Intraoperative Margin Assessment Research Articles

Application of Intraoperative Mass Spectrometry and Data Analytics for Oncological Margin Detection, A Review.

A common phase of early-stage oncological treatment is the surgical resection of cancerous tissue. The presence of cancer cells on the resection margin, referred to as positive margin, is correlated with the recurrence of cancer and may require re-operation, negatively impacting many facets of patient outcomes. There exists a significant gap in the surgeon's ability to intraoperatively delineate between tissues. Mass spectrometry methods have shown considerable promise as intraoperative tissue profiling tools that can assist with the complete resection of cancer. To do so, the vastness of the information collected through these modalities must be digested, relying on robust and efficient extraction of insights through data analysis pipelines. We review clinical mass spectrometry literature and prioritize intraoperatively applied modalities. We also survey the data analysis methods employed in these studies. Our review outlines the advantages and shortcomings of mass spectrometry imaging and point-based tissue probing methods. For each modality, we identify statistical, linear transformation and machine learning techniques that demonstrate high performance in classifying cancerous tissues across several organ systems. A limited number of studies presented results captured intraoperatively. Through continued research of data centric techniques, like mass spectrometry, and the development of robust analysis approaches, intraoperative margin assessment is becoming feasible. By establishing the relatively short history of mass spectrometry techniques applied to surgical studies, we hope to inform future applications and aid in the selection of suitable data analysis frameworks for the development of intraoperative margin detection technologies.

Abstract CT230: A prospective, multi-center, randomized, double-arm trial to determine the impact of the Perimeter B-Series OCT System on positive margin rates in breast conservation surgery

Abstract Background: Optical coherence tomography (OCT) is a high-resolution tissue-imaging modality that enables real-time imaging up to 2mm deep. The Perimeter B-Series OCT System combines wide field-OCT (WF-OCT) with an artificial intelligence system, ImgAssist, to assist clinicians in the detection of lesions suspicious for breast cancer. The objective of this investigational device trial is to assess adjunctive Perimeter B-Series OCT System use compared to standard care in identifying and addressing positive margins intraoperatively. Design: Prospective, multicenter, randomized, double-arm trial in females with biopsy-confirmed cancer undergoing breast conservation surgery (BCS) (NCT05113927). Following lumpectomy and standard-of-care intraoperative margin assessment participants will be randomized to a device or control arm (2:1 schema). Controls may undergo intraoperative pathology or frozen section analysis, per routine. WF-OCT will be done on all device arm specimens, with an opportunity to excise tissue from the lumpectomy cavity post-analysis. The new margin will be imaged with WF-OCT and the surgeon may take up to a maximum of 6 total shaves, including up to 2 shaves in each orientation. Eligibility: Adult females undergoing breast conservation surgery for biopsy-confirmed Stage 0-III invasive ductal and/or DCIS are eligible, including post-neoadjuvant therapy. Pregnant or lactating, those with Stage IV cancer, lobular carcinoma as primary diagnosis, previous ipsilateral breast surgery, multi-centric or bilateral disease, use of cryolocalization, or any treatment affecting margin integrity will be excluded. Specific Aim: The study hypothesis is that use of the Perimeter B-Series OCT System in BCS will reduce the proportion of subjects with at least 1 unaddressed positive margin. The primary endpoint is occurrence of aat least 1 unaddressed positive margin for a subject. The secondary endpoint is the number of unaddressed positive margins per subject. Safety includes Adverse Events; false-positive shaves per subject (device arm); and BREAST-Q Satisfaction with Breasts subscale. Other outcomes are total excised tissue volume, initial and all procedures including repeat surgeries; margin-level effectiveness (sensitivity, specificity, NPV and PPV); and operative time. Statistical Methods: The study was powered via the primary endpoint, assuming a 15% unaddressed margin rate, 90% power, 2:1 device-to-control ratio, and 10% loss of subjects due to screen or device failure. Both the primary and secondary effectiveness endpoints are based on within-subject comparison of the 2 treatments in the device arm (SOC+WF-OCT). Planned Accrual: 309 subjects (206 device, 103 control) will be enrolled at 8 centers over approximately 12 months. Citation Format: David Rempel, Andrew Berkeley, David Moos, Allison A. DiPasquale, Maryam Elmi, Richard E. Fine, Marie Lee, Bridget O’Brien, John F. Turner, Lee G. Wilke, Alastair Thompson. A prospective, multi-center, randomized, double-arm trial to determine the impact of the Perimeter B-Series OCT System on positive margin rates in breast conservation surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT230.

