Incomplete Tumor Removal Research Articles

TB-03 Newly Established Meningioma Organoid Model Elucidated an Important Role of FOXM1 in Meningioma Progression

Meningioma is the most frequently occurring intracranial neoplasms in adults. Tumor removal surgery and radiotherapy were the widely accepted standard treatment for meningioma. Most meningioma cases were cured by extended total removal. However, some tumors develop in locations less amenable to resection, resulting in tumor recurrence after incomplete tumor removal followed by radiotherapy. Although several comprehensive studies have revealed frequently found molecular alterations of meningiomas, effective treatment reagents targeting specific molecular alterations have not been identified yet because of limited number of representative research models such as tumor cell lines or animal models of meningiomas. Recently developed 3D culture technologies have led to the development of novel cancer models, termed organoid models, due to their quite high efficiency of establishment. In this study, we established primary organoid culture methods using malignant meningioma cell lines (e.g. HKBMM and IOMM-Lee) and patient-derived meningioma tissues. Using this novel method, we have been able to establish six organoid models (four WHO grade I meningiomas, one WHO grade III one and one solitary fibrous tumor (SFT)) using tumor tissues derived from six consecutive patients with 100% success rate. Histological analyses, whole exome sequencing and copy number analyses revealed that these organoids exhibited consistent histological features and molecular profiling with those of parental tumors. Using public database, we identified upregulated FOXM1 was correlated with increased tumor proliferation. Over-expression of FOXM1 in benign meningioma organoids increased organoid proliferation, while depletion of FOXM1 in malignant ones decreased their proliferation. We revealed that novel organoid model for meningioma enable to shed light on the tumor biology of meningioma.

Management of transmodiolar and transmacular cochleovestibular schwannomas with and without cochlear implantation.

IntroductionHearing rehabilitation with cochlear implants has attracted increasing interest also for patients with cochleovestibular schwannoma. The authors report their experience with the surgical management of tumors with rare transmodiolar or transmacular extension and outcomes after cochlear implantation (CI).MethodsThis retrospective case series included nine patients with either primary intralabyrinthine tumors or secondary invasion of the inner ear from the internal auditory canal. The primary endpoint with CI, performed in six patients, was word recognition score at 65 dB SPL (sound pressure level). Secondary endpoints were intra- and postoperative electrophysiological parameters, impedance measures, the presence of a wave V in the electrically evoked (via the CI) auditory brainstem responses, the specifics of postoperative CI programming, and adverse events.ResultsHearing rehabilitation with CI in cases of transmodiolar tumor growth could be achieved only with incomplete tumor removal, whereas tumors with transmacular growth could be completely removed. All six patients with CI had good word recognition scores for numbers in quiet conditions (80–100% at 65 dB SPL, not later than 6 to 12 months post CI activation). Four of these six patients achieved good to very good results for monosyllabic words within 1–36 months (65–85% at 65 dB SPL). The two other patients, however, had low scores for monosyllables at 6 months (25 and 15% at 65 dB SPL, respectively) with worsening of results thereafter.ConclusionsCochleovestibular schwannomas with transmodiolar and transmacular extension represent a rare entity with specific management requirements. Hearing rehabilitation with CI is a principal option in these patients.Video onlineThe online version of this article (10.1007/s00106-020-00919-9) includes a video (2D and 3D versions) of the described surgical technique. Article and supplementary material are available at www.springermedizin.de. Please enter the title of the article in the search field, the supplementary material can be found under “Ergänzende Inhalte”.

Biophotonic technologies for assessment of breast tumor surgical margins-A review.

Breast conserving surgery (BCS) offering similar surgical outcomes as mastectomy while retaining breast cosmesis is becoming increasingly popular for the management of early stage breast cancers. However, its association with reoperation rates of 20% to 40% following incomplete tumor removal warrants the need for a fast and accurate intraoperative surgical margin assessment tool that offers cellular, structural and molecular information of the whole specimen surface to a clinically relevant depth. Biophotonic technologies are evolving to qualify as such an intraoperative tool for clinical assessment of breast cancer surgical margins at the microscopic and macroscopic scale. Herein, we review the current research in the application of biophotonic technologies such as photoacoustic imaging, Raman spectroscopy, multimodal multiphoton imaging, diffuse optical imaging and fluorescence imaging using medically approved dyes for breast cancer detection and/or tumor subtype differentiation toward intraoperative assessment of surgical margins in BCS specimens, and possible challenges in their route to clinical translation.

