Tumor Positive Surgical Margins Research Articles

Formulation of a Thermosensitive Imaging Hydrogel for Topical Application and Rapid Visualization of Tumor Margins in the Surgical Cavity.

Simple SummaryWe have developed a formulation for an innovative, quenched, cathepsin-targeted, fluorescent molecular probe to enhance resection quality for several solid-tumor cancers. Unlike other formulations for imaging probes or tracers in development and entering the clinic, which require systemic administration hours before the procedure, this current formulation is applied topically into the surgical cavity immediately after a standard of care resection. Within minutes of application, the probe activates in the presence of residual cancer in the surgical wound and provides a strong fluorescent signal that precisely delineates any remaining cancer, enabling a more complete resection. Utilization of this imaging gel formulation for topical application to detect breast cancer in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life.Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care. Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical application and imaging of the BCa surgical cavity. Results: More than forty formulations of gel mixtures were investigated to enable easy fluid application and subsequent solidification once applied, preventing dripping and pooling in the surgical cavity. The final formulation was tested using human BCa orthotopic implants in nude and NSG patient-derived xenografts (PDX) mice. This formulation of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel was found to be a good solvent for the probe, with a desirable thermo-reversible solid–gel transition and mechanical strength for distribution of AKRO-QC-ICG on the surfaces of tissue. It demonstrated excellent ability to detect BCa tissue after 10 min exposure, with a high signal-to-noise ratio both in mouse xenografts and freshly excised human lumpectomy tissue. The in vivo efficacy of the AKRO-QC-ICG imaging gel to detect BCa revealed the levels of sensitivity/specificity = 0.92/1 in 12 nude mice, which was corroborated with the sensitivity/specificity = 0.94/1 in 10 PDX mice. Conclusions: Utilization of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel for topical application to detect BCa in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life.

A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent

PurposeIntra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery.ProceduresThirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology.ResultsAll six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion.ConclusionOur specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.

Real-time surgical margin assessment using ICG-fluorescence during laparoscopic and robot-assisted resections of colorectal liver metastases.

BackgroundAlmost a third of the resections in patients with colorectal liver metastases (CRLM) undergoing curative surgery, end up being tumor-margin positive (≤1 mm margin). Near-infrared fluorescent (NIRF) imaging using the fluorescent contrast agent indocyanine green (ICG) has been studied for many different applications. When administered in a relatively low dose (10 mg) 24 hours prior to surgery, ICG accumulated in hepatocytes surrounding the CRLM. This results in the formation of a characteristic fluorescent ‘rim’ surrounding CRLM when located at the periphery of the liver. By resecting the metastasis with the entire surrounding fluorescent rim, in real-time guided by NIRF imaging, the surgeon can effectively acquire margin-negative (>1 mm) resections. This pilot study aims to describe the surgical technique for using near-infrared fluorescence imaging to assess tumor-margins in vivo in patients with CRLM undergoing laparoscopic or robot-assisted resections.MethodsOut of our institutional database we selected 16 CRLM based on margin-status (R0; n=8, R1; n=8), which were resected by a minimally-invasive approach using ICG-fluorescence. NIRF images acquired during surgery, from both the resection specimen and the wound bed, were analysed for fluorescent signal. We hypothesized that a protruding fluorescent rim at the parenchymal side of the resection specimen could indicate a too close proximity to the tumor and could be predictive for a tumor-positive surgical margin. NIRF images were correlated to final histopathological assessment of the resection margin.ResultsAll lesions with a NIRF positive resection plane in vivo were reported as having a tumor-positive margin. Lesions that showcased no protruding rim in the wound bed in vivo were diagnosed as having a tumor-negative margin in 88% of cases. A 5-step surgical workflow is described to document the NIRF signal was used assess the resection margin in vivo for future clinical studies.ConclusionsThe pilot study shows that image-guided surgery using real-time ICG-fluorescence has the potential to aid surgeons in achieving a tumor-negative margin in minimally invasive liver metastasectomies. The national multi-centre MIMIC-Trial will prospectively study the effect of this technique on surgical tumor-margins (Dutch Trial Register number NL7674).

