Microscopic Tumor Research Articles

Surgery for parotid gland cancer-controversial and proven aspects

Due to the rarity of primary parotid malignancies, there are currently only limited clinical study data on the optimal surgical therapy. Parotid malignancies encompass abroad spectrum of more than 20different histological subtypes with varying biology, which thus represents a challenge for even experienced pathologists and head and neck surgeons with proven expertise in salivary gland surgery. The aim of this review article is to provide an overview of the current literature on surgical therapy of the primary tumor and the cN0 neck as well as treatment of the facial nerve, and to shed light on the various controversial aspects of this topic. In salivary gland oncology there is atrend towards safe (R0) but more conservative surgery. Currently, less-invasive surgical approaches could potentially be applied in asmall subgroup with carefully selected caudally located and R0-resected "low-grade tumors" in stages T1-T2 and cN0 in relatively young patients with high compliance and more in the context of structured clinical studies. Elective neck dissection in the case of cN0 status should be carried out if risk factors for occult cervical lymph node metastasis (T3-T4a, "high-grade subtypes," advanced age, lymphangitic carcinomatosis) are present. In cases of small "low-grade parotid carcinomas," narrow resection margins or even microscopic tumor residues on the facial nerve can potentially be adequately compensated with adjuvant radiation therapy. However, due to the lack of solid data, the significance of the actual effect of the radiation in this situation should be viewed with great caution.

Combined Infiltrative Macroscopic Growth Pattern and Infiltrative Microscopic Tumor Border Status Is a Novel Surrogate Marker of Poor Prognosis in Patients With Pancreatic Neuroendocrine Tumor.

Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous tumors with a wide range of malignant potential. Therefore, identification of prognostic factors is essential. To systematically assess the significance of tumor border, a well-known prognostic indicator in other cancers, in PanNETs. We evaluated the macroscopic growth pattern (expansile [Exp] versus infiltrative [Inf]) and the microscopic tumor border (pushing [Pus] versus Inf) of 203 surgically resected PanNETs and compared them with other clinicopathologic factors. Based on macroscopic growth pattern, 83 cases had Exp patterns whereas 84 had Inf patterns. According to microscopic tumor border, 122 PanNETs had Pus borders whereas 81 had Inf borders. Combining macroscopic growth pattern and microscopic tumor border, 65 PanNETs had Exp/Pus, 34 had Inf/Pus, 18 had Exp/Inf, and 50 had Inf/Inf status. PanNETs with Inf/Inf status were associated with higher tumor grade, pT classification, and American Joint Committee on Cancer stage grouping; lymph node metastasis; and lymphovascular and perineural invasions (all P < .001). Patients with PanNET having Inf/Inf status had significantly shorter overall survival (OS) and recurrence-free survival (RFS; all P < .001). Further, using multivariate analysis, Inf/Inf status was identified as an independent poor prognostic factor of OS (P = .02) and RFS (P = .03). In summary, combined Inf/Inf status was observed in approximately 25% of PanNETs and was associated with aggressive biological behavior and short OS and RFS. Therefore, assessing combined macroscopic growth pattern and microscopic tumor border can provide additional information regarding survival and recurrence in PanNET patients.

The impact of S-1 for the patient with lymph nodal metastasis biliary tract cancer as adjuvant chemotherapy: a multicenter database analysis.