Management of transmodiolar and transmacular cochleovestibular schwannomas with and without cochlear implantation. German version

Hearing rehabilitation with cochlear implants has attracted increasing interest also for patients with cochleovestibular schwannoma. The authors report their experience with the surgical management of tumors with rare transmodiolar or transmacular extension and outcomes after cochlear implantation (CI). This retrospective case series included nine patients with either primary intralabyrinthine tumors or secondary invasion of the inner ear from the internal auditory canal. The primary endpoint with CI, performed in six patients, was word recognition score at 65 dB SPL (sound pressure level). Secondary endpoints were intra- and postoperative electrophysiological parameters, impedance measures, the presence of awaveV in the electrically evoked (via the CI) auditory brainstem responses, the specifics of postoperative CI programming, and adverse events. Hearing rehabilitation with CI in cases of transmodiolar tumor growth could be achieved only with incomplete tumor removal, whereas tumors with transmacular growth could be completely removed. All six patients with CI had good word recognition scores for numbers in quiet conditions (80-100% at 65 dB SPL, not later than 6 to 12months post CI activation). Four of these six patients achieved good to very good results for monosyllabic words within 1-36months (65-85% at 65 dB SPL). The two other patients, however, had low scores for monosyllables at 6months (25 and 15% at 65 dB SPL, respectively) with worsening of results thereafter. Cochleovestibular schwannomas with transmodiolar and transmacular extension represent arare entity with specific management requirements. Hearing rehabilitation with CI is aprincipal option in these patients.

Navigated tissue characterization during skin cancer surgery.

Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer and is treated by surgical resection. Incomplete tumor removal requires surgical revision, leading to significant healthcare costs and impaired cosmesis. We investigated the clinical feasibility of a surgical navigation system for BCC surgery, based on molecular tissue characterization using rapid evaporative ionization mass spectrometry (REIMS). REIMS enables direct tissue characterization by analysis of cell-specific molecules present within surgical smoke, produced during electrocautery tissue resection. A tissue characterization model was built by acquiring REIMS spectra of BCC, healthy skin and fat from ex vivo skin cancer specimens. This model was used for tissue characterization during navigated skin cancer surgery. Navigation was enabled by optical tracking and real-time visualization of the cautery relative to a contoured resection volume. The surgical smoke was aspirated into a mass spectrometer and directly analyzed with REIMS. Classified BCC was annotated at the real-time position of the cautery. Feasibility of the navigation system, and tissue classification accuracy for ex vivo and intraoperative surgery were evaluated. Fifty-four fresh excision specimens were used to build the ex vivo model of BCC, normal skin and fat, with 92% accuracy. While 3 surgeries were successfully navigated without breach of sterility, the intraoperative performance of the ex vivo model was low (< 50%). Hypotheses are: (1) the model was trained on heterogeneous mass spectra that did not originate from a single tissue type, (2) during surgery mixed tissue types were resected and thus presented to the model, and (3) the mass spectra were not validated by pathology. REIMS-navigated skin cancer surgery has the potential to detect and localize remaining tumor intraoperatively. Future work will be focused on improving our model by using a precise pencil cautery tip for burning localized tissue types, and having pathology-validated mass spectra.

