Seza Gulec

Fractionated radioimmunotherapy with 90Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial

It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single‐dose yttrium‐90‐labeled hPAM4 (90Y‐hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low‐dose gemcitabine in this disease.

PET probe-guided surgery: applications and clinical protocol

IntroductionParallel to the advances in diagnostic imaging using positron emission tomography (PET), and availability of new systemic treatment options, the treatment paradigm in oncology has shifted towards more aggressive therapeutic interventions to include cytoreductive techniques and metastasectomies. Intraoperative localization of PET positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe.Materials and methodsRecords of patients who underwent PET probe-guided surgery were reviewed. Surgical indications and operative targets were determined based on diagnostic PET/PET-CT images performed prior to probe-guided surgical planning. PET probe-guided surgery was performed on a separate day using a high-energy gamma probe (PET probe, Care Wise Medical, Morgan Hills CA) 2–6 hours post-injection of 5–15 mCi FDG. Probe count rates, target-to-background ratios, and lesion detection success were analyzed.ResultsTwenty-four patients underwent PET probe-guided surgery; one patient had two PET-probe guided surgeries resulting in a total of 25 cases (5 colorectal cancer cases, 4 thyroid cancer cases, 6 lymphoma cancer cases, and 10 other cancer cases). Surgical indication was diagnostic exploration in 6 cases with lymphoma and 1 case with head and neck cancer (28%). The remaining 18 cases (72%) underwent PET probe-guided surgery with a therapeutic intent in a recurrent or metastatic disease setting. All the lesions identified and targeted on a preoperative FDG-PET scan were detected by the PET probe with satisfactory in-vivo lesion count rates and a TBR of ≥ 1.5. PET probe allowed localization of lesions that were non-palpable and non-obvious at surgical exploration in 8 patients.ConclusionThe use of the PET probe improves the success of surgical exploration in selected indications. Separate day protocol is clinically feasible allowing for flexible operating room scheduling.

Unfiltered sulfur colloid and sentinel node biopsy for breast cancer: technical and kinetic considerations.

Background: There are few clinical data on technical limitations and radiocolloid kinetics related to sentinel lymph node (SLN) biopsy for breast cancer.Methods: In 70 clinical node-negative patients, unfiltered99mTc sulfur-colloid was injected peritumorally and cutaneous hot spots were mapped with a gamma probe. SLN biopsy was performed followed by axillary lymph node dissection. Missed radioactive nodes (nodes not under hot spots) were removed from axillary lymph node dissection specimens and submitted separately.Results: At least one hot spot was mapped in 69 patients (98%) and SLNs were retrieved in 62 (89%). No radiolabeled nodes were found in five (7%) and only nodes not under hot spots were retrieved in three patients (4%). Residual nodes not under hot spots were retrieved in 17 patients (24%) in whom at least one SLN specimen had been found. Diffuse radioactivity around the radiocolloid injection site impeded identification of all radiolabeled nodes during SLN biopsy, and was responsible for one of two false negatives (20 node-positive patients; false-negative rate 10%). Hot spot radioactivity, number of radiolabeled nodes, and nodal radioactivity did not change with time interval from radiocolloid injection to surgery (0.75–6.25xa0hours).Conclusions: Although SLN localization rate is high, intraparenchymal injection may predispose to failure of radiocolloid migration, failure to identify SLNs because of high radiation background, and false-negative outcomes. Alternative routes of radiocolloid administration should be explored.

