found within the 31 treated patients, 41.3% of extirpated metastatic foci were localized only with the gamma detection probe and were not seen with preoperative imaging. The postoperative neck ¹³¹I scan on day 7 showed a negative pattern in 25 of 31 treated patients (80.6%). As such, the remaining 6 treated patients showed reduced ¹³¹I uptake, suggesting persistent iodine-avid residual disease. Alternative ¹³¹I dosage regimens and different timing regimens for radioguided surgery have been reported. Negele et al 447 reported using a diagnostic dosage of ¹³¹I in the range of 1.9 to 9.5 mCi (70 to 350 MBq) and radioguided neck surgery performed at 6 to 8 days after the original ¹³¹I dosage. Their utilization of a significantly lower diagnostic dosage of ¹³¹I, rather than a therapeutic dosage (100 mCi), avoided the need for hospitalization prior to the planned radioguided neck surgery 447. Furthermore, Scurry et al 454 reported that radioguided neck surgery was possible for up to three weeks after the administration of a therapeutic dosage of ¹³¹I.

In an effort to shorten the time interval between radionuclide administration and the time to radioguided surgery for iodine-avid recurrent thyroid cancer, Gallowitsch et al 455 reported using ¹²³I instead of ¹³¹I for radioguided surgery for recurrent papillary thyroid cancer using an oral ¹²³I dosage of 2 mCi (74 MBq). The short physical half-life of approximately 13 hours for ¹²³I allows it to be administered on the day of or on the day prior to the planned radioguided surgical procedure for an iodine-avid recurrent thyroid cancer 455456. Unlike ¹³¹I, ¹²³I is a pure gamma photon emitter, is not associated with the potential stunning effect on subsequent radioiodine uptake, and produces less radiation exposure to the patient and the surgeon 456. This concept of using ¹²³I has also been similarly applied to recurrent medullary thyroid cancer by Shimotake at al 457 in which they reported intravenously administering ¹²³I-MIBG at a dosage of 2.7 mCi (100 MBq) at a time 24 hours prior to the planned radioguided surgical procedure. Despite these potentially favorable reasons for utilizing ¹²³I instead of ¹³¹I, the greater expense and relatively limited availability of ¹²³I has contributed to the more popular continued use of ¹³¹I for radioguided surgery for iodine-avid recurrent differentiated thyroid cancers.

In contrast, radioguided surgery of iodine-negative recurrent differentiated thyroid cancer and recurrent medullary thyroid cancer has focused primarily upon the use of ^99mTc-labeled radiopharmaceutical agents, ¹¹¹In-labeled radiopharmaceutical agents, and ¹⁸F-FDG. While ^99mTc-MIBI 458, ^99mTc-dimercaptosuccinic acid (^99mTc(V)-DMSA) 459, and ^99mTc-tetrafosmin 460 have all been utilized for diagnostic gamma camera imaging of iodine-negative recurrent differentiated thyroid cancers, only ^99mTc-MIBI and ^99mTc(V)-DMSA have been described for gamma detection probe-directed radioguided surgery.

Rubello et al 461 reported on 37 patients who underwent a previous total thyroidectomy and subsequent ¹³¹I ablative therapy for differentiated thyroid cancer and who later demonstrated evidence of an iodine-negative recurrence. Each such patient had an elevated thyroglobulin level, a negative ¹³¹I scan, demonstration of recurrent locoregional recurrent disease on a preoperative ^99mTc-MIBI scan and on a high-resolution ultrasound, and no demonstration of distant metastatic disease 461462. Then, each patient was taken to the operating suite and, 10 minutes prior to starting the procedure, was intravenously injected with 1 mCi (37 MBq) of ^99mTc-MIBI. A gamma detection probe was then used to guide resection of all foci of ^99mTc-MIBI uptake. In total, 66 discrete nodules in 37 patients were identified by both high-resolution ultrasound and intraoperative gamma probe detection and were subsequently successfully resected 461. At follow-up ranging from 9 to 57 months, 27 of 37 patients remained disease-free. In contrast to other approaches, the use of ^99mTc-MIBI and intraoperative ultrasound for radioguided surgery of recurrent thyroid cancers is relatively far less expensive and far more available to most medical facilities.