Automated gigapixel circumferential surface microscopy of the prostate

Positive surgical margins, or cancer cells found at the boundary of an excised tumor mass, are a significant problem in the management of many cancers resulting in worsened patient outcomes. The problem is exacerbated in organ sites such as the prostate, where unnecessarily wide local excisions can result in significant deterioration of post-operative quality of life due to collateral damage to neighboring structures. Yet, at the same time, incomplete tumor removal results in worsened prognosis and need for additional interventions. Here, we report the design and development of a rapid and completely automated system for intraoperative gigapixel ex vivo microscopy of the circumferential surgical prostate margin within intra-operative timeframes, called the Automated Prostate Positioning System (APPS). The APPS leverages the rotational geometry of the prostate and high speed structured illumination microscopy (SIM) to generate continuous gigapixel panoramas of the fresh intact prostate circumference, including areas of the prostate adjacent to the neurovascular bundles, the rectum, and the bladder wall. Our previous work using SIM and a manual prostate handling method demonstrated the promise of the imaging technique for accurate detection of positive surgical margins. Our work here advances the technology toward clinical adoption, by demonstrating 10% greater tissue surface coverage fraction, 1.6× faster imaging throughput, and reduced number of required operator steps, compared to our prior approach. The APPS may be operated by a single person in the operating room suite within intraoperative time limits, while simultaneously delivering nearly two orders of magnitude higher tissue surface coverage than destructive and labor-intensive frozen section analysis techniques.

Charles H. Frazier's craniopharyngioma treatment: the pivotal role of the transfrontal approach.

Charles H. Frazier (1870-1936), one of the pioneers of neurosurgery in the US, is known worldwide for devising surgical procedures to relieve trigeminal neuralgia and intractable pain. Less well-known are his substantial contributions to understanding and treating pituitary and parahypophyseal lesions. Along with Bernard Alpers, he defined Rathke's cleft tumors as a different pathological entity from adenomas and hypophyseal stalk tumors (craniopharyngiomas [CPs]). The surgical challenge posed by CPs piqued Frazier's interest in these lesions, although he never published a complete account of his CP series. An examination of the Charles Frazier papers at the College of Physicians of Philadelphia allowed the authors to identify 54 CPs that he had treated during his career. In the early 1910s, Frazier developed the subfrontal approach, which would become the primary surgical route to access these lesions, providing better control of the adjacent vital neurovascular structures than the transsphenoidal route hitherto used. Nevertheless, strong adhesions between CPs and the third ventricle floor, the major reason underlying Frazier's disappointing results, moved him to advocate incomplete tumor removal followed by radiotherapy to reduce both the risk of hypothalamic injury and CP recurrence. This conservative strategy remains a judicious treatment for CPs to this day.

Fabrication of Curcumin-Modified TiO2 Nanoarrays via Cyclodextrin Based Polymer Functional Coatings for Osteosarcoma Therapy.

The incomplete removal of bone tumors leads to increased local recurrence and poor prognosis. To prevent ostoperative tumor recurrence and simultaneously repair surgery-caused bone defects, there is a need of great significance to develop implantable biomaterials possessing both cancer cell-killing ability and excellent bioactivity. In this work, a functionalized titanium-based implant is successfully fabricated by loading curcumin (CUR) onto cyclodextrin based polymer (pCD) modified titanium dioxide (TiO2 ) nanorod arrays. Herein, a polydopamine (pDA) assisted film is implemented as a first coating layer onto the surface of the TiO2 nanoarrays to guarantee the robust anchorage of the pCD. The pCD coating acts as a reservoir for CUR, allowing for efficient drug loading and sustained release of anticancer drugs. Studies show that the CUR-modified surfaces (TiO2 /pDA/pCD/CUR) can significantly promote apoptosis of osteosarcoma cells in vitro by inducing mitochondrial dysfunction caused by the ROS overproduction, and meanwhile, effectively inhibit the tumor growth in vivo. Moreover, such functionalized implants with surface density of loaded CUR at 22.48 µg cm-2 or lower support the attachment and proliferation of osteoblasts in vitro. These results successfully demonstrate that as-prepared TiO2 /pDA/pCD/CUR constructs have combined anticancer performance and good biocompatibility, which has great promise for the surgical therapy of bone tumors.