Development of an intraoperative breast cancer margin assessment method using quantitative fluorescence measurements

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery.

Clinical Impact of Intraoperative Margin Assessment in Breast-Conserving Surgery With a Novel Pegulicianine Fluorescence–Guided System

Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time. To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS. This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021. Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins. Adverse events and sensitivity, specificity, and reexcision rate. Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%). In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial. ClinicalTrials.gov Identifier: NCT03321929.

249P Significance of intraoperative frozen assessment of cavity shave margins in patients undergoing breast conservation surgery: A tertiary care centre experience

Breast conservation surgery (BCS) is the preferred surgical treatment modality for eligible breast cancer patients. Oncological safety and aesthetic outcomes remain the primary objective of breast conservation surgery. Positive margin status following BCS needs revision surgery, which leads to increased patient anxiety, cost of treatment and delay in start of adjuvant treatment. We evaluated the significance and accuracy of intraoperative frozen section assessment of cavity shave margins (IOFSA) in patients undergoing BCS.

Multiwavelength laser induced fluorescence spectroscopy for breast cancer diagnostics

Introduction: The 'Getting It Right First Time' report suggests a high rate of re-operative intervention following breast conserving surgery. Intraoperative margin assessment (IMA) tools may reduce re-excision rates. Laser induced fluorescence spectroscopy (LIFS) is a non-invasive optical modality which can be used for real-time discrimination of normal and malignant tissues. This pilot study investigates LIFS signals from varying tissue types, aimed towards IMA tool development.

3-dimensional intraoperative analysis of screen detected breast malignancies reduces re-excision rates

Introduction: In the UK 20-30% of patients undergoing breast conserving surgery require a re-excision due to positive margins. Intraoperative specimen radiography is often used to guide the primary excision in screen detected lesions. The recent introduction of 3-dimensional tomographic analysis of the specimen has the potential for a more accurate intraoperative assessment of excision margins to guide the extent of primary excision.

145: THE USE OF MACHINE LEARNING FOR REAL-TIME DETECTION OF OESOPHAGEAL AND GASTRIC CANCER BASED ON DIFFUSE REFLECTANCE SPECTROSCOPY: A VALIDATION STUDY

Abstract Background and aim The lack of a fast and accurate intraoperative tumour margin assessment tool contributes to high positive circumferential resection margin rates for oesophageal and gastric cancers, which is associated with local recurrence and poor long-term survival. Diffuse reflectance spectroscopy (DRS) can provide non-invasive, accurate, and real-time tissue classification based on quantification of light reflectance in tissue, providing a unique optical fingerprint of the tissue. This study aimed to validate the use of DRS for discrimination between normal and cancerous tissues based on ex-vivo gastric and oesophageal cancer resection specimens. Methods Consecutive patients undergoing resections for gastric and oesophageal carcinomas at a tertiary referral centre in London between July 2020 and June 2021 were included. Reflectance data in the 468-720 nm spectral range were recorded on ex-vivo specimens within 15 minutes of surgical specimen excision. Based on video recordings of the data acquisition procedure and probe tip tracking, sampling sites were correlated with histological reports manually labeled as either normal or cancer (Figure 1). Following spectral data normalisation and feature selection, four supervised machine learning approaches were tested for classification using 5-fold cross-validation. Overall classification accuracy and Area Under the Curve (AUC) across machine learning approaches were compared. Results A total of 32 patients (median age 68, 75% male) were included. 11,862 mean spectra (2990 spectra for normal oesophagus, 4628 for normal stomach, 2305 for gastric cancer, and 1939 for oesophageal cancer) were collected. For oesophageal cancer, classification accuracy was 96.22 ± 0.50 and AUC was 99.24 ± 0.19, while for gastric cancer, the accuracy was 93.86 ± 0.66, and AUC 98.50 ± 0.28 for gastric cancer. For both malignancy types, Extreme Gradient Boosting was the best performing classifier. The differences in spectral data between patients receiving neoadjuvant treatment and treatment naïve were non-significant. Conclusion Machine learning can be used to accurately differentiate between normal and cancerous oesophageal and gastric tissues in an ex-vivo setting, based on DRS data. Features used for class discrimination should be investigated to find possible physiological correlates of spectral data differences. Future intraoperative validation is required to assess the utility of this technology for real-time tumour margin mapping and its effect on long-term outcomes.