Peripheral Facial Nerve Palsy after High-Dose Radioiodine Therapy in Patients with Papillary Thyroid Carcinoma

Sialoadenitis is a frequent complication of radioiodine treatment, occurring clinically in 10% of patients [1], although biochemical alterations of saliva are present 100% of the time [2]. This is caused by the similar iodine avidity of the salivary gland and thyroid tissue, each achieving a tissue-to-serum ratio of approximately 50 [3]. Administration of thyroid-stimulating hormone can cause a tenfold increase in thyroid iodine uptake [4]. May [5] listed 81 distinct causes of peripheral facial nerve palsies, including traumatic, infectious, and metabolic. Idiopathic Bell palsy accounted for 57% of the 1575 cases he himself reported. Peripheral facial nerve palsy is associated with nonmalignant parotitis. Andrews and colleagues [6] found only 10 reported cases and presented three more. Our extensive MEDLINE search failed to reveal any previously reported associations between facial nerve palsy and radioiodine treatment. We present two cases of facial nerve palsies in patients who developed parotitis after radioiodine therapy. Figure 1. Diagnostic and posttherapy radioiodine scans. top bottom left right Case Reports Patient 1 A 51-year-old man had locally invasive (stage 2) papillary thyroid carcinoma, for which he was treated with a thyroidectomy with lymph node dissection. Nineteen years later, he had a second operation for recurrent disease, which was followed by 1070 MBq (29 mCi) of iodine-131. One year later, he had a radioiodine dosimetry with a thyroid-stimulating hormone of 134 mU/L. The 24-hour thyroid bed and right and left parotid gland uptakes were 2.4%, 9.6%, and 6.9%, respectively. When we retrospectively analyzed the available data points, using Medical Internal Radiation Dose techniques [7], we estimated that the radiation dose delivered with 9620 MBq (260 mCi) to the recurrent thyroid cancer, the right and left parotid glands, and the blood were 112 000, 21 000, 13 500, and 200 rad, respectively. The patient developed severe sialoadenitis with marked engorgement and tenderness of the parotids within 24 hours and lost taste sensation 3 to 4 days later. After 9 days, he developed a partial right peripheral facial nerve palsy and was treated with a 5-day course of prednisone. A magnetic resonance imaging scan of the face showed no abnormalities. At 3 months follow-up, he had nearly total recovery of facial nerve function but had persistent xerostomia. Patient 2 A 60-year-old man had locally invasive (stage 2) papillary thyroid carcinoma. He had a total thyroidectomy with modified neck dissection and two subsequent neck revisions for recurrent disease during the next 5 years. Iodine-131 dosimetry, done when his thyroid-stimulating hormone was 93 mU/L, showed residual tumor. Twenty-four-hour neck and right and left parotid gland uptakes were 2.1%, 0.5%, and 0.4%, respectively. With a 13 690 MBq (370 mCi) dose, the estimated radiation dose delivered to the thyroid cancer, the parotid glands, and the blood were 13 400, 2200, 1500, and 200 rad, respectively. He had only mild midline neck and parotid tenderness. However, 10 days later, he developed a right peripheral facial nerve palsy. No specific treatment was given, and the patient had nearly total resolution during the next few months. Discussion Bell palsy is common, especially in the third to fifth decades of life. The comorbidity of facial nerve palsy in our patients could have been merely chance. However, the compelling temporal relations suggest otherwise. Earll and Kolb [8] described two cases of facial paralysis occurring with severe myxedema. Operative findings in one of his patients suggested that the cause was increased pressure on the seventh cranial nerve within the facial canal. Cox described another patient whose idiopathic Bell palsy failed to resolve until the previously unrecognized hypothyroidism was treated [9]. The duration of frank hypothyroidism in our patients was only 2 to 3 weeks, and they had been restarted on thyroxine for at least 1 week. Nonetheless, myxedema may have contributed to the compression of the facial nerve. The first patient lost taste sensation. Rarely, patients with Bell palsy report an alteration in taste sensation, which is thought to represent concurrent inflammation of the chorda tympani. Alteration in taste is a common complaint in patients having radioiodine treatment. The exact mechanism is uncertain, but decreased saliva production and altered composition have been proposed. Typically, the chorda tympani branches separate from the facial nerve 4 mm proximal to the stylomastoid foramen. Thus, it is unlikely that parotitis should involve the chorda tympani. Inflammation involving the facial nerve could have caused the development of the paralyses in our patients. Lee described the development of vocal cord paralysis after radioiodine therapy and postulated that it was caused by local inflammation [10]. However, the onset of weakness occurred at least a week after the peak inflammation and several days after the clinical resolution of parotitis. Further, the patients differed in the degree of salivary gland uptake and clinical sialoadenitis (Figure 1). Neither patient had clinical evidence of tumor infiltration of the parotid glands. Another possible explanation is direct radiation injury to the facial nerve. The radiation from iodine-131 penetrates approximately 2 to 3 mm. Thus, highly concentrating parotid tissue surrounding a strategic point along the nerve or vaso nervosum could have caused sufficient damage. Conclusion Peripheral facial nerve palsy developed after high-dose radioiodine treatment in two patients. Possible causes include coincidental Bell palsy, parotitis, myxedematous changes, or direct radiation effect.