Immunotherapy: Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal‐Immunotherapy Efficiency of Solid Tumors (Small 42/2019)

Photothermal therapy (PTT) has been pre-clinically used in cancer treatment, but incomplete tumor removal and heat endurance of tumor cells could induce significant tumor relapse. In article number 1902636, Xiaolong Liu, Jingfeng Liu, and co-workers report a programmable antitumor strategy that combines artificially engineered natural killer cells with anti-heat endurance of DNAzyme as a powerful adjuvant for immuno-enhancing the therapeutic efficiency of PTT.

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors.

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A-NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn-CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn2+ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn-CONASHs exhibit excellent light-to-heat conversion ability, tumor microenvironment enhanced T1 -MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a-aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A-NK cells combined with antiheat endurance as a powerful strategy for immuno-enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.

Population-Based Study on Risk Factors for Tumor-Positive Resection Margins in Patients with Gastric Cancer

BackgroundRadical gastrectomy is the cornerstone of the treatment of locally advanced gastric cancer. This study was designed to evaluate factors associated with a tumor-positive resection margin after gastrectomy and to evaluate the influence of hospital volume.MethodsIn this Dutch cohort study, patients with junctional or gastric cancer who underwent curative gastrectomy between 2011 and 2017 were included. The primary outcome was incomplete tumor removal after the operation defined as the microscopic presence of tumor cells at the resection margin. The association of patient and disease characteristics with incomplete tumor removal was tested with multivariable regression analysis. The association of annual hospital volume with incomplete tumor removal was tested and adjusted for the patient- and disease characteristics.ResultsIn total, 2799 patients were included. Incomplete tumor removal was seen in 265 (9.5%) patients. Factors associated with incomplete tumor removal were: tumor located in the entire stomach (odds ratio (OR) [95% confidence interval (CI): 3.38 [1.91–5.96] reference: gastroesophageal junction), cT3, cT4, cTx (1.75 [1.20–2.56], 2.63 [1.47–4.70], 1.60 [1.03–2.48], reference: cT0-2), pN+ (2.73 [1.96–3.80], reference: pN−), and diffuse and unknown histological subtype (3.15 [2.14–4.46] and 2.05 [1.34–3.13], reference: intestinal). Unknown differentiation grade was associated with complete tumor removal (0.50 [0.30–0.83], reference: poor/undifferentiated). Compared with a hospital volume of < 20 resections/year, 20–39, and > 39 resections were associated with lower probability for incomplete tumor removal (OR 0.56 [0.42–0.76] and 0.34 [0.18–0.64]).ConclusionsTumor location, cT, pN, histological subtype, and tumor differentiation are associated with incomplete tumor removal. The association of incomplete tumor removal with an annual hospital volume of < 20 resections may underline the need for further centralization of gastric cancer care in the Netherlands.

Use of intraoperative intracavitary (direct-contact) ultrasound for resection control in transsphenoidal surgery for pituitary tumors: evaluation of a microsurgical series

Perisellar infiltration may be responsible for incomplete removal of pituitary tumors. Since intraoperative visualization of parasellar structures is difficult during transsphenoidal surgery, we are describing the use of intraoperative direct contact ultrasound (IOUS). Within 5years, in 113 transsphenoidal operations (58 male, 55 female, age 14-81years, 110 pituitary adenomas (mean diameter 26.6mm, 69 non-secreting adenomas, 41 secreting adenomas), and 1 of each Rathke's cleft cyst, craniopharyngioma, and xanthogranuloma), IOUS was applied. After wide opening of the sellar floor and removal of the intrasellar tumor portions, a commercially available side fire ultrasound probe is introduced, and in direct contact to the sellar envelope, the perisellar space is scanned perpendicular to the axis of the working channel. We compared the results of IOUS to postoperative MRI after 3-6months. Identification of the intracavernous ICA, the anterior optic pathway, and the ACA, was possible, it was safe to operate close to them. In 65 operations (58%), further resection of tumor remnants was performed after IOUS. In this selected series, complete resection of tumors (stated by postoperative MRI after 3-6months) was achieved in 75 operations (66%) and remission was achieved in 18 operations of secreting adenomas (44%). Compared to MRI after 3 to 6months, the sensitivity of IOUS was 0.568 and the specificity was 0.907. No complications related to IOUS were seen. Visualization of the perisellar compartments by IOUS is easy and fast to perform. It allows the surgeon to identify resectable tumor remnants intraoperatively, which otherwise could be missed.