Although adjuvant chemotherapy is expected to improve the prognosis for patients with biliary tract cancer after curative resection, there is limited evidence regarding the efficacy and prognostic factors of adjuvant chemotherapy. We investigated the effective subgroups for whom adjuvant chemotherapy with S-1 in biliary tract cancer patients. 413 patients who underwent curative resection for biliary tract cancer at our four affiliated hospitals between 2009 and 2019 were included in this study. The association of adjuvant chemotherapy with long-term outcomes in overall and patient subgroups were investigated by univariate and multivariate analyses. Among overall patients, adjuvant chemotherapy with S-1 did not improve disease free survival (p = 0.29) and overall survival (p = 0.83). In thesubgroup analysis, adjuvant chemotherapy with S-1 improved both disease-free and overall survival in patients with lymph node metastasis, advanced Stage (III and IV), and microscopic residual tumor. In 135 patients with lymph node metastasis, adjuvant chemotherapy with S-1 was given in 67 patients (50%). In the patients with lymph node metastasis, preoperative bile duct drainage (p = 0.01) and adjuvant chemotherapy (p = 0.04) were independent and significant predictors of disease-free survival, while preoperative bile duct drainage (p = 0.03), tumor differentiation (p = 0.03), and adjuvant chemotherapy (p = 0.03) were independent and significant predictors of overall survival. After resection of biliary tract cancer, adjuvant chemotherapy with S-1 appears to benefit those who had lymph node metastasis.

Rapid Automated Analysis of Skull Base Tumor Specimens Using Intraoperative Optical Imaging and Artificial Intelligence.

Accurate specimen analysis of skull base tumors is essential for providing personalized surgical treatment strategies. Intraoperative specimen interpretation can be challenging because of the wide range of skull base pathologies and lack of intraoperative pathology resources. To develop an independent and parallel intraoperative workflow that can provide rapid and accurate skull base tumor specimen analysis using label-free optical imaging and artificial intelligence. We used a fiber laser-based, label-free, nonconsumptive, high-resolution microscopy method (<60 seconds per 1 × 1 mm2), called stimulated Raman histology (SRH), to image a consecutive, multicenter cohort of patients with skull base tumor. SRH images were then used to train a convolutional neural network model using 3 representation learning strategies: cross-entropy, self-supervised contrastive learning, and supervised contrastive learning. Our trained convolutional neural network models were tested on a held-out, multicenter SRH data set. SRH was able to image the diagnostic features of both benign and malignant skull base tumors. Of the 3 representation learning strategies, supervised contrastive learning most effectively learned the distinctive and diagnostic SRH image features for each of the skull base tumor types. In our multicenter testing set, cross-entropy achieved an overall diagnostic accuracy of 91.5%, self-supervised contrastive learning 83.9%, and supervised contrastive learning 96.6%. Our trained model was able to segment tumor-normal margins and detect regions of microscopic tumor infiltration in meningioma SRH images. SRH with trained artificial intelligence models can provide rapid and accurate intraoperative analysis of skull base tumor specimens to inform surgical decision-making.

Ectopic Recurrence of Skull Base Chordoma after Proton Therapy.

Simple SummaryChordoma are very rare tumors of the spine and skull base. Due to close proximity of crucial organs, like the brain stem, complete removal can often not be achieved, and tumor tissue, either macroscopic or microscopic, remains in situ. Local recurrence up to 88% occurs in 10 years. Ectopic recurrence as an early sign of treatment failure is considered rare. We retrospectively reviewed five patients with ectopic recurrence as a first sign of treatment failure after treatment with surgery and proton therapy, and studied the applied treatment strategies and imaging follow-up. We found 18 ectopic recurrences in these five patients, of which 17 (94%) could be related to prior surgical tracts. Our theory is that these relapses occur due to microscopic tumor spill during surgery. These cells did not receive a therapeutic radiation dose. Advances in surgical possibilities and adjusted radiotherapy target volumes might improve local control and survival.Background: Chordoma are rare tumors of the axial skeleton. The treatment gold standard is surgery, followed by particle radiotherapy. Total resection is usually not achievable in skull base chordoma (SBC) and high recurrence rates are reported. Ectopic recurrence as a first sign of treatment failure is considered rare. Favorable sites of these ectopic recurrences remain unknown. Methods: Five out of 16 SBC patients treated with proton therapy and surgical resection developed ectopic recurrence as a first sign of treatment failure were critically analyzed regarding prior surgery, radiotherapy, and recurrences at follow-up imaging. Results: Eighteen recurrences were defined in five patients. A total of 31 surgeries were performed for primary tumors and recurrences. Seventeen out of eighteen (94%) ectopic recurrences could be related to prior surgical tracts, outside the therapeutic radiation dose. Follow-up imaging showed that tumor recurrence was difficult to distinguish from radiation necrosis and anatomical changes due to surgery. Conclusions: In our cohort, we found uncommon ectopic recurrences in the surgical tract. Our theory is that these recurrences are due to microscopic tumor spill during surgery. These cells did not receive a therapeutic radiation dose. Advances in surgical possibilities and adjusted radiotherapy target volumes might improve local control and survival.