Versatile Mass Spectrometry-Based Intraoperative Diagnosis of Liver Tumor in a Multiethnic Cohort

Currently used techniques for intraoperative assessment of tumor resection margins are time-consuming and laborious and, more importantly, lack specificity. Moreover, pathological diagnosis during surgery does not often give a clear outcome. Recent advances in mass spectrometry (MS) and instrumentation have made it possible to obtain detailed molecular information from tissue specimens in real-time, with minimal sample pre-treatment. Probe Electro Spray Ionization MS (PESI-MS), combined with artificial intelligence (AI), has demonstrated its effectiveness in distinguishing liver cancer tissues from healthy tissues in a large Italian population group. As the MS profile can reflect the patient’s ethnicity, dietary habits, or particular operating room procedures, the AI algorithm must be well trained to distinguish different groups. We used a large dataset composed of liver tumor and healthy specimens, from the Italian and Japanese populations, to develop a versatile algorithm free from ethnic bias. The system can classify tissues with discrepancies <5% from the pathologist’s diagnosis. These results demonstrate the potential of the PESI-MS system to distinguish tumor from surrounding non-tumor tissues in patients, with minimal bias from race/ethnicity or etiological characteristics or operating room procedures.

417 Vibrational Spectroscopy: A Rapid Tool for Soft Tissue Sarcoma Assessment

Abstract Aim Soft tissue sarcomas (STS) are a comparatively unusual cluster of tumours; they arise from mesenchymal tissues. Surgery remains the primary and the only potentially curative treatment for most STS subtypes. Existing intraoperative margin assessment techniques are inadequate and the current gold standard for resection margin assessment of STS is post-operative histopathology, but this takes weeks to finalize. Consequently, an augmented surgical technique established by real-time non-destructive recognition of clear margins is essential to diminish the risk of local relapse, decrease the resection area, and enhance the effectiveness of surgical resection of STS. Vibrational spectroscopy (VS) is a non-destructive evaluation of the atomic oscillation within a molecule. Every molecule has a unique set of vibrational modes called molecular fingerprint. We aim to use Raman spectroscopy to analyse biomolecular spectra of sarcoma and develop a potential tool for intra operative margin assessment Method Human sarcoma was tissue obtained from the biobank at QEHB. The samples were identified as Lipoma and Liposarcoma. The samples underwent spectral measurement with the Raman microscope and the tissue samples were then sent for histopathological analysis. Results The spectral evaluation clearly demonstrates the biomolecular difference between the two groups and has a potential to become an intraoperative tool. Conclusions A positive resection margin is the ultimate prognosticator of local relapse. There is a need for a rapid and reliable tool that can offer surgeons with instant feedback during primary procedure.

Abstract P3-18-11: Meeting the challenge of successful one-stage lumpectomy for DCIS

