Methylene Blue/Collagen Mixture for CT-Guided Presurgical Lung Nodule Marking: High Efficacy and Safety.

PURPOSE: To assess outcomes of computed tomography (CT)-guided methylene blue/collagen marking of preoperative lung nodules before video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery (RATS). MATERIALS AND METHODS: A retrospective cohort study assessing 25 methylene blue/collagen solution CT-guided lung nodule localization procedures on 26 nodules in 25 patients was performed. The procedures were performed by a fellowship-trained radiologist 1-2 hours before scheduled surgery under local anesthesia. Approximately 4-6 ml of methylene blue/collagen solution was injected in a perinodular location under CT guidance with a 19-gauge trocar needle and along the track to the visceral pleural surface. Post-procedural CT images confirmed appropriate lung nodule location marking. RESULTS: Perinodular CT-guided trocar needle placement was achieved in all marking procedures (n = 26/26). Increased consolidation near the target nodule was also demonstrated in all patients on the post-procedural localized CT scans. One patient with moderate emphysema developed a small to moderate-sized pneumothorax (∼20%-30%), and an 8-Fr thoracentesis catheter was placed under CT guidance before surgery. There was no bleeding or hemoptysis in any patient. Methylene blue/collagen solution was readily visible by the thoracic surgeon in association with all target nodules. One patient required conversion to open procedure due to the proximal portion of the right lower lobe pulmonary artery segmental branch. Of the 26 identified nodules, pathology specimens confirmed the adequacy of nodule resection in all cases. CONCLUSIONS: Preoperative CT-guided methylene blue/collagen solution injection offers a safe and highly effective technique for marking subpleural lung nodules undergoing VATS or RATS.

Percutaneous Cryoablation of Renal Tumors: Is It Time for a New Paradigm Shift?

PURPOSE: To retrospectively assess long-term outcomes of percutaneous renal cryoablation, including factors affecting complications and local recurrence rates. MATERIALS AND METHODS: A total of 357 computed tomographic (CT) fluoroscopy-guided percutaneous cryoablation procedures were performed for 382 masses in 302 outpatients; 347 were biopsy-proven renal-cell carcinoma (RCC) or Bosniak category > III masses (n = 28). Benign pathologic conditions (n = 18) or metastatic non-RCC disease (n = 17) were included to analyze procedural complication rate, but recurrence rates, tumor staging, and nephrometry score were limited to RCCs. The average tumor diameter was 2.9 cm (range, 1-10.3 cm), and median nephrometry score for RCC was 8 (mean, 7.4). Protection of adjacent vital structures was performed in 34% of procedures (n = 121), and ureteral stent placement was performed for 9.2% (n = 33). All major complications were graded per surgical Clavien-Dindo criteria. RESULTS: The average CT-visible cryoablation zone diameter was 5 cm (range, 2.5-10.5 cm). Grade ≥ 3 complications occurred in 2.8% of procedures (n = 10), and appeared related to only high nephrometry scores (P = .0086) and larger tumors (P = .0034). No significant changes in renal function before and after the procedure were noted (P = .18). At a mean follow-up of 31.8 months, the local tumor recurrence rate was 3.2% (11 of 347) for RCC, and no significant difference was noted between tumors larger or smaller than 3 cm (P = .15). The difference reached significance only among the small number of stage ≥ T2 RCC tumors (P = .0039). CONCLUSIONS: Long-term follow-up of percutaneous renal cryoablation demonstrates low recurrence rates with preserved renal function, even for patients with high nephrometry scores and body mass index, assuming thorough cytotoxic technique and protection measures.

Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs.

Tyrosinemia type I (TYR I) is caused by autosomal recessive fumarylacetoacetate hydrolase deficiency and is characterized by development of severe liver disease in infancy and neurologic crises. If left untreated, most patients die of liver failure in the first years of life. Intervention with medication is effective when initiated during the first month of life. This improvement in the treatment of TYR I patients influenced the decision to include TYR I in the US Secretary of the Department of Health and Human Services' (HHS) Recommended Uniform Screening Panel. However, while tyrosine is routinely measured in newborn screening (NBS) by tandem mass spectrometry (MS/MS), elevated tyrosine levels are not specific to TYR I. To improve the specificity of NBS for TYR I, several assays were developed to measure succinylacetone (SUAC) in dried blood spots (DBS). SUAC is a pathognomonic marker of TYR I, and its detection by NBS MS/MS is possible. This review of the current status of NBS for TYR I in the US is the result of discussions at the HHS Secretary's (Discretionary) Advisory Committee on Heritable Disorders in Newborns and Children about the inconsistent implementation of effective NBS for TYR I in the US. We sought to understand the different TYR I screening practices in US NBS programs. Results indicate that 50 out of 51 NBS programs in the US screen for TYR I, and a successful SUAC performance evaluation scheme is available from the Centers for Disease Control and Prevention. Programmatic and methodological barriers were identified that prevent widespread adoption of SUAC measurements in NBS laboratories. However, since SUAC detection is currently the best approach to NBS for TYR I, a further delay of the addition of SUAC measurement into NBS procedures is discouraged. SUAC measurement should improve both the false positive and false negative rate in NBS for TYR I thereby yielding the desired benefits for affected patients at no expense to the overall population served.

Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes.

PURPOSE: To assess whether diverse tumor location(s) show differences in percutaneous cryoablation (PCA) outcomes of cancer control, morbidity, and ablation volume reduction for many soft-tissue tumor types. MATERIALS AND METHODS: A total of 220 computed tomography (CT)- and/or ultrasonography-guided percutaneous cryotherapy procedures were performed for 251 oligometastatic tumors from multiple primary cancers in 126 patients. Tumor location was grouped according to regional sites: retroperitoneal, superficial, intraperitoneal, bone, and head and neck. PCA complications were graded according to Common Terminology Criteria for Adverse Events (version 4.0). Local tumor recurrence and involution were calculated from ablation zone measurements, grouped into 1-, 3-, 6-, 12-, 18-, and 24-month (or later) statistical bins. RESULTS: Tumor and procedure numbers for each site were 75 and 69 retroperitoneal, 76 and 62 superficial, 39 and 32 intraperitoneal, 34 and 34 bone, and 27 and 26 head and neck. Average diameters of tumor and visible ice during ablation were 3.4 and 5.5 cm, respectively. Major complications (ie, grade >3) attributable to PCA occurred after five procedures (2.3%). At 11 months average follow-up (range, 0-82 mo), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. Average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%. CONCLUSIONS: CT-guided PCA is a broadly safe, effective local cancer control option for oligometastatic disease with soft-tissue tumors in most anatomic sites. Other than bowel and nerve proximity, PCA also shows good healing if proper visualization and precautions are followed.

Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation.

PURPOSE: To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312-$59,554 per LYG. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC.

Preliminary proficiency testing results for succinylacetone in dried blood spots for newborn screening for tyrosinemia type I.

BACKGROUND: Succinylacetone (SUAC) is the primary metabolite accumulated in tyrosinemia type I--an inborn error of metabolism that, if untreated, can cause death from liver failure during the first months of life. Newborn screening laboratories measure SUAC in dried blood spot (DBS) samples to detect asymptomatic tyrosinemia type I. We used panels of SUAC-enriched DBSs to compare and evaluate the performance of these screening tests. METHODS: We prepared sets of DBS materials enriched with predetermined SUAC concentrations and distributed samples of these materials, along with a screening practices questionnaire, to laboratories that perform SUAC tests. We compared their reported SUAC concentrations and questionnaire responses to identify screening practices that affect SUAC test outcomes. RESULTS: Data from 2 pilot surveys showed large differences among laboratories in SUAC recoveries, reproducible within-laboratory recoveries, and stable performance of the DBS materials. Results from 257 proficiency test analyses contained a total of 6 false-negative misclassifications. Reported recoveries of added SUAC ranged from 0 to >200%. Low-biased SUAC recoveries were associated with 1 method used by 5 laboratories. All laboratories that reported SUAC recoveries > or =100% used DBS matrix calibrators. CONCLUSIONS: The wide ranges of SUAC concentrations reported for pilot and proficiency testing specimens demonstrate a need to harmonize quantitative results among laboratories. Although DBS matrix calibrators are important for optimizing SUAC recoveries, the preparation of these calibrators is not standardized among laboratories. Certified DBS-based SUAC calibrators are needed for accuracy and harmonization.

Cryotherapy for breast cancer: a feasibility study without excision.