Novel multifunctional NIR-II aggregation-induced emission nanoparticles-assisted intraoperative identification and elimination of residual tumor

Incomplete tumor resection is the direct cause of the tumor recurrence and metastasis after surgery. Intraoperative accurate detection and elimination of microscopic residual cancer improve surgery outcomes. In this study, a powerful D1–π–A–D2–R type phototheranostic based on aggregation-induced emission (AIE)-active the second near-infrared window (NIR-II) fluorophore is designed and constructed. The prepared theranostic agent, A1 nanoparticles (NPs), simultaneously shows high absolute quantum yield (1.23%), excellent photothermal conversion efficiency (55.3%), high molar absorption coefficient and moderate singlet oxygen generation performance. In vivo experiments indicate that NIR-II fluorescence imaging of A1 NPs precisely detect microscopic residual tumor (2 mm in diameter) in the tumor bed and metastatic lymph nodes. More notably, a novel integrated strategy that achieves complete tumor eradication (no local recurrence and metastasis after surgery) is proposed. In summary, A1 NPs possess superior imaging and treatment performance, and can detect and eliminate residual tumor lesions intraoperatively. This work provides a promising technique for future clinical applications achieving improved surgical outcomes.Graphic

Hyperspectral Imaging for Tissue Classification after Advanced Stage Ovarian Cancer Surgery-A Pilot Study.

Simple SummarySurvival of ovarian cancer patients largely relies on the surgical removal of all cancer cells. To achieve this, good vision is crucial. In this study, we evaluate the ability of hyperspectral imaging to detect ovarian cancer. Images of surgically removed tissue samples of 11 patients were taken and compared to histopathology in order to train machine learning software. For training purposes, only healthy tissues and tissues with high tumor cell content (>50%) were included. In total, 26 tissue samples and 26,446 data points of 10 patients were included. Tissue classification as either tumorous or healthy was evaluated by leave-one-out cross-validation. This resulted in a power of 0.83, a sensitivity of 0.81, a specificity of 0.70 and a Matthew’s correlation coefficient of 0.41. To conclude, this study shows that hyperspectral imaging can be used to recognize ovarian cancer. In the future, the technique may enable real-time image guidance during surgery.The most important prognostic factor for the survival of advanced-stage epithelial ovarian cancer (EOC) is the completeness of cytoreductive surgery (CRS). Therefore, an intraoperative technique to detect microscopic tumors would be of great value. The aim of this pilot study is to assess the feasibility of near-infrared hyperspectral imaging (HSI) for EOC detection in ex vivo tissue samples. Images were collected during CRS in 11 patients in the wavelength range of 665–975 nm, and processed by calibration, normalization, and noise filtering. A linear support vector machine (SVM) was employed to classify healthy and tumorous tissue (defined as >50% tumor cells). Classifier performance was evaluated using leave-one-out cross-validation. Images of 26 tissue samples from 10 patients were included, containing 26,446 data points that were matched to histopathology. Tumorous tissue could be classified with an area under the curve of 0.83, a sensitivity of 0.81, a specificity of 0.70, and Matthew’s correlation coefficient of 0.41. This study paves the way to in vivo and intraoperative use of HSI during CRS. Hyperspectral imaging can scan a whole tissue surface in a fast and non-contact way. Our pilot study demonstrates that HSI and SVM learning can be used to discriminate EOC from surrounding tissue.