Abstract Introduction: Positive lumpectomy margins are associated with an increased risk for ipsilateral tumor recurrence, and necessitate additional procedures to achieve acceptable margins. Re-excision rates are higher in patients with ductal carcinoma in situ (DCIS) versus those with invasive carcinoma. The purpose of this study was to investigate the clinicopathologic characteristics, surgical techniques, and other outcomes associated with re-excision over time following primary breast conserving surgery for DCIS. Methods: Our institutional Breast Cancer Database was queried for patients treated with lumpectomy as the primary procedure for pure DCIS from 2010-2021. Cases of microinvasive disease were excluded. The primary endpoint was the rate of re-excision following lumpectomy. Variables of interest included patient demographics and clinicopathologic characteristics. As a secondary analysis, adjusted odds ratios for the association of MarginProbe® with re-excisions were calculated using a multivariable logistic regression model controlling for age, tumor size, breast density and DCIS subtype. Individual comparisons of continuous variables were based on t-tests, group proportions compared with one-way ANOVA, and categorical variables compared using Chi Square tests. Results: Out of a total of 695 patients in our cohort, 221 (32%) had re-excisions. There was a statistically significant 2% decline per year in the number of re-excisions (p=0.005). Patients who underwent re-excision had larger size of DCIS (2.37 cm vs 1.37 cm, p<0.001). Papillary-type DCIS was associated with an increased rate of re-excision surgery (Table 1). Prior to the introduction of the MarginProbe® for intraoperative margin assessment in 2014, approximately 42% of patients with DCIS underwent re-excisions. This decreased to 24.9% in the post-2013 time frame (p=0.02). In an unadjusted estimate for the odds ratio for association, patients who underwent lumpectomy with MarginProbe® were 81% less likely to require re-excision (OR = 0.19, 95% CI = 0.12, 0.31, p<0.0001). In a logistic regression model controlling for potential confounders with re-excision as the dependent variable and MarginProbe® as the primary explanatory variable, patients for whom the MarginProbe® was used were 66% less likely to require re-excision when controlling for age, tumor size, menopausal status, breast density, and pathology (OR = 0.34, 95% CI 0.16, 0.69). Of patients who required re-excision, 20% went on to mastectomies as their second procedure. After each unsuccessful re-excision, a larger proportion of patients converted to mastectomy. In total, 26% of patients who had unsuccessful primary surgery went on to mastectomies. Of patients who proceeded to mastectomy as their second procedures, 13% were found to carry BRCA1 or 2 mutations. Conclusions: In our study of patients diagnosed with pure DCIS and treated with primary breast conserving surgery, larger size of DCIS and papillary subtype were associated with an increased rate of re-excision procedures. A proportion of patients with unsuccessful primary lumpectomies required multiple procedures to complete their surgical treatment and 26% went on to mastectomy. Patients whose primary procedures included intraoperative margin assessment with the MarginProbe® were significantly less likely to require re-excision. Intraoperative margin assessment is an important tool that can support breast conserving surgery in the challenging population of patients with DCIS. Table 1.Clinicopathologic CharacteristicsVariableNo Re-excision (n=313)Re-Excision (n=100)P-ValueAge; mean (SD)61.48 (12.01)58.04 (13.39)0.016Age of Menopause; mean (SD)50.22 (5.18)48.13 (5.45)0.004Size of DCIS; mean (SD)1.37 (1.25)2.37 (2.00)<0.001Breast Density (%)0.149N/A6 (1.9)2 (2.0)Entirely Fatty10 (3.2)3 (3.0)Extremely Dense19 (6.1)13 (13.0)Heterogeneously Dense165 (52.7)42 (42.0)Scattered Fibroglandular113 (36.1)40 (4.0)DCIS SubtypePapillary93 (29.7)48 (48.0)0.001Cribiform206 (65.8)69 (69.0)0.641Solid190 (60.7)60 (60.0)0.994Comedo54 (17.3)25 (25.0)0.117Surgical Margins (%)<0.001Close (>0 and <1mm)3 (1.0)60 (60.0)Negative (≥1 mm)310 (99.0)13 (13.0)Positive (≤0 mm)0 (0.0)27 (27.0) Citation Format: Joshua A Feinberg, Charles DiMaggio, Nakisa Pourkey, Jennifer Chun Kim, Jenny Goodgal, Amber Guth, Deborah Axelrod, Freya Schnabel. Meeting the challenge of successful one-stage lumpectomy for DCIS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-11.

Abstract P3-18-10: Current options and future perspectives for breast margin assessment in clinical practice