Just as ^99mTc-MIBI has proven benefit for the management of recurrent differentiated thyroid cancer, ^99mTc(V)-DMSA has been shown to be effective in the diagnostic evaluation of recurrent medullary thyroid cancer, with a detection sensitivity of 95% 459. Adams et al 463 reported on medullary thyroid cancer recurrences in 25 patients evaluated by preoperative diagnostic tumor localization imaging by computed tomography, ¹¹¹In-DTPA-D-Phe¹-octreotide imaging, and ^99mTc-(V)-DMSA imaging, as well as by intraoperative surgical palpation and by radioguided surgery using an intraoperative gamma probe detection system. All patients were preoperatively injected with an intravenous dose of 6 mCi (222 MBq) of ¹¹¹In-DTPA-D-Phe¹-octreotide and an intravenous dose of 13.5 mCi (500 MBq) of ^99mTc-(V)-DMSA 463. ¹¹¹In-DTPA-D-Phe¹-octreotide imaging was performed 4 hours and 24 hours after injection. ^99mTc-(V)-DMSA imaging was performed 6 hours after injection. Radioguided surgery was performed approximately 24 hours after ¹¹¹In-DTPA-D-Phe¹-octreotide injection and approximately 6 hours after ^99mTc-(V)-DMSA injection. They demonstrated lesion detection sensitivities of 32%, 34%, and 65% for preoperative diagnostic tumor localization imaging by computed tomography, ¹¹¹In-DTPA-D-Phe¹-octreotide imaging, and ^99mTc-(V)-DMSA imaging, respectively 463. In addition, lesion detection sensitivities were 65% by intraoperative surgical palpation and 97% by radioguided surgery using a combination of channel selection for both ¹¹¹In and ^99mTc on the gamma probe detection unit. In this series, radioguided surgery detected metastases as small as 5 mm in greatest dimension, whereas intraoperative surgical palpation detected metastases only greater than or equal to 1 cm in greatest dimension. Likewise, radioguided surgery was able to identify more than 30% more foci of recurrent medullary thyroid carcinoma compared with conventional preoperative diagnostic tumor localization imaging and intraoperative surgical palpation. Despite these highly encouraging results with recurrent medullary thyroid cancer, ^99mTc(V)-DMSA is no longer commercially available for use.

As mentioned above, ¹¹¹In-DTPA-D-Phe¹-octreotide has been investigated in radioguided surgery for recurrent medullary thyroid cancer 463. However, the overall sensitivity of detecting metastases from recurrent medullary thyroid cancer on diagnostic ¹¹¹In-DTPA-D-Phe¹-octreotide imaging 463 is far less than the overall sensitivity of detecting metastases from iodine-negative recurrent differentiated thyroid cancer on diagnostic ¹¹¹In-DTPA-D-Phe¹-octreotide imaging (34% versus 74%, respectively) 464. Despite the better overall sensitivity of detecting metastases from iodine-negative recurrent differentiated thyroid cancer on diagnostic ¹¹¹In-DTPA-D-Phe¹-octreotide imaging, there is no published data on the use of ¹¹¹In-DTPA-D-Phe¹-octreotide imaging for radioguided surgery for iodine-negative recurrent differentiated thyroid cancer.

¹¹¹In RIGS has been limitedly investigated for recurrent medullary thyroid cancer in France 465466467. These studies have used a two-step radioimmunotargeting system, consisting of a bispecific antibody (composed of a fragment of anti-CEA monoclonal IgG1 that is coupled chemically with a fragment of anti-DTPA monoclonal IgG1) and an ¹¹¹In-labeled bivalent hapten (¹¹¹In-di-DTPA-tyrosyl-lysine). Patients were first intravenously injected with 0.1 mg/kg of body weight of the bispecific antibody. Approximately three to five day later, patients were then injected with 2.7 mCi to 10 mCi (100 MBq to 370 MBq) of the ¹¹¹In-labeled bivalent hapten. RIGS was then performed approximately two to four days later. Using this RIGS protocol for detecting recurrent and metastatic medullary thyroid cancer, de Labriolle-Vaylet et al 467 most recently reported an accuracy of 86%, a sensitivity of 75%, and a specificity of 90% and suggested its value in the surgical management of this disease process.