Evaluation of Microscopic Tumour Extension in Localized Stage Non-Small-Cell Lung Cancer for Stereotactic Radiotherapy Planning.

Simple SummaryStereotactic radiotherapy for localised stage non-small-cell lung carcinoma is an alternative indication for patients who are inoperable or refuse surgery. A study showed that the microscopic tumour extension of non-small-cell lung carcinoma varied according to the histological type, which allowed us to deduce adapted margins for the clinical target volume. The objectives of our retrospective study are. The objective of our study is to measure the microscopic tumour extension of T1N0 or T2aN0 primary lung tumors who underwent surgery. The margin required to cover the microscopic tumour extension with a 95% probability is 4.4 mm and 2.9 mm for squamous cell carcinoma and adenocarcinoma, respectively. Multivariate analysis showed a statistically significant relationship between the maximum microextension distance and size with the shrinkage coefficient.Background: Stereotactic radiotherapy for localised stage non-small-cell lung carcinoma (NSCLC) is an alternative indication for patients who are inoperable or refuse surgery. A study showed that the microscopic tumour extension (ME) of NSCLC varied according to the histological type, which allowed us to deduce adapted margins for the clinical target volume (CTV). However, to date, no study has been able to define the most relevant margins for patients with stage 1 tumours. Methods: We performed a retrospective analysis including patients with adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of localised stage T1N0 or T2aN0 who underwent surgery. The ME was measured from this boundary. The profile of the type of tumour spread was also evaluated. Results: The margin required to cover the ME of a localised NSCLC with a 95% probability is 4.4 mm and 2.9 mm for SCC and ADC, respectively. A significant difference in the maximum distance of the ME between the tumour-infiltrating lymphocytes (TILs), 0–10% and 50–90% (p < 0.05), was noted for SCC. There was a significant difference in the maximum ME distance based on whether the patient had chronic obstructive pulmonary disease (COPD) (p = 0.011) for ADC. Multivariate analysis showed a statistically significant relationship between the maximum microextension distance and size with the shrinkage coefficient. Conclusion: This study definitively demonstrated that the ME depends on the pathology subtype of NSCLC. According to International Commission on Radiation Units and Measurements (ICRU) reports, 50, 62 and 83 CTV margins, proposed by these results, should be added to the GTV (Gross tumour volume). When stereotactic body radiation therapy is used, this approach should be considered in conjunction with the dataset and other margins to be applied.

Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).

TPS233 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N = 1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the Guardant Reveal assay, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Enrollment continues across North America to the 540-patient phase II endpoint. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.

NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US).

TPS212 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in CC patients (pts) and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using Natera’s Signatera assay, those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP + Ox vs more intensive AC with addition of irinotecan (I) for 6 mos. The primary objectives for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs delayed AC arms. The primary objective for Cohort B is DFS in the FP + Ox vs FP + Ox + I arms for both phase II and phase III portions of the trial. Secondary objectives include prevalence of detectable ctDNA post-operatively, time-to event outcomes (overall survival &amp; time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/ normal blood samples will be collected for exploratory correlative research. Study will activate in early 2022 across the NCTN. NCT#: Pending. Support: U10-CA-180868, -180822; UG1CA-189867; Natera.