Abstract Background: Ensuring negative margins at the time of breast conserving surgery for invasive breast cancer or ductal carcinoma in situ is necessary to minimize the chance of local recurrence and avoid re-excisions that cause patient concern and may delay adjuvant therapy. However, about 25% of women who have lumpectomy have a second surgery to remove residual disease, suggesting an ongoing need for improved methods of intraoperative margin assessment. This study aimed to perform a contemporary review of methods of intraoperative margin assessment during breast conservation surgery. Methods: A review of the scientific literature from 2009 to 2021 comprising 62 manuscripts of the current and proposed. intraoperative techniques for breast margin assessment during breast conservation surgery was conducted via PubMed and Google Scholar. The methods assessed were grouped into 10 categories based on the technology employed: bioimpedance/radiofrequency, high-resolution imaging, optical imaging, mass spectrometry, magnetic-resonance imaging, 2D/3D specimen CT, X-ray, multimodal optical microscopy, pharmacologic and pathological margin assessment. All technologies were reviewed for overall effectiveness in lowering re-excision rates derived from their respective advantages, limitations, sensitivity, and specificity. Results: Overall, 8 current and 7 technologies under development were assessed (Table 1). Frozen section and cytology yielded the highest diagnostic accuracy; however, these can be time-consuming, resource-intensive, and have limited sampling points. Conversely, 2D specimen CT provides rapid results but is limited by relatively low sensitivity. Future technologies such as optical coherence tomography showed promising results in demonstrating higher diagnostic accuracy for lumpectomy and margin shaves, but remain to be proven in clinical practice. Conclusion: Intraoperative margin assessments can lower final positive margins and subsequent re-excisions rates. A number of current and upcoming technologies that assess margin status range in their respective efficacies and limitations. There remains demand for improved margin assessment at the time of breast conserving surgery, but which technologies will become standard of care remains, at present, unclear. Table 1.Methods of intraoperative margin assessmentMethod:Brand:Sensitivity:Specificity:Source:Bioimpedence• ClearEdge™87.3%75.6%Dixon et al. 2016• MarginProbe75.2%70-87%Schanabel et al., 2014Cytology:• Imprint72%97%Esbona & Zhanhai 2012; Qui et al., 2018Frozen Section–83%95%Schmidt et al, 2020; Schwarz & Schmidt, 2020Mass Spectrometry• iKnife93.4-94.7%94.7-96.2%St. John et al., 2017• MasSpec Pen83-95%95-100%Garza et al., 2020Multimodal optical microscopy• fluorescence imaging combination withRCM/OCT subsystemTBDTBDScimone et al., 2021MRI• ClearSight™93%92%Moshe et al., 2016Optical Coherence Tomography (OCT)• OTIS™96%92%Mojahed et al., 2020; Schmidt et al. 2020Pharmacology• Bevacizumab98%79%Koch et al., 2017• Lumicell2-3D specimen CT• Mozart®93%78%Black et al., [poster]• Faxitron78.6-85.6%100%Emmadi & Wiley 2012; Bathla et al. 2011• MicroCT56%100%Qiu et al. 2018X-ray• XPCI83%83%Massimi et al. 2021 Citation Format: Huma Javaid, Ivan Marin, Jessica Montalvan, Logan Healy, Brian Menegaz, Cary Hsu, Eric Silberfein, Elizabeth Bonefas, Stacey A. Carter, Alastair M. Thompson. Current options and future perspectives for breast margin assessment in clinical practice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-10.

Abstract P1-02-07: Accuracy and predictive value of resection margin assessment by intraoperative frozen section after neoadjuvant therapy: An analysis of the ABCSG 24 and 34 trials

Abstract Data on the accuracy of intraoperative resection margin assessment and its influence on survival after neoadjuvant therapy (NT) are scarce. In the present study, we analyzed the accuracy of resection margin assessment by intraoperative frozen section (IFS) in the prospectively randomized neoadjuvant clinical trials ABCSG 24 and ABCSG 34.164 patients with early breast cancer who received NT within the ABCSG 24 and ABCSG 34 trials between 2005 and 2015, and received IFS resection margin assessment were included in our analysis. Resection margin status by IFS was compared to subsequent FFPE resection margin status, which was considered the gold standard. According to the rate of FFPE-based false-negative and false-positive diagnoses, we determined sensitivity and specificity of IFS. Correlation of IFS diagnosis with definitive FFPE assessment was described by Cohen´s kappa coefficient, the distributional probability was analyzed by McNemar test. The association of patient- and tumor-related factors (menopausal status, residual tumor size, tumor grade, lymph node status, multifocality, DCIS component, lymph vessel invasion, ER/PR/HER2/Ki67 expression and RCB category) with correct IFS diagnosis was analyzed by chi2 test and Fisher´s exact test. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and log-rank test. Median age of patients was 55 years. IFS diagnosis for negative margins (no tumor on ink) was correct in 131 (80%) cases, translating into a sensitivity of 0.571 and specificity of 0.877 (false negative rate: 43%, false positive rate 12%). Correlation coefficient for IFS and FFPE diagnosis yielded a Cohen´s kappa value of 0.459. 58 patients (35%) were re-excised during the first operation, in 27 patients (17%), a second surgical intervention was performed. Overall re-excision rates in patients with true positive, false positive and false negative IFS diagnoses were 96%, 93% and 78%, respectively. Rate of second surgical interventions in patients with true positive, false positive and false negative IFS diagnoses were 38%, 7% and 44%, respectively. Correct IFS diagnosis correlated with smaller residual tumor size (p=0.032), lymph node status (p=0.007), HER2 negativity (p=0.049), presence of a DCIS component (p=0.013) and absence of lymph vessel invasion (p=0.007). Despite of re-operation resulting in negative margins, false negative IFS diagnosis was associated with worse recurrence-free survival (p=0.0278). The impact of IFS diagnosis on OS did not reach statistical significance (p=0.0995), although patients with false negative IFS diagnosis showed a shorter OS. IFS assessment of margins after NT displayed high specificity and limited sensitivity in the ABCSG 24 and ABCSG 34 trials. Residual tumor size, lymph node status, HER2 positivity, presence of a DCIS component and lymph vessel invasion correlated with accuracy of IFS. Patients with false negative IFS margin status showed a significantly shorter RFS despite of a second intervention yielding negative margins. Larger studies are needed to confirm the effects of IFS margin assessment on OS. Our data could help to lower rates of subsequent surgical interventions for re-excision after NT and identify patients by the above mentioned tumor characteristics who are at an increased risk of recurrence despite negative margin status. Citation Format: Karin Rokitte, Kristina Tendl-Schulz, Ulrike Heber, Kerstin Wimmer, Rupert Bartsch, Stephanie Kacerovsky-Strobl, Georg Pfeiler, Günther G. Steger, Christian F. Singer, Dominik Hlauschek, Michael Gnant, Florian Fitzal, Zsuzsanna Bago-Horvath. Accuracy and predictive value of resection margin assessment by intraoperative frozen section after neoadjuvant therapy: An analysis of the ABCSG 24 and 34 trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-07.