The Role of Portoenterostomy with Aggressive Hilar Dissection in Biliary Tract Tumors: Report of Case Series and Review of the Literature

Hepaticojejunostomy is a challenging and complex procedure to be done with confidence in conditions that contain a large number of segmental bile ducts. Portoenterostomy can be defined as the joining of multiple bile ducts into a single cavity using segmenter bile duct ends, stents, and surrounding connective tissues. During surgery, in cases with advanced stage biliary tract tumors that cannot be performed hepatectomy, after aggressive dissections to provide a negative surgical margin, a large number of segmental bile ducts can be revealed and needs to ensure the continuity of bile flow. Here, our clinical series of portoenterostomy (PE) in which we applied in patients who had aggressive hilar dissection and resection for hilar cholangiocarcinomas and biliary tract tumors were discussed. The study included 15 patients who underwent PE for biliary tract tumors and hilar cholangiocarcinomas between 2015 and 2019. Six of the patients had a tumor-negative surgical margin, with a mean follow-up of 14.4 months (range 2 to 28 months). Nine of the patients had a tumor-positive surgical margin, with a mean follow-up of 7.7 months (range 2 to 17 months). Portoenterostomy instead of hepaticojejunostomy in small and multiple biliary radicles and bile duct cancers has been successfully performed in 15 patients of bile duct cancer and Klatskin tumor. In the presence of active inflammation, fibrosis, major bile duct trauma, and thin bile duct radicles, this method, which is described in detail, provides an excellent salvage surgical procedure with less morbidity.

MRI predictors of tumor-positive margins after breast-conserving surgery

PurposeThe purpose of this study is to identify predictors of tumor-positive surgical margins after breast-conserving surgery on dynamic contrast-enhanced (DCE) MRI. Materials and methodsWe conducted a retrospective study of consecutive women who underwent DCE MRI before breast-conserving surgery from 2005 to 2014. Patient demographics, indication for surgery, MRI findings, biopsy pathology results, and surgical outcomes were reviewed. The unpaired t-test and chi-square test were used to compare the positive and negative margins groups. Results554 women (mean age, 56; range, 26–90) underwent DCE MRI before 575 breast-conserving surgeries for invasive carcinoma (n = 473) or ductal carcinoma in situ (DCIS) (n = 102). Positive margins requiring re-excision occurred in 19.7% (93/473) of surgeries for invasive carcinoma and 31.4% (32/102) of surgeries for DCIS. For invasive carcinoma surgeries, positive margins were more common when MRI demonstrated the finding of non-mass enhancement (NME) rather than the finding of enhancing mass (33.8% [22/65] versus 16.9% [61/360], p < 0.01). Tumor size on MRI was significantly larger in the positive margins group (2.5 cm versus 1.9 cm, p < 0.001). Positive margins were more common with invasive lobular rather than invasive ductal histology at core biopsy (38.3% [18/47] versus 16.0% [56/350], p < 0.001). For DCIS surgeries, there were no significant differences in positive margin rates related to MRI features. ConclusionFor invasive carcinoma surgeries, positive margins are associated with NME on MRI, larger tumor size on MRI, and lobular histology at core biopsy. These findings may be used to predict which patients are at risk for positive margins after breast-conserving surgery.

An Oncoplastic Breast Augmentation Technique for Immediate Partial Breast Reconstruction following Breast Conservation.