A Thousand Points of Light or Just Dim Bulbs? Radiolabeled Antibodies and Colorectal Cancer Imaging

Radioimmunoscintigraphy (RIS) is coming into its own as an imaging modality in clinical oncology. Early experience with indium-111-labeled intact murine monoclonal antibodies (MoAbs) in colorectal cancer suggested that RIS images hepatic metastases poorly. Moreover, an antimurine immune response was frequently provoked, precluding multiple follow-up RIS studies in individual patients due to reticuloendothelial sequestration of the radioimmunoconjugate before tumor targeting could occur. Recent trials of technetium-99m-labeled antibody fragments and human MoAbs have demonstrated significant improvement in imaging efficacy, and repeated or serial imaging is possible because of the absence of associated immunogenicity. RIS is demonstrably more sensitive than conventional diagnostic modalities (CDM) such as computed tomography (CT) for detection of extrahepatic abdominal and pelvic colorectal carcinoma and is complementary to CDM in imaging liver metastases. In a surgical decision-making analysis comparing CT, RIS (IMMU-4 99mTc-Fab; CEA-Scan), and CT plus RIS in patients with recurrent or metastatic colorectal cancer, CT plus RIS improved correct prediction of resectability by 40% and correct prediction of unresectability by 100% compared with CT alone. At the present time, RIS used in combination with CDM contributes an incremental improvement in diagnostic accuracy in colorectal cancer patients with known or suspected recurrent disease. Basic and clinical research currently in progress promises to yield agents and methods that provide rapid high-resolution imaging, high tumor-to-background ratios in all organs at risk for tumor recurrence or metastasis, negligible immunogenicity and toxicity, and a significant further improvement in the accuracy of clinical decision making in oncology patients.

A 3-D Liver Segmentation Method with Parallel Computing for Selective Internal Radiation Therapy

This study describes a new 3-D liver segmentation method in support of the selective internal radiation treatment as a treatment for liver tumors. This 3-D segmentation is based on coupling a modified k-means segmentation method with a special localized contouring algorithm. In the segmentation process, five separate regions are identified on the computerized tomography image frames. The merit of the proposed method lays in its potential to provide fast and accurate liver segmentation and 3-D rendering as well as in delineating tumor region(s), all with minimal user interaction. Leveraging of multicore platforms is shown to speed up the processing of medical images considerably, making this method more suitable in clinical settings. Experiments were performed to assess the effect of parallelization using up to 442 slices. Empirical results, using a single workstation, show a reduction in processing time from 4.5 h to almost 1 h for a 78% gain. Most important is the accuracy achieved in estimating the volumes of the liver and tumor region(s), yielding an average error of less than 2% in volume estimation over volumes generated on the basis of the current manually guided segmentation processes. Results were assessed using the analysis of variance statistical analysis.