Multifocal Diffuse Sclerosing Papillary Thyroid Carcinoma: A Rare Variant with Diagnostic Challenges

Diffuse sclerosing papillary thyroid carcinoma (DS PTC) is a relatively rare variant of papillary thyroid carcinoma. It is characterized by distinct histological features like scattered microscopic tumor islands, diffuse sclerosis, lymphocytic infiltration, numerous psammoma bodies, radiological features like snowstorm appearance and biologically aggressive behavior in the form of invasion and metastasis. A preoperative diagnosis is often challenging in the absence of nodules and scanty fine needle aspiration cytology sample. We describe a case of multifocal diffuse sclerosing variant of papillary thyroid carcinoma in a 29 year old young male who presented with a swelling in the right side of neck of 2 month duration in the absence of a visible thyroid swelling. Neck swelling was non tender, well defined, firm, not moving with deglutition. Laboratory studies showed normal thyroid function, neck ultrasound revealed heteroechoic right lobe with multiple punctate echogenic foci and enlarged right sided cervical nodes with echogenic foci, fine needle aspiration cytology of which was consistent with metastasis from papillary adenocarcinoma. Based on the above investigations, a total thyroidectomy with central compartment lymph node dissection and modified radical neck dissection of right side was performed. Histological analysis revealed Multifocal Diffuse Sclerosing variant of papillary Thyroid Carcinoma. Clinical and histological challenges usually occur when DS PTC present as diffuse thyroid enlargement, dispersed microscopic tumor islands, extensive fibrosis, abundant lymphocytic infiltration mimicking thyroiditis and when the fine needle aspiration cytology sample is non representative.

Tumor growth, angiogenesis, and invasion as clinical hallmarks of glioblastoma: A case report

The clinical hallmarks of tumor growth, angiogenesis, and invasion were identified in a patient with isocitrate dehydrogenase-1 wild-type glioblastoma at initial diagnosis and management issues were examined. The head magnetic resonance imaging (MRI) showed multiple solid and cystic contrast enhancements in the rostral portion of the tumor located within the left motor gyrus and the adjacent brain. Extensive tumor invasion was noted along the left corticospinal tract extending into the cerebral peduncle and pons. After an open craniotomy for tissue biopsy, the patient underwent external beam radiotherapy and concomitant temozolomide, and his motor deficit was stabilized with concurrent bevacizumab infusion while dexamethasone was weaned off. After two cycles of adjuvant temozolomide, the patient experienced worsening motor deficit in the right hand. A repeat gadolinium-enhanced head MRI revealed increased fluid-attenuated inversion recovery hyperintensity in the left cerebral peduncle indicating tumor progression. This case illustrates the extensive invasion from a glioblastoma that cannot be adequately quantified or effectively treated. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin in this patient. This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 onMay 5, 2020.

Neoadjuvant pyrotinib plus trastuzumab and nab-paclitaxel for HER2-positive early or locally advanced breast cancer: an exploratory phase II trial.

The anti-tumor activity and acceptable tolerability of pyrotinib plus chemotherapy have been demonstrated in phase III trials in human epidermal growth factor receptor 2-positive metastatic breast cancer (BC). In this study, we assessed the efficacy and safety of neoadjuvant pyrotinib plus trastuzumab and albumin-bound paclitaxel in women with human epidermal growth factor receptor 2-positive early or locally advanced BC. In this single-arm exploratory phase II trial, patients with untreated human epidermal growth factor receptor 2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily, trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg once a week, and albumin-bound paclitaxel 125 mg/m2 once a week for four 21-day cycles before surgery. The primary endpoint of the study was total pathological complete response (pCR) rate, defined as no microscopic invasive tumor remnants in the breast and axillary lymph nodes. The secondary endpoints were investigator-assessed objective response rate (ORR) and adverse event profiles. Between May 17, 2019 and November 26, 2019, a total of 21 patients were enrolled. The total pCR rate was 57.1% (12/21), whereas 23.8% (5/21) and 19.0% (4/21) of patients had minimal and moderate residual disease (RD), respectively. The ORR reached 100% (21/21) at the end of the neoadjuvant therapy. Grade ≥3 treatment-related adverse events were observed in 42.9% (9/21) of patients, including decreased neutrophil count [7 (33.3%)], diarrhoea [6 (28.6%)], decreased white blood cell count [5 (23.8%)], and vomiting [2 (9.5%)]. Adverse event-related dose reduction and interruption of pyrotinib occurred in 6 (28.6%) and 11 (52.4%) patients, respectively. In women with human epidermal growth factor receptor 2-positive early or locally advanced BC, neoadjuvant pyrotinib plus trastuzumab and albumin-bound paclitaxel effectively promoted total pCR rate with an acceptable safety profile (ClinicalTrials.gov, NCT04152057).