Patients with a small breast volume and a relative large lumpectomy volume are at risk of developing severe breast deformity and asymmetry following breast conservation, presenting a unique surgical challenge. A series of patients undergoing immediate reconstruction by means of an oncoplastic breast augmentation technique following breast conservation are described. The technique includes local tissue rearrangement and bilateral subpectoral breast augmentation with implants of different sizes and shapes, immediately after lumpectomy for a malignant tumor. Twenty-one consecutive patients underwent the oncoplastic breast augmentation technique (mean follow-up, 23 months; range, 12 to 48 months). Three patients (14.3 percent) had tumor-positive surgical margins. Postoperative complications included grade III/IV capsular contracture in five patients (23.8 percent) and breast infection in two patients (10 percent). All patients received postoperative radiation therapy. The cosmetic outcome was evaluated at least 6 months after radiation therapy, and it was favorable according to the reported high patient satisfaction (81 percent) and independent observers' evaluation scores (76 percent). The oncoplastic breast augmentation technique described in this article is an acceptable option in small-breasted patients with a relatively large lumpectomy volume who elect to undergo breast conservation. This technique allows conservation of the affected breast and minimizes potential breast deformation and asymmetry following radiation therapy. Therapeutic, IV.

Follow-up after cystectomy: Regularly scheduled, risk adjusted, or symptom guided?: Patterns of recurrence, relapse presentation, and survival after cystectomy

AimsTo evaluate the efficacy of follow-up based on the patterns of recurrence, relapse presentation and survival after cystectomy, and to define a risk adjusted follow-up schedule. Patients and methodsThe records of 343 patients with regular follow-up after cystectomy were reviewed for primary site of recurrence, accompanying symptoms, means of recurrence diagnosis, and clinicopathological factors. Based on Cox proportional hazard models, and the results of imaging studies low and high risk groups are identified and a risk adjusted follow-up protocol is proposed. ResultsThe risk of a recurrence was related to increasing pT, tumour positive lymph nodes, tumour positive surgical margins, and pre-operative dilatation of the upper urinary tract, and low and high risk groups were defined consequently. 84% of all recurrences occurred within 2 years, with only one recurrence beyond 2 years in the low risk group. Although the minority of all patients (34%) is asymptomatic at time of recurrence, symptomatic recurrences were adversely associated with survival. CT-scans and chest X-rays accounted for 90% of the diagnostic tools to detect a recurrence in patients without symptoms. ConclusionsAsymptomatic patients may benefit from early treatment after disease recurrence. A risk adjusted follow-up strategy based on stage of disease and additional clinicopathological factors can dichotomise patients at high and low risk for recurrence. The small benefit in survival after early detection has to be confirmed in future studies, and weighed against the available treatment options of recurrences and their subsequent costs.

Aggressive fibromatosis: evaluation of prognostic factors and outcomes of surgical treatment

The aim of this study was to evaluate the results of surgical treatment of aggressive fibromatosis and the effects of prognostic factors on recurrence. Forty patients (24 female, 16 male; average age: 31.2 years) diagnosed with aggressive fibromatosis were evaluated retrospectively. Nine patients with tumor-positive surgical margins macroscopically were excluded. Prognostic factors such as age, gender, localization, admission status, compartment status, surgical margin, tumor size and adjuvant radiotherapy were evaluated. Recurrence rate was 29%. Average disease free survival was 46±4 months. There was no statistically significant relation between prognostic factors and recurrence. Clinical results of the patients receiving adjuvant radiotherapy were more satisfactory. Adjuvant radiotherapy administration appears to be a rational treatment method instead of sacrificing function to achieve wide surgical margins.

High-resolution, handheld camera use for occult breast lesion localization plus sentinel node biopsy (SNOLL): A single-institution experience with 186 patients

BackgroundSentinel node and occult lesion localization (SNOLL) calls for a combination of two specific procedures: intraoperative detection of sentinel lymph node (SLN) via gamma probe and radioguided occult lesion localization (ROLL). This applies to nonpalpable invasive breast cancer or high-grade in situ carcinoma. As opposed to standard techniques, today's handheld gamma cameras enable intraoperative scintigraphic images. MethodsA cohort (N = 186) of consecutive patients with breast cancer was subjected to radioguided conservative surgery (quadrantectomy and SLN biopsy), using a standard gamma probe and a high-resolution handheld camera. Intraoperative SLN frozen section was also performed. ResultsNeoplastic lesions were removed in 99.4% of all patients, and SLN biopsy was achieved in 99%. Of the 137 patients with invasive cancer, SLN metastasis was confirmed in 21. In 12% of patients, a second operation was required for close or tumor-positive surgical margins. DiscussionThis combination of procedures represents an improvement in the surgical management of occult breast carcinomas and is the method of choice for accurate tumor localization and SLN biopsy. Handheld cameras have the potential to become highly useful intraoperative aids.