Liver Resection for Metastatic Disease After Y90 Radioembolization: A Case Series with Long-Term Follow-Up

IntroductionThere are only few reports of liver resections for metastatic disease in patients previously treated with Y-90 radioembolization (RE), and long-term outcome data are sparse. We reviewed our center’s experience in patients undergoing hepatectomy after hepatic RE.MethodsA retrospective chart review of patients undergoing RE from 2004 to 2011 was performed. Demographic, clinicopathologic, operative, and long-term outcomes variables were collected. Independent pathologic review of tumor necrosis and normal liver tissue grading of fibrosis and inflammation after resection was performed. Data are expressed as medians and ranges.ResultsRE was delivered to 106 patients with primary and metastatic disease of the liver, of whom 9 patients (6 males, 3 females, median age 54 (47–76) years) with metastatic disease ultimately underwent resection. RE was previously administered to the right liver in five, the left liver in one, and to the whole liver in three. Two patients had a second RE performed before resection. Six of the nine patients had previously received several infusions of cytotoxic therapy. The operations occurred at a median of 115 (56–245) days after RE and included right lobectomy (nxa0=xa05), left lobectomy (nxa0=xa01), left-lateral sectionectomy (nxa0=xa01), and bilobar wedge resections (nxa0=xa02). Extrahepatic sites were resected in three patients. Median blood loss was 900 (range 250–3600)xa0ml. Grade 3 or higher complications occurred in seven cases (78xa0%). Follow-up was complete all nine patients. Three patients (33xa0%) died within 30xa0days of resection. All those surviving the operative period had disease recurrence (time to recurrence: 202 [range 54–315]xa0days), and all have since died (overall survival: 584 [range 127–1230]xa0days). Review of resected specimens demonstrated median tumor necrosis of 70xa0% (range 20–90xa0%). In nontumor-bearing liver, fibrosis grade (0–4) and inflammation score (0–4) was 2 or less in all specimens.ConclusionsIn this small cohort of highly selected and heavily pretreated patients, long-term survival in patients undergoing resection after RE appears possible, but the operations may carry substantial risks—highlighting the importance of careful patient selection for these resections. The etiology of morbidity and mortality is likely multifactorial and additional reports that include long-term outcomes will be necessary to identify more clearly the impact of RE on postoperative complications and death.

Lyophilized Kit for the Preparation of the PET Perfusion Agent [68Ga]-MAA

Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was 68Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with 68Ga. Labeling was performed at different temperatures and times. 68Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a 68Ga purification system was used, compared to 80% with unpurified 68Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours.

An algorithm for PET tumor volume and activity quantification: Without specifying camera's point spread function (PSF)