Impact of TNM® 8th edition on thyroid cancer retrospective staging

Introduction: Thyroid carcinoma has a global survival close to 97% in 15 years. The 8th TNM® has recently been proposed, with changes that include an increase in the cut-off age from 45 to 55 years, a change in the role of microscopic extra-thyroidal tumor invasion (which is no longer considered a criterion for the classification of T3 tumors), and the presence of cervical metastases as a criterion for staging. As a result, a large proportion of patients are transferred to earlier stages. Methods: Retrospective descriptive cross-sectional study carried out through analysis of the medical records of patients undergoing thyroidectomy at HC-UFPR from January 2014 to December 2017. Inclusion criteria were patients with a postoperative pathological anatomic diagnosis of well-differentiated thyroid carcinoma (DTC) who underwent primary surgery in the study period. Results: 197 patients underwent thyroidectomy during the period considered, 58 with thyroid neoplasia and 34 with DTC. Eight patients had lymph node metastasis, five (14.70%) as N1a and three (8.83%) as N1b. Of the total sample, six (12.5%) patients presented downstaging from the 7th to the 8th edition of the TNM®. One of the re-staged patients had bone metastasis during follow-up and died during surgery to correct a pathological fracture. Conclusion: In this study sample, the update of the TNM® in its 8th edition resulted in the downstaging of six (12.5%) patients with DTC. A longer follow-up and a larger sample are necessary to correctly assess the impact of this change on patient prognosis.

Oncologic outcomes of microscopic tumor cut-through in locally advanced oral squamous cell carcinoma

Oncologic outcomes of microscopic tumor cut-through in locally advanced oral squamous cell carcinoma

Melanoma trials that defined surgical management: Overview of trials that established NCCN margin guidelines.

Since the observation that clearance of all visible and microscopic tumors from cutaneous melanoma is critical to prevent a recurrence, wide surgical margins have been central to surgical dogma. In the last several decades, more conservative margin widths have been vigorously studied by surgical investigators to lessen wound complications, the need for reconstruction, and healthcare costs. This review summarizes surgeon-led clinical trials that define current guidelines and highlights the challenges to initiate and perform trials today.

Characterization of tumor remnants in intraoperative MRI-assisted microscopic and endoscopic transsphenoidal resection of less invasive pituitary adenomas