The use of ¹⁸F-FDG for gamma probe-directed radioguided surgery of iodine-negative recurrent thyroid tumors has been recently investigated in a limited fashion 424547468469470. It is well-established that ¹⁸F-FDG PET imaging is particularly useful in the detection of iodine-negative recurrent differentiated thyroid cancer with reported sensitivities ranging from 85% to 95% 471472 and a specificity as high as 90% 472.

In 2005, Kraeber-Bodéré et al 42 first reported on the use of ¹⁸F-FDG-directed radioguided surgery in 10 patients with iodine-negative recurrent differentiated thyroid cancer. All 10 patients had previously undergone a diagnostic preoperative ¹⁸F-FDG PET/CT scan demonstrating abnormal hypermetabolic activity suggesting cervical recurrence, but with no evidence of distant disease. Then, on the day of surgery, at approximately 30 minutes prior to the start of the surgical procedure, patients were injected with a mean dose of 7.2 mCi (265 MBq) of ¹⁸F-FDG and a subsequent intraoperative radioguided survey of the operative field was performed with a handheld gamma detection probe. Likewise, a completion lymph node dissection was performed in all patients after the intraoperative radioguided survey. A total of 12 abnormal findings were demonstrated on both ¹⁸F-FDG PET/CT and on the intraoperative radioguided survey, with no additional abnormal finding demonstrated on the intraoperative radioguided survey with the gamma detection probe. Based on the results of the completion lymph node dissection that were performed on all of the patients, they demonstrated that diagnostic preoperative ¹⁸F-FDG PET/CT scan and intraoperative radioguided survey failed to identify all sites of additional lymph node microscopic metastases in five of the patients.

More recently, Gulec et al 45 reported on four cases of iodine-negative recurrent thyroid cancer undergoing radioguided surgery among a series of 25 patients with various malignancies 45. In this series, patients were injected with an intravenous dose of 5 to 15 mCi (185 to 555 MBq) of ¹⁸F-FDG at approximately 2 to 6 hours prior to the planned surgical procedure. Subsequent radioguided surgery was performed with successful localization of nonpalpable metastatic lymph nodes and other target tissues.

Most recently, Agrawal et al 470 reported on two cases of iodine-negative recurrent thyroid cancer at The Ohio State University in which a multimodality approach of perioperative ¹⁸F-FDG PET/CT imaging (preoperative patient imaging, specimen imaging, and postoperative patient imaging), intraoperative gamma probe detection, and intraoperative ultrasound were utilized for tumor localization and resection of all sites of hypermetabolic activity. The two patients were intravenously injected with 15 to 20 mCi (555 to 740 MBq) of ¹⁸F-FDG at approximately 120 minutes prior to the planned time of surgery and this multimodality approach allowed for successful identification and resection of all occult sites of iodine-negative recurrent thyroid cancer.

The utility of SLN biopsy for differentiated thyroid cancer remains a topic of major debate. Although it is reported that up to 80% of differentiated thyroid cancer patients have neck lymph node metastases when a lymphadenectomy accompanies the total thyroidectomy 473, only a minority (3% to 30%) of patients will later develop recurrent neck disease 473474. Furthermore, in an extensive literature review, Grebe and Hay 474 concluded that nodal disease at presentation was not a predictor of patient survival for papillary thyroid cancer. As a result, the current management of the central neck compartment lymph nodes consists of intraoperatively identifying suspicious lymph nodes, followed by central compartment and superior mediastinal nodal clearance 475.