Benefits of image-guided stereotactic hypofractionated radiation therapy as adjuvant treatment of craniopharyngiomas. A review.

Craniopharyngiomas account for 5.6-13% of intracranial tumors in children. Despite being histologically benign, these tumors remain a major neurosurgical challenge because of the typical tight adherence to adjacent critical structures. The optimal therapeutic approach for this disease is controversial. Large cystic size and adherence to neurovascular, neuroendocrine, and optic structures without a clear line of cleavage make complete resection problematic and often hazardous. For these reasons, partial resection and adjuvant treatment play an important role. Post-operative radiation therapy (RT) following either complete or incomplete tumor removal is associated with significantly decreased recurrence rates. The aim of this review is to analyze the potential advantage of the most modern technical advancements for RT of craniopharyngiomas. This narrative review on the topic of craniopharyngiomas was based on published data available on PUBMED/Medline. All data concerning adjuvant or upfront radiation therapy treatment of craniopharyngioma were reviewed and summarized. A more detailed analysis of fractionated frameless steretactic radiosurgery of these tumors is provided as well. We reviewed the possible improvement provided by intensity modulated beams, arc therapy, image guidance, proton radiation, and fractionated stereotactic radiosurgery. Many published findings on outcome and toxicity after RT involve the use of relatively outdated RT techniques. Technologic improvements in imaging, radiation planning, and delivery have improved the distribution of radiation doses to desired target volumes and reduced the dose to nearby critical normal tissues. Currently available techniques, providing image guidance and improved radiation doses distribution profile, have shown to maintain the efficacy of conventional techniques while significantly reducing the toxicity. Image-guided radiosurgery holds the dose distributions and precision of frame-based techniques with the remarkable advantage of multiple-session treatments that are better tolerated by sensitive peritumoral structures, such as the optic pathway and hypothalamus. This, together with the comfort of a frameless technique, candidates frameless image-guided radiosurgery to be the first option for the adjuvant post-operative treatment of craniopharyngiomas in children and young adults when total resection cannot be achieved, in particular those with hypothalamic involvement, and when the residual tumor is mostly solid.

A fiber optoacoustic guide with augmented reality for precision breast-conserving surgery

Lumpectomy, also called breast-conserving surgery, has become the standard surgical treatment for early-stage breast cancer. However, accurately locating the tumor during a lumpectomy, especially when the lesion is small and nonpalpable, is a challenge. Such difficulty can lead to either incomplete tumor removal or prolonged surgical time, which result in high re-operation rates (~25%) and increased surgical costs. Here, we report a fiber optoacoustic guide (FOG) with augmented reality (AR) for sub-millimeter tumor localization and intuitive surgical guidance with minimal interference. The FOG is preoperatively implanted in the tumor. Under external pulsed light excitation, the FOG omnidirectionally broadcasts acoustic waves through the optoacoustic effect by a specially designed nano-composite layer at its tip. By capturing the acoustic wave, three ultrasound sensors on the breast skin triangulate the FOG tip’s position with 0.25-mm accuracy. An AR system with a tablet measures the coordinates of the ultrasound sensors and transforms the FOG tip’s position into visual feedback with <1-mm accuracy, thus aiding surgeons in directly visualizing the tumor location and performing fast and accurate tumor removal. We further show the use of a head-mounted display to visualize the same information in the surgeons’ first-person view and achieve hands-free guidance. Towards clinical application, a surgeon successfully deployed the FOG to excise a “pseudo tumor” in a female human cadaver. With the high-accuracy tumor localization by FOG and the intuitive surgical guidance by AR, the surgeon performed accurate and fast tumor removal, which will significantly reduce re-operation rates and shorten the surgery time.

