[en] A new interstitial breast localization marker is proposed which exhibits positive contrast in T1-weighted MRI, ultrasound and x-ray mammography. Unlike previous markers which provide MRI contrast on the basis of a susceptibility-induced signal void, this marker provides a clear positive contrast without any loss of signal or spatial distortion. The marker is composed of 400 μm diameter copper microspheres suspended in a Gd-DTPA-doped gel matrix. Optimal contrast in T1-weighted spoiled gradient recalled MRI was found to occur with the addition of 10 mM Gd-DTPA. Ultrasound contrast was generated on the basis of scattering from the copper microspheres. X-ray contrast was provided by the high x-ray attenuation properties of the copper microspheres. The study demonstrates potential suitability of the marker for use as a breast localization marker based on ex vivo studies of chicken breast. (note)

[en] Introduction: The human epidermal growth factor receptor-2 (HER2) gene is amplified in 25% of invasive breast cancers, and receptor overexpression has been noted in up to 60% of early stages of the disease [ductal carcinoma in situ (DCIS)]. Preclinical studies have revealed high tumor/blood ratios (>27:1) for ¹¹¹In-labeled Fab fragments of the HER2 monoclonal antibody, trastuzumab (Herceptin) (¹¹¹In-DTPA-trastuzumab Fab) at 72 h pi in athymic mice bearing subcutaneous human breast cancer xenografts. Our aim in this study was to formulate a kit for preparation of ¹¹¹In-DTPA-trastuzumab Fab injection under good manufacturing practice (GMP) conditions suitable for human administration in a Phase I clinical trial of imaging and radioimmunoguided surgery (RIGS) of HER2-positive breast cancer. Methods: Fab fragments were produced by digestion of trastuzumab IgG (Herceptin) with immobilized papain for 20 h at 37^oC. Fab fragments were purified by ultrafiltration, then reacted with a 10-fold molar excess of diethylenetriaminepentaacetic acid (DTPA) dianhydride. DTPA-Fab fragments were purified, then sterilized by filtration into unit dose glass vials (kits). Kits were tested against specifications for volume (0.9-1.1 ml), protein concentration (0.45-0.55 mg/ml), pH (5.5-6.5), DTPA substitution (0.5-4.0 mol DTPA/mol Fab), appearance (clear, colorless and particle free), labeling efficiency (≥85%), and sterility and apyrogenicity (USP XXXII). Immunoreactivity of ¹¹¹In-DTPA-trastuzumab Fab towards HER2 was measured by saturation radioligand binding assays using SKBR-3 human breast cancer cells (specifications: K_a=0.6-9.6x10⁷ L/mol; B_max=0.6-10.4x10⁶ sites/cell). ¹¹¹In-DTPA-trastuzumab Fab injection was prepared by adding 80-100 MBq of ¹¹¹InCl₃ to a single kit vial and incubating for 30 min at room temperature. ¹¹¹In-DTPA-trastuzumab Fab was assayed for the amount of radioactivity and tested for pH, radiochemical purity (RCP), appearance and sterility. Results: Pure and homogeneous Fab fragments were produced. Eleven lots of kits met established quality specifications. The labeling efficiency with ¹¹¹In was 90.6±2.2%. ¹¹¹In-DTPA-trastuzumab Fab bound specifically to HER2 on SKBR-3 cells (K_a=4.8±2.5x10⁷ L/mol and B_max=1.6±0.8x10⁶ sites/cell). Thirteen lots of ¹¹¹In-DTPA-trastuzumab injection met all established specifications. Kits were stable for 90 days and ¹¹¹In-DTPA-trastuzumab Fab injection was stable for 24 h stored at 4^oC. Conclusions: A kit was formulated under GMP conditions for the preparation of ¹¹¹In-DTPA-trastuzumab Fab injection suitable for human administration. The kits were approved by Health Canada.

[en] This paper describes an in vitro investigation into the composition, structure and development of an magnetic resonance imaging (MRI), ultrasound (US) and x-ray imaging compatible marker for breast tumour localization. The marker is composed of 0.4-0.6 mm glass and iron-containing aluminium microspheres suspended in a gelatin matrix. The final form of the marker is a cylindrical shape 7 mm long with 2.05 mm diameter to facilitate delivery through a 12 gauge biopsy needle. To get optimal reflectivity for the US contrast, the glass microsphere concentration was found to be 40% by weight. US contrast is independent of marker orientation and the cylindrical shape made its US signal appearance distinctive thus ensuring confident identification. To control the MRI contrast, iron content was varied to generate a clear and local susceptibility signal void to reflect the marker position. Optimal iron content was found to be 52 μg iron which produced a clear signal void in spoiled gradient recalled MR images. The appearance of the susceptibility artefact is determined by the marker's shape, orientation and echo time. The final marker produces a dark artefact in MRI while appears as a clear hyperintense structure with acoustic shadowing in US images. The x-ray image showed the marker as a radio-opaque structure. This in vitro study demonstrates that the marker forms an alternative to traditional wire localization currently used for breast surgical procedures and creates new opportunities for US guided surgical procedures