PURPOSEnThe authors have developed an algorithm for segmentation and removal of the partial volume effect (PVE) of tumors in positron emission tomography (PET) images. The algorithm accurately measures functional volume (FV) and activity concentration (AC) of tumors independent of the cameras full width half maximum (FWHM).nnnMETHODSnA novel iterative histogram thresholding (HT) algorithm is developed to segment the tumors in PET images, which have low resolution and suffer from inherent noise in the image. The algorithm is initiated by manually drawing a region of interest (ROI). The segmented tumors are subjected to the iterative deconvolution thresholding segmentation (IDTS) algorithm, where the Van-Citterts method of deconvolution is used for correcting PVE. The IDTS algorithm is fully automated and accurately measures the FV and AC, and stops once it reaches convergence. The convergence criteria or stopping conditions are developed in such a way that the algorithm does not rely on estimating the FWHM of the point spread function (PSF) to perform the deconvolution process. The algorithm described here was tested in phantom studies, where hollow spheres (0.5-16 ml) were used to represent tumors with a homogeneous activity distribution, and an irregular shaped volume was used to represent a tumor with a heterogeneous activity distribution. The phantom studies were performed with different signal to background ratios (SBR) and with different acquisition times (1 min, 3 min, and 5 min). The parameters in the algorithm were also changed (FWHM and matrix size of the Gaussian function) to check the accuracy of the algorithm. Simulated data were also used to test the algorithm with tumors having heterogeneous activity distribution.nnnRESULTSnThe results show that changing the size and shape of the ROI during initiation of the algorithm had no significant impact on the FV. An average FV overestimation of 30% and an average AC underestimation of 35% were observed for the smallest tumor (0.5 ml) over the entire range of noise and SBR level. The difference in average FV and AC estimations from the actual volumes were less than 5% as the tumor size increased to 16 ml. For tumors with heterogeneous activity profile, the overall volume error was less than 10%. The average overestimation of FV was less than 10% and classification error was around 11%.nnnCONCLUSIONSnThe algorithm developed herein was extensively tested and is not dependent on accurately quantifying the cameras PSF. This feature demonstrates the robustness of the algorithm and enables it to be applied on a wide range of noise and SBR within an image. The ultimate goal of the algorithm is to be able to be operated independent of the camera type used and the reconstruction algorithm deployed.PURPOSEnThe authors have developed an algorithm for segmentation and removal of the partial volume effect (PVE) of tumors in positron emission tomography (PET) images. The algorithm accurately measures functional volume (FV) and activity concentration (AC) of tumors independent of the cameras full width half maximum (FWHM).nnnMETHODSnA novel iterative histogram thresholding (HT) algorithm is developed to segment the tumors in PET images, which have low resolution and suffer from inherent noise in the image. The algorithm is initiated by manually drawing a region of interest (ROI). The segmented tumors are subjected to the iterative deconvolution thresholding segmentation (IDTS) algorithm, where the Van-Citterts method of deconvolution is used for correcting PVE. The IDTS algorithm is fully automated and accurately measures the FV and AC, and stops once it reaches convergence. The convergence criteria or stopping conditions are developed in such a way that the algorithm does not rely on estimating the FWHM of the point spread function (PSF) to perform the deconvolution process. The algorithm described here was tested in phantom studies, where hollow spheres (0.5-16 ml) were used to represent tumors with a homogeneous activity distribution, and an irregular shaped volume was used to represent a tumor with a heterogeneous activity distribution. The phantom studies were performed with different signal to background ratios (SBR) and with different acquisition times (1 min, 3 min, and 5 min). The parameters in the algorithm were also changed (FWHM and matrix size of the Gaussian function) to check the accuracy of the algorithm. Simulated data were also used to test the algorithm with tumors having heterogeneous activity distribution.nnnRESULTSnThe results show that changing the size and shape of the ROI during initiation of the algorithm had no significant impact on the FV. An average FV overestimation of 30% and an average AC underestimation of 35% were observed for the smallest tumor (0.5 ml) over the entire range of noise and SBR level. The difference in average FV and AC estimations from the actual volumes were less than 5% as the tumor size increased to 16 ml. For tumors with heterogeneous activity profile, the overall volume error was less than 10%. The average overestimation of FV was less than 10% and classification error was around 11%.nnnCONCLUSIONSnThe algorithm developed herein was extensively tested and is not dependent on accurately quantifying the cameras PSF. This feature demonstrates the robustness of the algorithm and enables it to be applied on a wide range of noise and SBR within an image. The ultimate goal of the algorithm is to be able to be operated independent of the camera type used and the reconstruction algorithm deployed.

A multimodality localization technique for radio-guided surgery

BackgroundIntraoperative localization of image or endoscopy-detected lesions occasionally pose surgical challenges due to the small lesion size and/or difficult anatomic exposure. Identification of such lesions can be facilitated using a hand-held gamma probe with utilization of Tc-99m macroaggregate albumen (MAA) localization technique. The radiopharmaceutical injection can be performed using ultrasound (US) or endoscopy guidance.Case presentationsThe clinical use of the Tc-99m MAA protocol gamma probe-guided surgery was discussed in three representative cases. Surgical indication was diagnostic exploration in two patients with suspicious lymphadenopathy, and determination of extent of surgical resection in a patient with polyposis. Lesion localization with 100 microcurie (3.7 MBq) Tc-99m MAA prior to surgical exploration resulted in definitive localization of lesions intraoperatively.ConclusionThe use Tc-99m MAA deposition technique at the site of surgical target is a highly efficient radio-guided surgery technique with definitive impact on the success of surgical exploration in selected indications.