PD48 OTL38, A Tumour-Specific Agent In Surgery For Ovarian Cancer

Introduction:Ovarian cancer (OC) has the highest mortality rate of all gynecologic malignancies. Completeness of cytoreductive surgery is a key prognostic factor for survival. To differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is difficult and can lead to incomplete tumour removal. OTL38 is a folate analogue conjugated to a near-infrared fluorescent dye which has high specificity and affinity for folate receptor alpha (FRα) expressed in OC. OTL38 together with a specific imaging system can help the surgeon to visualize diseased tissue. The objective of this work is to know the effectiveness and safety of OTL38 in of OC surgery.Methods:Early assessment of OTL38 identified through the early-awareness and alert-system, “SINTESIS-new technologies”, of AETS-ISCIII. The searched databases were: PubMed, WOS, Tripdatabase, Dynamed, Cochrane Library and ICTRP. Clinical studies using the OTL38 in cytoreductive surgery in OC published until September 2017 were reviewed.Results:Only one publication, supported by industry, was retrieved. The study assesses the pharmacokinetics and tolerability of OLT38 in 30 healthy people randomized into 4 groups with different doses and a control group. The study also analyses the percentage of cytoreduction in 12 OC patients. Infusion of 0.025, 0.05, and 0.1 mg/kg OTL38 doses was associated with mild adverse events which did not require intervention. The 0.2 mg/kg dose was associated to adverse events of moderate severity. In OC patients, 0.0125 mg/kg dose was considered the optimal dose with mild adverse events. OTL38 accumulated in FRα-positive tumours and metastases allowed the surgeon to resect an additional 29 percent of malignant lesions which were not detected using standard inspection and palpation methods.Conclusions:The OTL38 is an emergent health technology, which could help in cytoreductive surgery for ovarian cancer. However, the evidence is scarce and it would be necessary to continue further studies.

Efficacy of different postoperative adjuvant therapy strategies for stage II/III thoracic esophageal squamous cell carcinoma

Objective To evaluate the efficacy and adverse reactions of postoperative chemoradiotherapy (S+ CRT) and postoperative radiotherapy (S+ RT) for stage Ⅱ/Ⅲ thoracic esophageal squamous cell carcinoma. Methods Clinical data were collected from 215 patients with stage Ⅱ/Ⅲ thoracic esophageal squamous cell carcinoma who received radical resection and postoperative adjuvant radiotherapy or chemoradiotherapy from 2007 to 2010. Survival rates were calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were made by the log-rank test and Cox proportional model, respectively. Results The data were comparable between the S+ CRT group and the S+ RT group (P=0.055-0.988). The numbers of patients who received 1-, 3-, and 5-year follow-up were 203, 133, and 108, respectively. In all the patients, the 1-, 3-, and 5-year overall survival (OS) rates were 94.0%, 61.4%, and 49.3%, respectively, and the 1-, 3-, and 5-year disease-free survival (DFS) rates were 74.9%, 53.5%, 46.7%, respectively. Preoperative mediastinal lymph node enlargement on computed tomography (CT), the degree of adhesion of esophageal lesions to peripheral tissues during surgery, pathological N staging, vascular tumor thrombus, the number of positive lymph nodes, and treatment strategy were independent prognostic factors for OS (P=0.000-0.034). Preoperative mediastinal lymph node enlargement revealed on CT, the degree of adhesion of esophageal lesions to peripheral tissues during surgery, incomplete removal of tumor from the esophagus, the number of positive lymph nodes, and treatment strategy were independent prognostic factors for DFS (P=0.000-0.049). The S+ CRT group had significantly improved OS and DFS rates than the S+ RT group (P=0.002, 0.002). The result of stratified analysis showed that for the patients with stage Ⅱ disease and those with stage N1 disease, the S+ CRT group had significantly improved OS and DFS rates than the S+ RT group (P=0.041, 0.001, 0.021, 0.024). The S+ CRT group had significantly higher incidence rates of grade ≥2 radiation-induced gastritis and marrow suppression than the S+ RT group (P=0.000, 0.015). Conclusions Both S+ CRT and S+ RT achieve satisfactory treatment outcomes in patients with stage Ⅱ/Ⅲ thoracic esophageal squamous cell carcinoma. Compared with S+ RT, S+ CRT can significantly improve the OS and DFS in patients with stage Ⅱ or N1 disease; S+ CRT causes more severe but tolerable adverse reactions. Prospective randomized phase Ⅲ clinical studies are still required to confirm the final conclusions. Key words: Esophageal neoplasms/surgery; Esophageal neoplasms/postoperative radiotherapy; Esophageal neoplasms/postoperative chemoradiotherapy; Prognosis