PURPOSE: To assess the feasibility of percutaneous multiprobe breast cryoablation (BC) for diverse presentations of cancers that remained in situ after BC. MATERIALS AND METHODS: After breast magnetic resonance (MR) imaging and thorough consultation, patients underwent BC after giving informed consent. This study was approved by the institutional review board. In 12 BC sessions, 22 breast cancer foci (stages I-IV) were treated in 11 patients who refused surgery by using multiple 2.4-mm cryoprobes. Five patients had recurrent disease and six had new diagnoses. With use of only local anesthesia, six patients were treated with ultrasonographic (US) guidance and five were treated with both computed tomographic (CT) and US guidance. Saline injections and warming bags were used to protect the skin. Procedure success was defined as 1 cm visible ice beyond all tumor margins. MR imaging and/or clinical follow-up were available for up to 72 months after BC. RESULTS: US produced sufficient ice visualization for small tumors, whereas CT helped confirm overall ice extent. The mean pretreatment breast tumor diameter was 1.7 cm +/- 1.2 (range, 0.5-5.8 cm), and an average of 3.1 cryoprobes produced 100% procedural success with mean ice diameters of 5.1 cm +/- 2.2 (range, 2.0-10.0 cm). No significant complications, retraction, or scarring were noted. Biopsies at the margins of the cryoablation site immediately after BC and at follow-up were all negative. No local recurrences have been noted at an average imaging follow-up of 18 months. CONCLUSIONS: In conjunction with thorough pre- and postablation MR imaging, CT/US-guided multiprobe BC safely achieved 1 cm visible ice beyond tumor margins with minimal discomfort, good cosmesis, and no short-term local tumor recurrences.

Image-guided percutaneous cryotherapy for the management of gynecologic cancer metastases.

OBJECTIVE: To report the clinical response to image-guided percutaneous cryotherapy (IPC) for the palliative management of localized metastases in patients with gynecologic malignancies. METHODS: Institutional review board approval and patient consent were obtained. Gynecologic oncology patients were identified from our institution's cryotherapy database from August 2003 to August 2007. Cryotherapy was performed with 2.4 mm diameter probes (Endocare, Irvine, CA) with ultrasound or computerized tomography (CT) guidance under conscious sedation and local anesthesia. Follow-up was conducted by imaging studies and clinical encounters, using Response Evaluation Criteria in Solid Tumors (RECIST criteria). RESULTS: Twenty-eight ablation sessions were performed for 41 metastatic foci in 15 patients with gynecologic malignancies. Twelve patients had prior chemotherapy and 5 patients had prior radiation. Median follow-up was 317.5 days (range 95-1189). Median post-procedure pain score: 3/10 (range 0-5). Mean initial tumor size was 2.6 cm in maximal diameter. Median reduction in tumor diameter at 1 month was 21.4% (range 2-67.4%), at 3 months was 43.6% (range 16-80.4%), at 6 months was 54.7% (range (16.6-88.9%) and at 9 months was 58.2% (range 32-88.9%). Ten patients received concurrent chemotherapy, 8 had progression of disease at other sites and 2 had stable disease, while the cryotherapy site improved. One of 5 patients who had cryotherapy in the previously irradiated zone had recurrence. A liver capsule hematoma developed as an immediate complication in one patient and an enterocutaneous fistula developed in another. CONCLUSION: IPC is a well-tolerated, effective tool for local control of isolated metastatic foci as a single-modality treatment and for local control of symptomatic metastases in select patients undergoing systemic therapy for the management of gynecologic malignancies.

CT-guided percutaneous cryotherapy of renal masses.

PURPOSE: To assess the results of initial and current techniques for percutaneous renal cryotherapy, including long-term imaging outcomes. MATERIALS AND METHODS: Computed tomography (CT)-guided percutaneous cryotherapy was performed on 49 masses in 48 outpatients and procedure comfort noted for each. These 49 masses included 36 primary renal cell carcinomas (RCCs), 3 oncocytomas, 1 angiomyolipoma, 6 renal inflammatory lesions, 2 benign parenchymal changes, and 1 colon cancer metastasis. All complications were graded according to standardized criteria. RESULTS: Patients received only local anesthesia and moderate sedation during the procedure and were discharged with minimal discomfort within 4-6 hours. All cryotherapy zones were well defined by CT during ablation as hypodense ice with an average diameter of 5.3 cm, covering an average tumor size of 3.3 cm. Average ablation zone diameters showed significant reduction over time (P < .001), becoming significantly less than the original tumor size by 12 months (P < .05). Major and minor complications were seen in 3 (6%) and 11 (22%) procedures, respectively. At a mean follow-up of 1.6 years (range, 1 week to 3.8 years) for primary RCC patients, four failures (11.1%) by imaging criteria were noted, but one proved to be inflammatory tissue at re-biopsy (estimated neoplastic failure rate = 3/36 = 8.3%). CONCLUSIONS: Percutaneous renal cryotherapy is a well-tolerated outpatient procedure that allows safe, CT monitoring of ice formation beyond visible tumor margins. With appropriate cryoprobe placements, a low failure rate appears less dependent on tumor size or location. Ablation volume involution was >80% after 6 months.

Percutaneous cryoablation of hepatic tumors: long-term experience of a large U.S. series.

