Microscopic Extension Research Articles

Determining optimal clinical target volume margins based on microscopic extracapsular extension of metastatic nodes in patients with non-small-cell lung cancer after chemotherapy or chemotherapy combined with immunotherapy

BackgroundNo standard has been established for the clinical target volume (CTV) margins of lymph nodes (LNs) in patients with non-small-cell lung cancer (NSCLC) receiving chemotherapy or chemotherapy combined with immunotherapy followed by radiotherapy. This study aimed to discuss the CTV range of NSCLC after chemotherapy or chemotherapy combined with immunotherapy by observing the microscopic extent of tumor spread beyond the LN capsule.MethodsWe retrospectively analyzed the data of 240 patients with stage II and III NSCLC who underwent surgery without neoadjuvant therapy, with neoadjuvant chemotherapy (NAC), or with NAC combined with immunotherapy (NACI). We measured the maximal distance of extracapsular extension (ECE) using a digital microscope, analyzed the correlation between clinicopathological features and ECE distance, and determined the CTV margins of metastatic LN under different treatment methods.ResultsThe ECE distance differed significantly among the three groups (p < 0.001). We determined appropriate margin widths based on a 5% error risk as 3.00, 2.30, and 1.40 mm for direct surgery, NAC, and NACI, respectively. Multivariate analysis revealed that the ECE of metastatic LN correlated with the treatment methods and LN size.ConclusionThe existing CTV delineation standards may increase the radiation toxicity of patients. We believe that different CTV margins should be used for LN in patients with NSCLC receiving different treatments. To ensure 95% coverage of ECE, the gross tumor volume of untreated, chemotherapy-treated, and chemotherapy combined with immunotherapy-treated patients should be expanded by 3.00, 2.30, and 1.40 mm, respectively, to obtain the CTV.

Are Clinically Node-Negative Patients with a Positive Preoperative Axillary Lymph Node Biopsy Appropriate Candidates for Sentinel Lymph Node Biopsy?

Whether cN0 patients with image-detected nodal metastases are appropriate for sentinel lymph node biopsy (SLNB) or should proceed directly to axillary lymph node dissection (ALND) or neoadjuvant chemotherapy (NAC) is controversial. We sought to determine how often ALND is needed with upfront surgery and to identify factors associated with ≥ 3 positive SLNs after a positive preoperative lymph node (LN) biopsy. Patients with cT1-2N0 breast cancer and a positive LN biopsy treated from 2014 to 2022 were identified from a prospective database. Patients who received NAC were excluded. Clinicopathologic characteristics were compared between women with 1-2 positive SLNs and ≥ 3 positive SLNs. Of 90 eligible patients, 66 (73%) had 1-2 positive SLNs and 24 (27%) had ≥ 3 positive SLNs. The median patient age was 62 years, median tumor size was 2.2 cm, and 16 women (18%) received a mastectomy. There was no difference in body mass index, tumor size, histology, grade, multifocality, presence of lymphovascular invasion, and receptor status between groups. On multivariable analysis, having ≥ 3 positive SLNs was associated with > 1 abnormal LN on preoperative imaging (odds ratio [OR] 4.36, 95% confidence interval [CI] 1.47-14.0; p = 0.01), microscopic extracapsular extension in the SLNs (OR 3.83, 95% CI 1.25-13.7; p = 0.025), and a higher median number of SLNs removed (OR 1.42, 95% CI 1.10-1.88; p = 0.01). More than 70% of women with cT1-2 breast cancer with image-detected nodal metastases had < 3 positive SLNs and did not require ALND. To avoid multiple trips to the operating room, frozen section can be considered in women with multiple abnormal LNs on imaging.

Retinoblastoma with and without Extraocular Tumor Extension: A Global Comparative Study of 3435 Patients

PurposeTo study the treatment, and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). DesignMulticenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naïve patients. Cases with microscopic orbital extension detected post-enucleation were excluded from the study. ParticipantsA total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE Intervention(s)Chemotherapy, enucleation, exenteration, radiotherapy. Main outcomes(s)Systemic metastasis and death. ResultsOf the 3435 RB patients included in this study, 309 (9%) were from low-income countries, 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from low-income countries, 197 (6%) lower middle-income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (p=0.0001). The outcomes were statistically significant for RB-EOE compared to RB-w/o-EOE: systemic metastasis (32% vs 4% respectively; p=0.0001) and metastasis-related death (63% vs 6% respectively; p=0.0001). Multimodal treatment was the most common form of treatment (n=177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n=97; 30%). Adjuvant external beam radiotherapy after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan-Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk for death from RB-EOE was greater in patients aged >4 years than <2 years (hazard ratio (HR)=2.912; p<0.001) and for unimodal (surgery or intravenous chemotherapy) and bimodal (surgery and intravenous chemotherapy) treatment than trimodal treatment (surgery, intravenous chemotherapy and external beam radiotherapy) (HR=2.023; p=0.004 and HR 1.819; p=0.027 respectively). ConclusionRetinoblastoma with extraocular tumor extension is associated with a higher risk for metastasis and death. Patients with RB-EOE are likely to benefit from trimodal treatment (intravenous chemotherapy, surgery, and external beam radiotherapy) rather than treatment protocols excluding external beam radiotherapy.