IntroductionIntraoperative magnetic resonance imaging (iMRI) improves the intraoperative detection of adenoma remnants in transsphenoidal surgery. iMRI might be redundant in endoscopic pituitary surgery in non-invasive tumors (Knosp 0–2) due to a superior visualization of anatomical structures in the periphery of the sella turcica compared to the microscopic technique. We identified the anatomical location of tumor remnants in iMRI and evaluated risk factors for secondary resection after iMRI and hereby selected patients with pituitary adenomas who may benefit from iMRI-assisted resection.MethodsWe conducted a retrospective monocenter study of patients who underwent iMRI-assisted transsphenoidal surgical resection of pituitary adenomas at our department between 2012 and 2020. A total number of 190 consecutive iMRI-assisted transsphenoidal surgeries of pituitary adenomas graded as Knosp 0–2 were selected for analysis. Exclusion criteria were missing iMRI availability or pathologies other than adenomas. Of these 190 cases, 46.3% (N = 88) were treated with microscopic, 48.4% (N = 92) with endoscopic, and 5.3% (N = 10) with endoscopic-assisted technique. Volumetric measurement of preoperative, intraoperative, and postoperative tumor extension was performed. Demographic data, tumor characteristics, and MRI features were evaluated. Additionally, analysis of adenoma remnants identified by iMRI was performed.ResultsAn additional resection after iMRI was performed in 16.3% (N = 31). iMRI helped to reach gross total resection (GTR) in 83.9% (26/31) of these cases. False-positive resection was found in 1 patient (0.5%). Multivariable logistic analysis identified tumor volume (OR = 1.2, p = 0.007) recurrence (OR = 11.3, p = 0.002) and microscopic technique (OR = 2.8, p = 0.029) as independent risk factors for additional resection. Simultaneously, the endoscopic technique was significantly associated with GTR as evaluated by iMRI (OR = 2.8, p = 0.011) and postoperative MRI (OR = 5.8, p = 0.027). The detailed analysis of adenoma remnants on iMRI revealed the suprasellar location in a diaphragm fold, penetrating tumor above the diaphragm, or undetected invasion of cavernous sinus as well as in case of microscopic resection tumor location outside the line of sight as the main reasons for incomplete resections.ConclusionTumor volume, recurrence, and microscopic technique were identified as independent predictors for additional resection in patients with Knosp 0–2 adenomas. iMRI might increase the extent of resection (EOR) safely even after the endoscopic visualization of the sella with very low risk for false-positive findings. Remnants of tumors hidden within the diaphragmic folds, intrathecally, or behind the infiltrated wall of cavernous sinus not recognized on preoperative MRI were the most common findings in iMRI.

Symptomatic retro-odontoid pseudotumor causing calcium pyrophosphate dihydrate deposition combined with multilevel cervical spondylotic myelopathy.

IntroductionSymptomatic retro-odontoid pseudotumor (ROP) caused by cervical compression and myelopathy is rare. Pathological diagnosis is recommended for differential diagnosis including the following: inflammatory disease, primary bone tumor, metastatic disease and calcium pyrophosphate dihydrate deposition (CPPD) also known as “crowned dens syndrome”. The authors report a rare case of ROP caused by CPPD deposition combined with multilevel cervical spondylotic myelopathy (MCSM) which was treated by tumor resectioning using a transoral approach combined with posterior decompression and fusion.Case presentationA 66-year-old male presented with progressive neck pain and spastic gait with no history of trauma. Radiographic imaging revealed degenerative change involving the atlanto-axial and atlanto-occipital joints with calcified enhancing soft tissue around the odontoid process causing cord compression and cervical instability at the C1-C2 level combined with MCSM and spinal cord compression at C3 to C7. Microscopic assisted transoral tumor resection combined with posterior decompression and fusion was performed at the occiput to T2. The pathology report describes a rhomboid-shaped crystal caused by calcium pyrophosphate dihydrate deposition (CPPD) disease. At the 6-month follow-up following the operation, the patient's neck pain and spastic gait were improved compared to the preoperative examination.DiscussionCervical compression and myelopathy from ROP causing CPPD combined with MCSM is rare. Pathology diagnosis and surgical management are highly recommended.ConclusionIn this case, a combined surgical approach: tumor resection using a transoral approach and a posterior approach for decompression and fusion at occiput to T2 was an effective option for this condition.

Clinicopathologic analysis of microscopic tumor extension in glioma for external beam radiotherapy planning