PURPOSE: To report our long-term experience with percutaneous cryotherapy for primary and metastatic liver tumors, including historical perspectives on complications over time and local recurrence rates. MATERIALS AND METHODS: Following IRB approval under HIPAA compliance, 342 CT fluoroscopic-guided, percutaneous cryotherapy procedures were performed for 443 masses in 212 outpatients with hepatocellular carcinoma (HCC; N = 36), or metastatic disease (N = 176), grouped as colorectal carcinoma (CRC) and non-CRC metastases. Tumor and ablation sizes were noted in relation to adjacent vasculature. All complications were graded according to standardized criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, 24 months and yearly thereafter. Local recurrences were defined as either "procedural" within the ice ablation zone, or "satellite" within 1 cm of the ablation rim to evaluate recurrence patterns. RESULTS: Average tumor diameter of 2.8 cm was treated by average cryoprobe number of 4.5, which produced CT-visible ice ablation zone diameters averaging 5.2 cm. Grade >3 complications were primarily hematologic [N = 20/342; (5.8%)], and appeared related to pre-procedural anemia/thrombocytopenia, carcinoid tumor type, and large ablation volumes. No significant central biliary leak, strictures, or bilomas were noted. At a mean follow-up of 1.8 years, local tumor recurrences were 5.5%, 11.1%, and 9.4% for HCC, CRC, and non-CRC metastases, respectively, consisting mainly of satellite foci. No significant difference was noted for local recurrences near major blood vessels or tumors >3 cm diameter. CONCLUSIONS: Percutaneous hepatic cryotherapy is a well-visualized, safe procedure that produces very low local recurrence rates, even for tumors near vasculature and diameters over 3 cm. Cryoablation deserves to be in the armamentarium of percutaneous hepatic ablation, especially with careful patient selection for tumors <4 cm and patients with platelet counts >100,000. Percutaneous hepatic cryoablation represents a highly flexible technique with particular benefits near central biliary structures and/or adjacent crucial structures.

Galactose-1-phosphate uridyltransferase dried blood spot quality control materials for newborn screening tests.

OBJECTIVES: We aimed to prepare dried-blood-spot (DBS) quality control (QC) materials for galactose-1-phosphate uridyltransferase (GALT), to evaluate their stability during storage and use, and to evaluate their performance in five DBS GALT test methods. DESIGN AND METHODS: We prepared and characterized GALT-normal and GALT-deficient DBS materials and compared GALT activities in DBSs after predetermined storage intervals at controlled temperatures and humidities. External evaluators documented the suitability of the DBS QC materials for use in five GALT test methods. RESULTS: GALT activity losses from DBSs stored in low (<30%) humidity for 14 days at 45°C, 35 days at 37°C, 91 days at room temperature, 182 days at 4°C, and 367 days at -20°C were 54%, 53%, 52% 23%, and 7% respectively. In paired DBSs stored in high humidity (>50%) for identical intervals, losses were: 45°C-68%; 37°C-79%; room temperature-72%, and 4°C-63%. GALT activities in DBSs stored at 4°C were stable throughout 19 excursions to room temperature. Twenty-five of 26 external evaluators, using five different GALT test methods, classified the GALT-deficient DBSs as "outside normal limits". All evaluators classified the GALT-normal DBSs as "within normal limits". CONCLUSIONS: Most of the GALT activity loss from DBSs stored at elevated or room temperature was attributable to the effects of storage temperature. Most of the loss from DBSs stored at 4°C was attributable to the effects of elevated humidity. Loss from DBSs stored at -20°C was insignificant. The DBS materials were suitable for monitoring performance of all five GALT test methods.

Outcomes from tandem mass spectrometry (MS/MS) workshops in the United States and the performance evaluation of MS/MS laboratories.

Disorders of fatty acid oxidation and organic acid metabolism produce serious clinical problems including death. Introduction of MS/MS technology for newborn screening allowed detection of these disorders in a single process, more than doubling the number of disorders that can be detected from dried-blood spots in newborn screening. Expanded newborn screening has become a critical issue with increased public awareness and demands. Screening by MS/MS is operational in several private testing and public health laboratories. Guidelines and quality assurance services are essential to enhance program expansions. The first of two workshops was organized in June 2000 and the second in September of 2001 to discuss procedures for integrating MS/MS into newborn screening programs. Both workshops addressed technical problems encountered with implementing MS/MS testing. One outcome of the first workshop was a pilot survey for assessing performance of MS/MS laboratories worldwide, which occurred in September 2000. This pilot survey led to the expansion of the proficiency testing services to include MS/MS testing. There are 32 participating laboratories, three of the ten countries represented are from the Asia-Pacific Region.