Near-infrared fluorescence (NIRF) imaging in breast-conserving surgery: Assessing intraoperative techniques in tissue-simulating breast phantoms

PurposeBreast-conserving surgery (BCS) results in tumour-positive surgical margins in up to 40% of the patients. Therefore, new imaging techniques are needed that support the surgeon with real-time feedback on tumour location and margin status. In this study, the potential of near-infrared fluorescence (NIRF) imaging in BCS for pre- and intraoperative tumour localization, margin status assessment and detection of residual disease was assessed in tissue-simulating breast phantoms. MethodsBreast-shaped phantoms were produced with optical properties that closely match those of normal breast tissue. Fluorescent tumour-like inclusions containing indocyanine green (ICG) were positioned at predefined locations in the phantoms to allow for simulation of (i) preoperative tumour localization, (ii) real-time NIRF-guided tumour resection, and (iii) intraoperative margin assessment. Optical imaging was performed using a custom-made clinical prototype NIRF intraoperative camera. ResultsTumour-like inclusions in breast phantoms could be detected up to a depth of 21 mm using a NIRF intraoperative camera system. Real-time NIRF-guided resection of tumour-like inclusions proved feasible. Moreover, intraoperative NIRF imaging reliably detected residual disease in case of inadequate resection. ConclusionWe evaluated the potential of NIRF imaging applications for BCS. The clinical setting was simulated by exploiting tissue-like breast phantoms with fluorescent tumour-like agarose inclusions. From this evaluation, we conclude that intraoperative NIRF imaging is feasible and may improve BCS by providing the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time. Clinical studies are needed to further validate these results.

Lipid peroxidation product acrolein as a predictive biomarker of prostate carcinoma relapse after radical surgery

Cancer recurrence after radical surgery might happen even in the case of patients with localized prostate carcinoma treated by radical prostatectomy. Therefore, identifying predictive markers of tumour recurrence is very important, so this study evaluated the presence of lipid peroxidation product acrolein in primary prostate carcinomas, assuming that acrolein could be involved in prostate carcinogenesis as was recently shown for colon cancer. Samples obtained by radical prostatectomy of 70 patients were analysed, out of which 27 patients suffered afterwards from tumour recurrence, while 43 patients were disease free. Immunohistochemistry using genuine monoclonal antibodies against acrolein-protein adducts revealed the association of acrolein with progression of carcinoma. The logistic regression combining clinical parameters together with the biochemical markers of disease and acrolein immunohistochemistry has shown that the relapse might be predicted with 90% accuracy if tumour-positive surgical margins, stage of disease and the intensity of acrolein presence in tumour stroma were taken together.

Molecular Detection of Minimal Residual Cancer in Surgical Margins of Head and Neck Cancer Patients

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins.Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters.A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p &lt; 0.001), and the group of patients with histopathological tumor-free surgical margins (p = 0.001).This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising.

Molecular detection of minimal residual cancer in surgical margins of head and neck cancer patients.

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins.Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters.A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p < 0.001), and the group of patients with histopathological tumor-free surgical margins (p = 0.001).This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising.

Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay

Objective. Because up to 40 percent of surgically treated patients with prostate cancer are subsequently found to be clinically understaged, a more sensitive staging modality to identify extraprostatic disease prior to surgery is required. Methods. We describe an enhanced reverse transcriptase (RT) polymerase chain reaction (PCR) assay utilizing oligonucleoticie primers specific for the human prostate-specific antigen (PSA). This assay identifies PSA-synthesizing cells from reverse transcribed mRNA. This assay was applied to RNAs extracted from the peripheral blood lymphocytes of 65 patients with clinically localized prostate cancer. In addition, blood from 20 women, 20 young men, 25 age-matched control men under treatment for benign prostatic hyperplasia (BPH), and 18 men with established, untreated metastatic prostate cancer was tested. Results. An RTPCR assay for PSA can recognize one PSA-expressing cell diluted into one hundred thousand lymphocytes. The sensitivity of this assay can be enhanced by the addition of digoxigenin-modified nucleotides to the PCR reaction and this assay was applied to RNAs extracted from the peripheral lymphocyte fraction of 148 prostate cancer patients and controls at this institution. Although no specimen from women or men without cancer was positive in this assay, 14 of 18 metastatic prostate cancer patients were positive (77.8%). Additionally, 25 of 65 (38.5%) patients with clinically localized disease (T1-2b) were positive from blood specimens obtained prior to surgery. Final pathologic results from this group of patients identified a correlation between positivity on this assay and the presence of capsular tumor penetration (sensitivity, 68%; specificity, 84%) as well as a strong correlation with the finding of carcinoma at the surgical margin (sensitivity, 87%; specificity, 76%). Logarithmic regression analysis of the results of the RT-PCR assay indicates its remarkable superiority to digital rectal examination, computed tomography scan, endorectal coil magnetic resonance imaging, PSA, prostate-specific antigen density, or Gleason score for predicting the true pathologic stage of prostate cancer in these surgically treated patients. Conclusions. An RT-PCR assay using PSA primers to detect p7rostate cells in the peripheral circulation of surgical-candidate patients is significantly correlated with capsular penetration and tumor-positive surgical margins. This molecular assay provides a sensitive and specific means to stage correctly apparent localized prostate cancer prior to radical prostatectomy.

Treatment of paranasal sinus cancer with cranial base surgery: Results

Paranasal sinus cancer has been difficult to treat with surgery. A significant negative factor has been the high frequency of tumor-positive surgical margins. The goal of this study was to evaluate the effectiveness of cranial base surgery in achieving higher tumor-free resective margins and its impact on the disease control. Fifty patients with paranasal sinus cancer were treated with cranial base surgery and retrospectively evaluated. Surgery was performed for both primary and recurrent disease ("salvage"), with more than half of the surgeries being salvage procedures. The survival at 40 months of mean follow-up is 74%, and 64% of the patients either have no evidence of disease (NED) or have died of other causes (DOC). Cranial base surgery is an effective treatment of paranasal sinus cancer. The ability to achieve tumor-free surgical margins (77% in squamous cell carcinoma [SCC]) is directly related to NED status (75% of NED patients had free margins).

Adjuvant perioperative hepatic arterial mitomycin C and floxuridine combined with surgical resection of metastatic colorectal cancer in the liver.

Twenty patients with colon cancer metastatic to the liver underwent successful hepatic resection and adjuvant perioperative therapy that included hepatic arterial mitomycin C and floxuridine (FUDR). The median survival for all 20 patients was 51 months: 10 are still alive with a median postoperative follow-up of 49 months; 6 are disease-free with a median postoperative follow-up of 43 months. Among 10 patients in whom the surgical margins of the specimen contained tumor cells, the median survival was 52 months. This survival was comparable to that among 10 patients in whom the surgical margins were tumor free (P = 0.22). Neither the number of metastatic liver deposits nor the disease-free interval between the primary diagnosis of colorectal carcinoma and the development of liver metastases significantly affected survival. A transient chemical hepatitis which resolved before the next scheduled treatment was associated with 50% of arterial chemotherapy cycles (approximately 70% of the patients). Gastric or duodenal ulcerations occurred in 23% of the patients. Surgical complications were either pulmonary such as pleural effusion or atelectasis, or wound infections and subphrenic abscesses. Although these results compare favorably with the results in previously published series, this aggressive adjuvant chemotherapy appears to be particularly justified in patients with tumor positive surgical margins or those with multiple tumor masses and, therefore, are characterized by a poor prognosis.