EpCAM as multi-tumour target for near-infrared fluorescence guided surgery.

BackgroundEvaluation of resection margins during cancer surgery can be challenging, often resulting in incomplete tumour removal. Fluorescence-guided surgery (FGS) aims to aid the surgeon to visualize tumours and resection margins during surgery. FGS relies on a clinically applicable imaging system in combination with a specific tumour-targeting contrast agent. In this study EpCAM (epithelial cell adhesion molecule) is evaluated as target for FGS in combination with the novel Artemis imaging system.MethodsThe NIR fluorophore IRDye800CW was conjugated to the well-established EpCAM specific monoclonal antibody 323/A3 and an isotype IgG1 as control. The anti-EpCAM/800CW conjugate was stable in serum and showed preserved binding capacity as evaluated on EpCAM positive and negative cell lines, using flow cytometry and cell-based plate assays. Four clinically relevant orthotopic tumour models, i.e. colorectal cancer, breast cancer, head and neck cancer, and peritonitis carcinomatosa, were used to evaluate the performance of the anti-EpCAM agent with the clinically validated Artemis imaging system. The Pearl Impulse small animal imaging system was used as reference. The specificity of the NIRF signal was confirmed using bioluminescence imaging and green-fluorescent protein.ResultsAll tumour types could clearly be delineated and resected 72 h after injection of the imaging agent. Using NIRF imaging millimetre sized tumour nodules were detected that were invisible for the naked eye. Fluorescence microscopy demonstrated the distribution and tumour specificity of the anti-EpCAM agent.ConclusionsThis study shows the potential of an EpCAM specific NIR-fluorescent agent in combination with a clinically validated intraoperative imaging system to visualize various tumours during surgery.

A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer.

Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers. We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging. Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation. This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929-38. ©2016 AACR.

Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping.

The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging.

Clinical significance of the muscle-retracting sign during colorectal endoscopic submucosal dissection.

Background and study aims: During colorectal endoscopic submucosal dissection (ESD), the feature of a muscle layer being pulled toward a neoplastic tumor is sometimes detected. We call this feature the muscle-retracting sign (MR sign). The aim of this study was to evaluate whether the MR sign is associated with particular types of neoplastic lesions and whether it has any clinical significance for ESD sessions. Patients and methods: A total of 329 patients underwent ESD for 357 colorectal neoplasms. The frequency of positivity for the MR sign was evaluated in different morphologic and histopathologic types of neoplasm. The success rate of complete resection and the incidence of complications were also evaluated according to whether lesions were positive or negative for the MR sign. Results: The rates of positivity for the MR sign in the various lesion types were as follows: laterally spreading tumor – granular nodular mixed type (LST-G-M), 9.6 %; laterally spreading tumor – granular homogeneous type (LST-G-H) and laterally spreading tumor – nongranular type (LST-NG), 0 %; sessile type, 41.2 %. The resection rate was 100 % (329 /329) in lesions negative for the MR sign; however, it was 64.3 % (18 /28) in lesions positive for the MR sign, which was significantly lower (P < 0.001). Conclusions: The MR sign was present only in some protruding lesions, and more importantly, it was associated with a high risk of incomplete tumor removal by ESD. Our data indicate that lesions positive for the MR sign lesions should be dissected with great caution; alternatively, based on the features of the individual case, a switch to surgery should be considered for the benefit of the patient.