Imaging of Lumpectomy Surface with Large Field-of-View Confocal Laser Scanning Microscopy ‘Histolog® Scanner’ for Breast Margin Assessment in comparison with Conventional Specimen Radiography

Background: The objective of breast conserving surgery (BCS) for breast cancer patients is based upon resecting as little healthy tissue as necessary to enable a satisfying aesthetic outcome while at the same time achieving negative resection margins and thereby adhering to oncologic principles. The aim of intraoperative margin assessment is to assist in balancing these confounding factors. The Histolog® Scanner (SamanTree Medical SA, Lausanne, Switzerland) is a large field-of-view confocal laser scanning microscope designed to allow intraoperative margin assessment by production of high-quality histological images ready for assessment in the operating room.

Development of intraoperative assessment of margins in breast conserving surgery: a narrative review.

We intend to provide an informative and up-to-date summary on the topic of intraoperative assessment of margins in breast conserving surgery (BCS). Conventional methods as well as cutting-edge technologies are analyzed for their advantages and limitations in the hope that clinicians can turn to this for reference. This review can also offer guidance for technicians in the future design of intraoperative margin assessment tools. Achieving negative margins during BCS is one of the vital factors for preventing local recurrence. Conducting intraoperative margin assessment can ensure negative margins to a large extent and possibly relieve patients of the anguish of re-interventions. In recent years, innovative methods for margin assessment during BCS are advancing rapidly. And there is a lack of summary regarding the development of intraoperative margin assessment in BCS. A PubMed search with keywords "intraoperative margin assessment" and "breast conserving surgery" was conducted. Relevant publications were screened manually for its title, abstract and even full text to determine its true relevance. Publications on neo-adjuvant therapy and intraoperative radiotherapy were excluded. References from the searched articles and other supplementary articles were also looked into. Conventional methods for margin assessment yields stable outcome but its use is limited because of the demand on pathology staff and the trade-off between time and precision. Conventional imaging techniques pass the workload to radiologists at the cost of a significantly low duration of time. Involving artificial intelligence for image-based assessment is a further improvement. However, conventional imaging is inherently flawed in that occult lesions can't show on the image and the showing ones are ambiguous and open to interpretation. Unconventional techniques which base their judgment on cellular composition are more reassuring. Nonetheless, unconventional techniques should be subjected to clinical trials before putting into practice. And studies regarding comparison between conventional methods and unconventional methods are also needed to evaluate their relative efficacy.

Performance and survival outcomes of defect-driven versus specimen-driven method of frozen section intraoperative margin assessment in oral cancers

Margin status is one of the most important prognostic factors in oral cancers. Intraoperative frozen section (FS) can be performed to ensure a margin-negative resection, however the method of FS assessment is debatable. The aim of this study was to compare the defect-driven (DDA) versus specimen-driven (SDA) approach for intraoperative assessment of tumour margins in oral cancer resections and their impact on loco-regional recurrence and survival. The primary study endpoint was margin status determined from the final histopathological examination report. Secondary endpoints were disease recurrence and survival. This retrospective cohort study compared the two methods of FS in terms of their performance and survival outcomes. All oral squamous cell carcinoma patients who underwent surgery as the primary treatment from January 2018 to February 2019 were included. The involved margin rate was slightly lower with SDA than DDA (7.5% vs 11.8%), however the difference was not statistically significant. The recurrence rate was higher with DDA (19/51, 37.2%) than SDA (14/53, 26.4%), although this was not statistically significant. Local recurrence-free survival (DDA 62% vs SDA 75%; P = 0.653) and overall survival (DDA 76% vs SDA 78%; P = 0.300) at 18 months of follow-up were comparable. There was no significant difference in sensitivity or specificity of intraoperative FS for margin assessment between SDA and DDA. The type of intraoperative FS technique used did not affect loco-regional recurrence or overall survival.