In the current literature, only a limited number of studies have been published on the feasibility of radioguided SLN biopsy for thyroid cancer 443476477478479480481482. Those available studies report success of localization in the range of 78% to 100%. In those studies, 0.11 mCi to 3.2 mCi (4 MBq to 120 MBq) of ^99mTc colloidal human albumin was injected intratumorally in a total volume of 0.1 mL to 0.5 mL of normal saline. Preoperative lymphoscintigraphy was generally performed. The hemithyroidectomy or total thyroidectomy was generally performed first, followed by the radioguided SLN biopsy procedure, in order to minimize the "shine through" effect which can be especially problematic in the central neck compartment where the lymph nodes may be otherwise within close proximity to the thyroid gland 476. Despite these encouraging results, it still remains unclear as to whether radioguided SLN biopsy will prove to be of any prognostic value in the management of differentiated thyroid cancer.

Since first described for ovarian cancer by Martin et al in 1988 149578, the feasibility of RIGS has been evaluated by several groups of investigators 149575576577578579580581582. The focus of all these RIGS protocols has been the detection of occult recurrence in those ovarian cancer patients undergoing both second look laparotomy and those undergoing surgery for suspected or confirmed recurrence. Martin et al 149578 evaluated ¹²⁵I-B72.3 murine monoclonal antibody, McIntosh et al 582 evaluated ¹²⁵I-CC49 murine monoclonal antibody, and Krag et al 580 evaluated ¹¹¹I-B72.3 murine monoclonal antibody. Gitsch et al 575576577 and Jäger et al 579 evaluated ¹³¹I-OC125 (anti-CA125) murine monoclonal antibody. Finally, Ind et al 581 evaluated ^99mTc labeled murine monoclonal antibodies SM3 and H17E2. Each of these RIGS protocols utilized similar regimens with intravenous injection of 2 to 5 mCi (74 to 185 MBq) of the radiolabeled monoclonal antibody at an interval of 4 to 42 days prior to the planned surgical procedure 149575576577578579580581582. The reported detection rates for RIGS in these reports ranged from 50% to 80%. Despite these early promising results, no further investigations into RIGS for ovarian cancer have been made in over the last 10 years.

Most recently, ¹⁸F-FDG-directed surgery has been evaluated in the setting of recurrent ovarian cancer 4553583. In 2005, Barranger et al 583 first described ¹⁸F-FDG-directed surgery in a single patient case report for a patient undergoing laparoscopic excision of recurrent ovarian cancer using a ¹⁸F-FDG dose of 0.11 mCi/kg (4 MBq/kg). The most recent and largest report to date is by Cohn et al 53 at The Ohio State University. Three patients undergoing laparotomy for recurrent ovarian cancer underwent preoperative intravenous injection of approximately 10 to 20 mCi (370 to 740 MBq) of ¹⁸F-FDG at approximately 60 to 120 minutes prior to the planned surgical procedure. A combined approach of intraoperative gamma probe detection, specimen PET/CT imaging, and postoperative PET/CT patient imaging was utilized, and demonstrated the feasibility of this approach for establishing the location and extent of disease and confirming complete cytoreduction in selected cases of recurrent ovarian cancer.

The utilization of radioguided SLN biopsy for prostate cancer was first reported in 1999 by Wawroschek et al 610. Since that time, multiple reports have been published on the potential application of radioguided SLN biopsy in the surgical management of prostate cancer 611612613614615616617618619620621622623624625626627628629630631632. Most frequently, ^99mTc colloidal human albumin has been used. However, ^99mTc phytate, ^99mTc sulfur colloid, and ^99mTc rhenium sulfur colloid have also been utilized. Patients undergo the radiocolloid injection at an interval from 6 hours to 24 hours before the planned surgery by an ultrasound-guided transrectal approach and into one to three sites within the peripheral zone of the prostate gland. Total dosage range for the radiocolloid is from 1.6 mCi (60 MBq) to 10.8 mCi (400 MBq), which is injected in a total volume of normal saline from 0.2 mL to 3.0 mL. In most series, a SLN was generally identified in 90% to 100% of patients, a SLN was positive in 12% to 25% of cases, and false negative rates were generally reported as 5% or less.