BackgroundThere is no consensus regarding the clinical target volume (CTV) margins in radiotherapy for glioma. In this study, we aimed to perform a complete macropathologic analysis examining microscopic tumor extension (ME) to more accurately define the CTV in glioma.MethodsThirty-eight supra-total resection specimens of glioma patients were examined on histologic sections. The ME distance, defined as the maximum linear distance from the tumor border to the invasive tumor cells, was measured at each section. We defined the CTV based on the relationships between ME distance and clinicopathologic features.ResultsBetween February 2016 and July 2020, a total of 814 slides were examined, corresponding to 162 slides for low-grade glioma (LGG) and 652 slides for high-grade glioma (HGG). The ME value was 0.69 ± 0.43 cm for LGG and 1.29 ± 0.54 cm for HGG (P < 0.001). After multivariate analysis, tumor grade, O6-methylguanine-DNA-methyltransferase promoter methylated status (MGMTm), isocitrate dehydrogenase wild-type status (IDHwt), and 1p/19q non-co-deleted status (non-codel) were positively correlated with ME distance (all P < 0.05). We defined the CTV of glioma based on tumor grade. To take into account approximately 95% of the ME, a margin of 1.00 cm, 1.50 cm, and 2.00 cm were chosen for grade II, grade III, and grade IV glioma, respectively. Paired analysis of molecularly defined patients confirmed that tumors that had all three molecular alterations (i.e., MGMTm/IDHwt/non-codel) were the most aggressive subgroups (all P < 0.05). For these patients, the margin could be up to 1.50 cm, 2.00 cm, and 2.50 cm for grade II, grade III, and grade IV glioma, respectively, to cover the subclinical lesions in 95% of cases.ConclusionsThe ME was different between the grades of gliomas. It may be reasonable to recommend 1.00 cm, 1.50 cm, and 2.00 cm CTV margins for grade II, grade III, and grade IV glioma, respectively. Considering the highly aggressive nature of MGMTm/IDHwt/non-codel tumors, for these patients, the margin could be further expanded by 0.5 cm. These recommendations would encompass microscopic disease extension in 95% of cases.Trial registrationThe trial was registered with Chinese Clinical Trial Registry (ChiCTR2100049376).

TMOD-11. A PREDICTIVE MICROFLUIDIC MODEL OF VASCULARIZED GLIOMA TUMORS TO ASSESS TRAFFICKING OF THERAPEUTICS ACROSS THE BLOOD-BRAIN BARRIER

Abstract Although important distinctions exist between subtypes of HGGs, all patients fare poorly with a 5-year survival of &amp;lt; 5%. The infiltrative growth of HGGs imposes significant challenges to treatment, with the presence of residual microscopic tumors post-surgery and hampered chemotherapeutic penetration due to the blood-brain barrier (BBB), a highly selective endothelium regulating transport between blood and brain. Moreover, current preclinical models are costly, low throughput, and often fail to predict drug performance in the clinic. There is thus an increasing need for in vitro models of HGG tumors, surrounded by a realistic BBB vasculature, to recapitulate therapeutic trafficking. To this end, we engineered a high-throughput microfluidic model composed entirely of human cells where HGG spheroids are embedded in a BBB microvascular network of endothelial cells, pericytes, and astrocytes. Tumors co-opt the vasculature as observed in patients and BBB permeability measurements with perfused dextran demonstrate unaltered paracellular transport near and far from the tumors. Lipoprotein receptor protein 1 (LRP1) expression, however, is increased near HGG spheroids. These results were leveraged to synthesize layer-by-layer nanoparticles with angiopep-2 ligands exhibiting high affinity to LRP1 for targeted delivery. Angiopep-2 nanoparticles displayed the largest permeability across the BBB near tumors compared to bare nanoparticles. Knock-down of LRP1 in the BBB-HGG model decreased angiopep-2 nanoparticle permeability confirming LRP1-mediated transport. We next assessed the therapeutic implications of our findings by encapsulating cisplatin in the particles. Administration of cisplatin-loaded angiopep-2 nanoparticles resulted in significant tumor shrinkage with targeted apoptosis in the tumor area compared to bare cisplatin nanoparticles or free cisplatin which damaged the surrounding healthy BBB vessels. Validations in orthotopic tumor-bearing mice are ongoing. In summary, we propose a novel preclinical model with a functional human BBB vasculature surrounding HGG tumors for high-throughput investigations and validate that this platform predicts the transport of targeted drug-loaded carriers.