Frozen Section Analysis and Real-Time Magnetic Resonance Imaging of Surgical Specimen Oriented on 3D Printed Tongue Model to Assess Surgical Margins in Oral Tongue Carcinoma: Preliminary Results.

BackgroundA surgical margin is the apparently healthy tissue around a tumor which has been removed. In oral cavity carcinoma, a negative margin is considered ≥ 5 mm, a close margin between 1 and 5 mm, and a positive margin ≤ 1 mm. Currently, the intraoperative surgical margin status is based on the visual inspection and tissue palpation by the surgeon and intraoperative histopathological assessment of the resection margins by frozen section analysis (FSA). FSA technique is limited and susceptible to sampling errors. Definitive information on the deep resection margins requires postoperative histopathological analysis.MethodsWe described a novel approach for the assessment of intraoperative surgical margins by examining a surgical specimen oriented through a 3D-printed specific patient tongue with real-time Magnetic Resonance Imaging (MRI). We reported the preliminary results of a case series of 10 patients, prospectively enrolled, with oral tongue carcinoma who underwent surgery between February 2020 and April 2021. Two radiologists with 5 and 10 years of experience, respectively, in Head and Neck radiology in consensus evaluated specimen MRI and measured the distance between the tumor and the specimen surface. We performed intraoperative bedside FSA. To compare the performance of bedside FSA and MRI in predicting definitive margin status we computed the weighted sensitivity (SE), specificity (SP), accuracy (ACC), area under the ROC curve (AUC), F1-score, Positive Predictive Value (PPV), and Negative Predictive Value (NPV). To express the concordance between FSA and ex-vivo MRI we reported the jaccard index.ResultsIntraoperative bedside FSA showed SE of 90%, SP of 100%, F1 of 95%, ACC of 0.9%, PPV of 100%, NPV (not a number), and jaccard of 90%, and ex-vivo MRI showed SE of 100%, SP of 100%, F1 of 100%, ACC of 100%, PPV of 100%, NPV of 100%, and jaccard of 100%. These results needed to be validated in a larger sample size of 21- 44 patients.ConclusionThe presented method allows a more accurate evaluation of surgical margin status, and the first clinical experiences underline the high potential of integrating FSA with ex-vivo MRI of the fresh surgical specimen.

Does conventional specimen radiography after neoadjuvant chemotherapy of breast cancer help to reduce the rate of second surgeries?

PurposeThis is the first study to systematically evaluate the diagnostic accuracy of intraoperative specimen radiography on margin level and its potential to reduce second surgeries in patients treated with neoadjuvant chemotherapy.MethodsThis retrospective study included 174 cases receiving breast conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) of primary breast cancer. Conventional specimen radiography (CSR) was performed to assess potential margin infiltration and recommend an intraoperative re-excision of any radiologically positive margin. The histological workup of the specimen served as gold standard for the evaluation of the accuracy of CSR and the potential reduction of second surgeries by CSR-guided re-excisions.Results1044 margins were assessed. Of 47 (4.5%) histopathological positive margins, CSR identified 9 correctly (true positive). 38 infiltrated margins were missed (false negative). This resulted in a sensitivity of 19.2%, a specificity of 89.2%, a positive predictive value (PPV) of 7.7%, and a negative predictive value (NPV) of 95.9%. The rate of secondary procedures was reduced from 23 to 16 with a number needed to treat (NNT) of CSR-guided intraoperative re-excisions of 25.In the subgroup of patients with cCR, the prevalence of positive margins was 10/510 (2.0%), PPV was 1.9%, and the NNT was 85.ConclusionPositive margins after NACT are rare and CSR has only a low sensitivity to detect them. Thus, the rate of secondary surgeries cannot be significantly reduced by recommending targeted re-excisions, especially in cases with cCR. In summary, CSR after NACT is inadequate for intraoperative margin assessment but remains useful to document removal of the biopsy site clip.