The largest radioguided SLN biopsy series reported to date was recently published by Weckermann and associates from Augsburg, Germany 627. In their report, they describe 1,055 patients with clinically organ confined prostate cancer undergoing radioguided SLN biopsy, pelvic lymph node dissection, and radical retropubic prostatectomy. A SLN was detected in all patients. A positive SLN were found in 205 patients (19.4%), and only two false negative cases (< 1%) were encountered. One to three positive lymph nodes were found in 95, 50, and 21 cases, respectively, and more than 3 positive lymph nodes were found in 41 cases. Approximately 63% of patients having positive lymph nodes had such positive lymph nodes found outside the region of the standard pelvic lymphadenectomy field. Therefore, Weckermann et al 627 strongly recommended that patients with a positive SLN should undergo extended pelvic lymphadenectomy rather than standard pelvic lymphadenectomy since, in such cases, tumor cells were also additionally detected in non-SLNs.

Finally, several series have reported upon the feasibility of laparoscopic radioguided SLN biopsy 622624629632. Such a minimally-invasive diagnostic approach to the lymph nodes in the management of prostate cancer may ultimately prove valuable in the evaluation of the lymph node status in patients with an intermediate or high risk of nodal metastases who are either being considered for external beam radiation therapy or for robotic prostatectomy. However, no prospective randomized data are available at this time to more fully address this question.

The investigation of RIGS in prostate cancer has been limited to a single report on ¹²⁵I-B72.3 monoclonal antibody and a single report on ¹¹¹In-capromab pendetide. In 1993, Badalament et al 633 from The Ohio State University reported their RIGS feasibility study from ten patients with prostate cancer who were planned for radical retropubic prostatectomy and bilateral pelvic lymphadenectomy and that were intravenously injected with 2 mCi (74 MBq) of ¹²⁵I-B72.3 monoclonal antibody at an interval from 17 to 38 days prior to the anticipated date of surgery. RIGS successfully localized tumor in all ten patients, identified otherwise occult bilateral intraprostatic tumor in three patients, correctly identified regional lymph node metastases in two patients, and demonstrated no false-negative results. In 2000, Anderson et al 634 reported a single case of suspected metastatic prostate cancer in which the patient was intravenously injected with 5 mCi (185 MBq) of ¹¹¹In-capromab pendetide. Four days later, the patient underwent RIGS with surgical excision of a RIGS-positive lymph node in the left supraclavicular region that confirmed the diagnosis of metastatic prostate cancer. Despite these two early reports on RIGS in prostate cancer, no further investigations have occurred since that time.

To date, only three reports exist in the literature on radioguided SLN biopsy for testicular cancer 635636637. The technique of laparoscopic radioguided SLN biopsy was first described in 2002 for clinical stage I testicular cancer by Tanis et al 635 and by Ohyama et al 636.

In a series of 5 patients, Tanis et al described the technique of laparoscopic radioguided SLN biopsy in two patients 635. All patients received an intratesticular injection of 1.4 to 3.7 mCi (52 to 135 MBq) of ^99mTc colloidal human albumin in 0.15 to 0.3 ml of normal saline and underwent subsequent lymphoscintigraphy. The last two patients underwent same-day transperitoneal laparoscopic radioguided SLN biopsy, with identification of two radioactive SLNs in one patient (with no nodal metastases identified) and no radioactive SLNs identified in the second patient.

In a series of 15 patients, Ohyama et al 636 described the technique of laparoscopic radioguided SLN biopsy in five patients. The day before surgery, each patient was injected into the testicular tissue around the tumor in the testicular tunica albuginea with 0.2 mCi (7.5 MBq) of ^99mTc phytate in 0.2 ml of normal saline and underwent subsequent lymphoscintigraphy. The following day, patients one through ten underwent extraperitoneal laparoscopic retroperitoneal lymph node dissection, patients 11 through 14 underwent extraperitoneal laparoscopic radioguided SLN biopsy (with 11 to 14 SLNs removed in each patient and with no nodal metastases identified), and patient 15 underwent extraperitoneal laparoscopic radioguided SLN biopsy with a subsequent confirmatory extraperitoneal laparoscopic retroperitoneal lymph node dissection (with the finding to two micrometastatic disease in SLNs and no metastatic disease in any non-SLNs). Ohyama et al 636 simply concluded that extraperitoneal laparoscopic radioguided SLN biopsy is technically feasible, but requires further clinical study.