Stabilities of hemoglobins A and S in dried blood spots stored under controlled conditions.

OBJECTIVE: We aimed to measure separately the contributions of heat and humidity to changes in levels of hemoglobins A and S in dried-blood-spot (DBS) samples. DESIGN AND METHODS: We stored paired sets of DBSs at 37°C for predetermined intervals in low-humidity and high-humidity environments. Hemoglobin A and S levels of all samples in each complete set were measured in a single high performance liquid chromatography run. RESULTS: During the one-month storage intervals, both hemoglobin species lost about 35% of initial levels in low-humidity storage and almost all of initial levels in high-humidity storage. CONCLUSIONS: Minimizing both humidity and temperature in the transportation and storage environments of DBS samples is essential to maintaining the integrity of the hemoglobin tetramer molecules.

Induction of specific cellular and humoral responses against renal cell carcinoma after combination therapy with cryoablation and granulocyte-macrophage colony stimulating factor: a pilot study.

Cryotherapy offers a minimally invasive treatment option for the management of both irresectable and localized prostate, liver, pulmonary, and renal tumors. The antineoplastic effects of cryotherapy are mediated by direct tumor lysis and by indirect effects, such as intracellular dehydration, pH changes, and microvascular damage resulting in ischemic necrosis. In this study, we investigated whether percutaneous cryoablation of lung metastasis from renal cell carcinoma (RCC) in combination with aerosolized granulocyte-macrophage colony stimulating factor can induce systemic cellular and humoral immune responses in 6 patients with RCC. Peripheral blood mononuclear cells (PBMCs) were sequentially studied up to 63 days post cryoimmunotherapy (CI). PBMC from pre and post CI were phenotyped for lymphocyte subsets and tested for cytotoxicity and interferon-γ EliSpots directed at RCC cells. Humoral responses were measured by in vitro antibody synthesis assay directed at RCC cells. The immune monitoring data showed that CI induced tumor specific cytotoxic T lymphocyte, specific in vitro antitumor antibody responses, and enhanced Th1 cytokine production in 4 of 6 patients. More importantly, the magnitude of cellular and humoral antitumor response seems to be associated with clinical responses. These pilot data show that CI can induce robust and brisk cellular and humoral immune responses in patients with metastatic RCC, but requires further evaluation in optimized protocols.

Performance properties of filter paper devices for whole blood collection.

BACKGROUND: The Newborn Screening Quality Assurance Program at the Centers for Disease Control and Prevention assesses the adherence to established performance standards of manufactured lots of whole blood filter paper collection devices that are registered by the US FDA. We examined 26 newborn screening analytes measured from blood applied to filter papers from two FDA-cleared sources, Whatman(®) Grade 903 and Ahlstrom Grade 226. The dried blood spots contained analytes at both single levels and dose-response series. RESULTS: We observed overlap at one standard deviation for each analyte, with no more than 4-5% difference between the papers. CONCLUSION: The data demonstrated similarities of analyte recovery between the papers, indicating comparability of the devices for newborn screening and other applications.

Quantification of malonylcarnitine in dried blood spots by use of MS/MS varies by stable isotope internal standard composition.

BACKGROUND: The utilization of MS/MS for the analysis of amino acids and acylcarnitines from dried blood spots (DBS) is routine in many newborn screening (NBS) laboratories. Recently, malonylcarnitine (C3DC) was shown to be elevated in the DBS of affected infants with malonic acidemia. Quantitative features were unknown, so that its measurement was an approximation. Synthesis of malonylcarnitine enabled both a study in the analytical characteristics of C3DC and a survey of its measurement in NBS laboratories. METHODS: Malonylcarnitine was enriched in blood and spotted onto filter paper cards. The DBS were sent to several laboratories for analysis, and the results were returned to the Centers for Disease Control and Prevention (CDC) for evaluation. Reports included a description of the MS/MS method utilized. RESULTS: A pilot proficiency survey shows a bimodal distribution of data from 98 laboratories. Analysis of proficiency data reveals the use of different stable isotope internal standards for quantification. Analysis of standard, labeled or unlabelled ((2)H(3)-octanoylcarnitine (C8), glutarylcarnitine (C5DC) and malonylcarnitine (C3DC) revealed significantly different ion detection values. Quantification in laboratories is based on the ratio of the metabolite in question to a reference stable isotope standard. CONCLUSIONS: Quantification of metabolites depends upon the reference isotope standard utilized. Quantification requires describing the standards used for estimation of concentration (a pseudo-concentration) and a notation that includes a reference to the isotope standard used. This descriptive method will enable harmonization of data in screening laboratories.