Oncological Outcomes in Patients with Appendicular Myxofibrosarcomas: A Retrospective Study.

Background Myxofibrosarcoma (MFS) is notorious for its infiltrative growth pattern, making wide excisions difficult to achieve. Our objective was to assess the impact of surgical margins and other factors that affected rates of local recurrence (LR), distant metastasis (DM), and overall survival (OS) of individuals undergoing resection for MFS. Methods We retrospectively reviewed the medical records of 209 patients with appendicular soft tissue sarcomas between January 2012 and June 2018. Of these, 29 patients (14%) were diagnosed with myxofibrosarcoma. These patients underwent a total of 33 resections. The pathological analyses were conducted by an experienced musculoskeletal (MSK) pathologist. Demographics data, operative details, adjuvant therapy, and oncological outcomes were assessed. Results Of the 29 patients (33 resections), the overall LR rate was 24% (7/29) and the 2-year LR rate was 17% (5/29). Factors associated with negative oncological outcomes were as follows: tumor size ≤10 cm (2-year local recurrence-free rates (LRFRs), 65%; 95% CI, 44–86%; p=0.02) and positive surgical margins grouped with surgical margins ≤0.1 cm (hazard ratio (HR), 11.74; 95% CI, 1.41–97.74; p=0.02). Chemotherapy and radiotherapy together increased the 2-year LRFR (LRFR, 100%; 95% CI, 100%, p=0.001). Two-year DM and OS rates were 15% and 79%, respectively. Female gender was a predictor of distant metastasis. Local recurrence had a negative impact on overall survival. Intraoperative analysis of resection margin accuracy was 75% (12/16) when non-MSK pathologists were involved but 100% accurate (12/12) when analyzed by an MSK pathologist. Conclusion Myxofibrosarcomas showed high LR rates after treatment. Close margins (≤0.1 cm) should be considered as a risk factor for LR, and LR is associated with negative overall survival. Neoadjuvant therapy in terms of combined chemotherapy and radiation therapy associates with decreased LR rates. If intraoperative assessment of margins is to be done, it should be performed by an experienced MSK pathologist.

A New Look into Cancer-A Review on the Contribution of Vibrational Spectroscopy on Early Diagnosis and Surgery Guidance.

Simple SummaryCancer is a leading cause of death worldwide, with the detection of the disease in its early stages, as well as a correct assessment of the tumour margins, being paramount for a successful recovery. While breast cancer is one of most common types of cancer, head and neck cancer is one of the types of cancer with a lower prognosis and poor aesthetic results. Vibrational spectroscopy detects molecular vibrations, being sensitive to different sample compositions, even when the difference was slight. The use of spectroscopy in biomedicine has been extensively explored, since it allows a broader assessment of the biochemical fingerprint of several diseases. This literature review covers the most recent advances in breast and head and neck cancer early diagnosis and intraoperative margin assessment, through Raman and Fourier transform infrared spectroscopies. The rising field of spectral histopathology was also approached. The authors aimed at expounding in a more concise and simple way the challenges faced by clinicians and how vibrational spectroscopy has evolved to respond to those needs for the two types of cancer with the highest potential for improvement regarding an early diagnosis, surgical margin assessment and histopathology.In 2020, approximately 10 million people died of cancer, rendering this disease the second leading cause of death worldwide. Detecting cancer in its early stages is paramount for patients’ prognosis and survival. Hence, the scientific and medical communities are engaged in improving both therapeutic strategies and diagnostic methodologies, beyond prevention. Optical vibrational spectroscopy has been shown to be an ideal diagnostic method for early cancer diagnosis and surgical margins assessment, as a complement to histopathological analysis. Being highly sensitive, non-invasive and capable of real-time molecular imaging, Raman and Fourier transform infrared (FTIR) spectroscopies give information on the biochemical profile of the tissue under analysis, detecting the metabolic differences between healthy and cancerous portions of the same sample. This constitutes tremendous progress in the field, since the cancer-prompted morphological alterations often occur after the biochemical imbalances in the oncogenic process. Therefore, the early cancer-associated metabolic changes are unnoticed by the histopathologist. Additionally, Raman and FTIR spectroscopies significantly reduce the subjectivity linked to cancer diagnosis. This review focuses on breast and head and neck cancers, their clinical needs and the progress made to date using vibrational spectroscopy as a diagnostic technique prior to surgical intervention and intraoperative margin assessment.