Most recently in 2005, Satoh et al 637 reported the most comprehensive series on radioguided SLN biopsy in 22 patients with clinical stage I testicular cancer. The day before surgery, each patient was injected into the testicular tissue around the tumor in the testicular tunica albuginea with 0.4 mCi (15 MBq) of ^99mTc phytate in 0.4 ml of normal saline and underwent subsequent lymphoscintigraphy. The following day, patients underwent extraperitoneal laparoscopic radioguided SLN biopsy with a subsequent confirmatory extraperitoneal laparoscopic retroperitoneal lymph node dissection. Radioactive SLNs were identified in 21 of 22 patients (95%), with one radioactive SLN identified in 15 patients and 2 to 4 radioactive SLN identified in the six other patients. Only two patients (9.5%) had micrometastatic disease in radioactive SLNs. Likewise, none of the 21 patients in which a radioactive SLN was identified had metastatic disease in any non-SLNs harvested at the time of the subsequent confirmatory extraperitoneal laparoscopic retroperitoneal lymph node dissection. Two patients with no metastatic disease in their radioactive SLNs or in their subsequent confirmatory extraperitoneal laparoscopic retroperitoneal lymph node dissection developed lymph node disease in the paraaortic lymph nodes at the level of the renal vein and in the obturator lymph nodes at 10 and 20 months after surgery, respectively. Satoh et al 637 concluded that extraperitoneal laparoscopic radioguided SLN biopsy is technically feasible and has potential value in staging and treatment of patients with early-stage testicular cancer. Nevertheless, the lack of any other subsequent reports in the literature or the mention of radioguided SLN biopsy in the National Comprehensive Cancer Network (NCCN) clinical guidelines for testicular cancer 638 leads one to conclude that this is not yet considered an accepted standard of care.

There is a single reported case in the literature by Gulec et al 43 for using ¹⁸F-FDG-directed surgery for the identification and resection of a hypermetabolic metastatic periaortic lymph node in a case of seminoma.

The utilization of radioguided SLN biopsy for non-small cell lung cancer was first reported in 2000 by Liptay et al 648. Since that time, multiple reports have been published on the potential application of radioguided SLN biopsy in the surgical management of non-small cell lung cancer 649650651652653654655656657658659660661662663664665666667668. ^99mTc tin colloid, ^99mTc sulfur colloid, and ^99mTc colloidal human albumin have all been utilized in radioguided sentinel lymph node biopsy for non-small cell lung cancer. Some authors have advocated preoperative injection of radiocolloid into or around the primary tumor by CT guidance on the day of surgery or on the day before surgery. Other authors have advocated intraoperative injection of radiocolloid into or around the primary tumor after direct visualization of the tumor. While still other authors advocate intraoperative endobronchial injection of radiocolloid into directly visualized endobronchial tumor or transbronchially at the most distal pulmonary sub-segment that could be reached endobronchially within proximity to the primary tumor. Total dosage range for the radiocolloid is from 0.25 mCi (9.25 MBq) to 8 mCi (296 MBq), which is injected in a total volume of normal saline from 0.5 mL to 2.0 mL. In all series reporting more than one hundred patients undergoing radioguided SLN biopsy for non-small cell lung cancer 657659662668, a SLN was generally identified in 70% to 100% of patients and false negative rates were generally reported as 10% or less. Despite these numerous reports and their encouraging results, the routine use of radioguided SLN biopsy in the surgical management of non-small cell lung cancer has not been embraced. Nevertheless, those authors who have played an active role in its evaluation in the surgical management of non-small cell lung cancer remain optimistic about its future applications 669.