[en] Breast MRI is frequently performed prior to breast conserving surgery in order to assess the location and extent of the lesion. Ideally, the surgeon should also be able to use the image information during surgery to guide the excision and this requires that the MR image is co-registered to conform to the patient’s position on the operating table. Recent progress in MR imaging techniques has made it possible to obtain high quality images of the patient in the supine position which significantly reduces the complexity of the registration task. Surface markers placed on the breast during imaging can be located during surgery using an external tracking device and this information can be used to co-register the images to the patient. There remains the problem that in most clinical MR scanners the arm of the patient has to be placed parallel to the body whereas the arm is placed perpendicular to the patient during surgery. The aim of this study is to determine the accuracy of co-registration based on a surface marker approach and, in particular, to determine what effect the difference in a patient’s arm position makes on the accuracy of tumour localization. Obtaining a second MRI of the patient where the patient’s arm is perpendicular to body axes (operating room position) is not possible. Instead we obtain a secondary MRI scan where the patient’s arm is above the patient’s head to validate the registration. Five patients with enhancing lesions ranging from 1.5 to 80 cm"3 in size were imaged using contrast enhanced MRI with their arms in two positions. A thin-plate spline registration scheme was used to match these two configurations. The registration algorithm uses the surface markers only and does not employ the image intensities. Tumour outlines were segmented and centre of mass (COM) displacement and Dice measures of lesion overlap were calculated. The relationship between the number of markers used and the COM-displacement was also studied. The lesion COM-displacements ranged from 0.9  to 9.3 mm and the Dice overlap score ranged from 20% to 80%. The registration procedure took less than 1 min to run on a standard PC. Alignment of pre-surgical supine MR images to the patient using surface markers on the breast for co-registration therefore appears to be feasible. (paper)

[en] 

Purpose

Studies examining symptom differences between surgeries for breast cancer patients rarely incorporate the effects of adjuvant treatment choice. We sought to understand differences in patient-reported symptoms between lumpectomy plus radiation and mastectomy in the year following surgery.

Methods

This cohort study used linked administrative datasets. The exposure was defined as lumpectomy plus radiation or mastectomy. The outcomes of moderate-to-severe (score ≥ 4) patient-reported symptoms were obtained using the Edmonton symptom assessment system (ESAS). Line plots were created to determine symptom trajectories in the 12 months following surgery, and the relationships between surgery and each of the nine symptoms were assessed using multivariable analyses. Clinical significance was determined as a difference of 10%.

Results

Of 13,865 Stage I–II breast cancer patients diagnosed 2007–2015, 11,497 underwent lumpectomy plus radiation and 2368 underwent mastectomy. Symptom trajectories were similar for all nine symptoms until approximately 5 months postoperatively when they diverged and mastectomy symptoms started becoming more severe. On multivariable analyses, patients undergoing mastectomy were at an increased risk of reporting moderate-to-severe depression (RR 1.19, 95% CI 1.09–1.30), lack of appetite (RR 1.11, 95% CI 1.03–1.20), and shortness of breath (RR 1.16, 95% CI 1.04–1.15) compared to those undergoing lumpectomy plus radiation.

Conclusions

Even with the addition of adjuvant radiation, patients who are treated with lumpectomy fare better in three of nine patient-reported symptoms. Further examination of these differences will assist in better shared decision-making regarding surgical treatments.

[en] Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with ¹¹¹In. The dissociation constant (K_d) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K_d=47 nM). ¹¹¹In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8±0.7% injected dose (ID)/g and tumor/blood ratio of 25.2±1.6 at 72 h postinjection compared with 2.7±0.7% ID/g and 7.0±0.9 for ¹¹¹In-HuM195 anti-CD33 Fab (significantly different, P<.001). Small (3-5 mm in diameter) BT-474 tumors were imaged with ¹¹¹In-trastuzumab Fab as early as 24 h postinjection

[en] Introduction: Our aim was to conduct a Phase I clinical trial to determine the feasibility of intraoperative detection of tumor margins in HER2 positive breast carcinoma using a hand-held γ-probe following administration of ¹¹¹In-DTPA-trastuzumab Fab fragments. Accurate delineation of tumor margins is important for preventing local recurrence. Methods: Six patients with HER2-positive in situ or invasive ductal carcinoma were administered 74 MBq (0.5 mg) of ¹¹¹In-DTPA-trastuzumab Fab fragments and counts in the tumor, surgical cavity wall and en face margins were measured intraoperatively at 72 h post-injection using the Navigator or C-Trak γ-probes. Margins were evaluated histologically. Quantitative whole body planar imaging was performed to estimate radiation absorbed doses using OLINDA/EXM software. SPECT imaging of the thorax was performed to evaluate tumor uptake. The pharmacokinetics of elimination from the blood and plasma were determined over 72 h. Results: There were no acute adverse reactions from ¹¹¹In-DTPA-trastuzumab Fab fragments and no changes in hematological or biochemical indices were found over a 3 month period. ¹¹¹In-DTPA-trastuzumab Fab fragments exhibited a biphasic elimination from the blood and plasma with t_1/2α = 11.9 h and 7.5 h, respectively, and t_1/2β = 26.6 and 20.7 h, respectively. The radiopharmaceutical accumulated in the liver, spleen and kidneys. SPECT imaging did not reveal tumor in any patient. The mean effective dose was 0.146 mSv/MBq (10.8 mSv for 74 MBq). Counts in excised tumors were low but were higher than in margins. Margins in two patients harboured tumor but this was not correlated with counts obtained using the γ-probes. Surgical cavity counts were high and likely due to detection of γ-photons outside the surgical field. Conclusion: We conclude that it was not feasible, at least at the administered amount of radioactivity used in this study, to reliably detect the margins of disease in patients with in situ or invasive ductal carcinoma intraoperatively using a hand-held γ-probe and ¹¹¹In-DTPA-trastuzumab Fab fragments due to low uptake in the tumor and involved margins