The application of RIGS technology to adenocarcinoma of the lung has been previously investigated and reported in an extremely limited fashion 670671. In 1998, Grazia et al 670 intraoperatively evaluated 9 patients with adenocarcinoma of the lung with the gamma detection probe after intravenous injection of 0.9 to 1.5 mCi (33 to 56 MBq) of ¹²⁵I-labeled monoclonal antibody B72.3 at 11 to 44 days (mean of 20.4 days) prior to the surgical procedure. Specific binding to histologically confirmed sites of adenocarcinoma of the lung was noted in all such cases. However, the high radioactive background counts found in the thorax, due to the heart and major vessels, was postulated as a drawback to further investigation of this technique. Likewise, in 1998, Mansi et al 671, evaluated both ¹²⁵I-labeled monoclonal antibody B72.3 and ^99mTc-labeled fragments of the murine anti-CEA monoclonal antibody F023C5 in lung cancer patients. In the first phase of their study, using immunohistochemistry, they found binding of monoclonal antibody B72.3 in only 6 of 45 primary non-small cell lung cancers. Only one operable patient was then intravenously injected with 2 mCi (74 MBq) of ¹²⁵I-labeled monoclonal antibody B72.3 and no selectivity for neoplastic cells was seen during RIGS using the gamma detection probe. In the second phase of their study, 11 patients with squamous cell lung cancer were intravenously injected with 15 mCi (555 MBq) of ^99mTc-labeled fragments of the murine anti-CEA monoclonal antibody F023C5. Immunoscintography was then performed six to 24 hours thereafter. Only one patient was operable and underwent RIGS in concert with a pneumonectomy and lymphadenectomy at a time some 36 hours after the original intravenous injection of the ^99mTc-labeled fragments of the murine anti-CEA monoclonal antibody F023C5. Using the gamma detection probe, in vivo detection of the primary tumor was not accomplished; however, resected neoplastic tissue demonstrated a 2:1 tumor-to-background ratio on ex vivo counting. Likewise, RIGS identified a small lymph node metastasis that was not previously identified by CT scan or immunoscintigraphy. Despite these two early reports on RIGS in lung cancer, no further investigations have occurred since that time.

In 2003, Wang et al 672 reported on a series of 37 patients with lung neoplasms who were intravenously injected with a non-specified dose of ^99mTc-peplomycin. Peplomycin is a semi-synthetic analog of bleomycin. Following injection, patients underwent preoperative scintigraphic imaging for identification of radiotracer uptake by tumor-bearing tissue and were then subsequently taken to the operating room for radioguided surgery using the gamma detection probe. The sensitivity, specificity, and accuracy was reported as 90%, 88%, and 89%, respectively, for identifying malignant lung lesions, and was reported as 91%, 88%, and 90%, respectively, for identifying lymph node metastases.

Much more recently, the application of intraoperative gamma probe detection after a preoperative same-day injection of ¹⁸F-FDG has been reported in a limited number of selected cases of non-small cell lung cancer 45673674. First reported in 2006, Nwogu et al 673 evaluated 10 patients with non-small cell lung cancer that were intravenously injected with approximately 10 mCi (370 MBq) of ¹⁸F-FDG on the day of surgery. All resected primary tumors were FDG-avid. With regards to evaluation of the thoracic lymph nodes, there were 5 cases of true-positive FDG-avid thoracic lymph nodes, 3 cases of false positive FDG-avid thoracic lymph nodes, and 2 false-negative cases in which the thoracic lymph nodes were not FDG-avid but were found to contain metastatic disease. In this regard, and of most recent note, Moffatt-Bruce et al at The Ohio State University 674 has recently reported a combined approach for radioguided localization of FDG-avid tissues for a single case of lung cancer using perioperative ¹⁸F-FDG PET/CT imaging (using a triad of preoperative PET/CT imaging, specimen PET/CT imaging, and postoperative PET/CT imaging) and intraoperative gamma probe detection, in which a dose of approximately 26.1 mCi (966 MBq) ¹⁸F-FDG was injected intravenously approximately 98 minutes prior to the start of radioguided localization of FDG-avid tissues.