Consider or not consider: the unsolved question on the use of radioactive iodine for differentiated thyroid cancer with low to intermediate risk of recurrence.

Surgery stands as the cornerstone treatment for differentiated thyroid cancer (DTC). After surgery, radioactive iodine (RAI) administration is primarily recommended for high-risk patients and commonly employed to address residual disease or mitigate the risk of recurrence. However, the optimal application of RAI in cases categorized as low to intermediate risk is still uncertain. This study aims to assess the indication of post-surgical RAI treatment specifically in patients diagnosed with DTC falling within the low to intermediate risk category for recurrent disease. retrospective analysis of consecutive patients with DTC falling within the low to intermediate risk category for recurrence and diagnosed between 2009-2015. Patients were categorized into either treated or untreated with RAI. Treatment effect was assessed by the inverse-probability weighted regression adjustment (IPWRA), by balancing the distribution of factors influencing outcome and treatment assignment. after surgery, 328 patients (69.9%) were treated with RAI while 141 (30.1%) were left untreated. Across the entire cohort, 44 individuals (9.4%) displayed biochemical or structural disease after a median time of 17.5 months following diagnosis. Recurrent disease was more prevalent in patients who underwent RAI treatment compared to those untreated (12.5% vs 2.1%, respectively, p < 0.001). Factors independently associated with recurrent disease, identified through multivariate logistic regression analysis, included lymph node metastases (pN1) (OR = 4.07; 95% CI 1.84-8.97), male sex (OR = 2.71; 95% CI 1.31-5.59), tumor size (OR = 1.03; 95% CI 1.00-1.06), and microscopic extrathyroidal extension (OR = 2.36; 95% CI 1.15-4.81). IPWRA analysis revealed that the occurrence of recurrent disease was 9.6% (95% CI = 6.3-12.9) in RAI-treated patients and 15.9% (95% CI = 11.1-20.71) in untreated patients (p = 0.021). As a consequence, if all patients underwent RAI treatment, the estimated risk of recurrence would be reduced by 42% (RR = 0.58; 95% CI = 0.35-0.91, p = 0.018). The greatest benefit was observed in patients with 2 intermediate risk factors. These results suggest that treatment with RAI in low to intermediate DTC can reduce the risk of recurrence in selected patients. However, definitive answers regarding whether to consider RAI therapy for this category of patients can only be attained through prospective clinical trials. Up to date these results recommend a meticulous assessment of tumor characteristics at diagnosis to guide the decision regarding RAI administration.

Central Neck Dissection in Papillary Thyroid Carcinoma: Benefits and Doubts in the Era of Thyroid Lobectomy.

Surgery is still the main line of treatment for papillary thyroid cancer (PTC) with a current trend for de-intensified treatment based on an excellent prognosis. The role of a routine prophylactic central neck dissection (PCND) is still debated as its impact on oncologic outcomes has never been cleared by a randomized clinical trial. In this study, we aimed to report our long-standing experience in PCND and its potential contemporary role in the treatment of PTC. A retrospective institutional review was performed on all patients who underwent operation for PTC including PCND between 1998 and 2021. The primary outcomes were the rate of central lymph node metastases (CLNMs), cancer recurrence and incidence of complications. Survivals were analyzed using the Kaplan-Meier estimator and Cox proportional hazard models. A total of 657 patients were included in this study with a median follow-up of 78 months (48-114 months). Two hundred and one patients presented occult CLNMs (30.6%). The presence of a pathological node represented the unique reason for a completion thyroidectomy and I131 therapy in 12.5% of the population. Age lower than 55 years, microscopic or macroscopic extra-thyroid extension (ETE) and multifocality were independent factors predicting CLNMs. The rate of recurrence in the whole population was 2.7% (18 patients). Five-year and ten-year disease-free survival (DFS) was 96.5% (94.7-97.7) and 93.3% (90.3-95.5), respectively. Two patients relapsed in the central neck compartment (0.3%). Age (>55 years), pathological staging (pT) and extranodal extension (ENE) were independent factors associated with a worse DFS. The rate of temporary and permanent vocal fold palsy was 12.8% and 1.8%, respectively, and did not depend on the type of surgical procedure performed. Hypoparathyroidism was temporary in 42.2% and permanent in 11.9% of the patients. A sub-analysis upon cT1b-T2 patients treated primarily with thyroid lobectomy and ipsilateral PCND demonstrated a 2.6% rate of permanent hypoparathyroidism. PCND allows for a high disease-free survival and a proper selection of patients needing adjuvant treatment, in particular, those treated with a unilateral procedure. On the other hand, bilateral approach is burdened by a not-neglectable rate of permanent hypoparathyroidism.

Occult residual ovarian tissue at the time of minimally invasive risk reducing surgery in women with BRCA mutations

ObjectiveTo describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. MethodsA prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. ResultsTwenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. ConclusionIn women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.

Diagnostic Accuracy of Preoperative Radiologic Findings in Papillary Thyroid Microcarcinoma: Discrepancies with the Postoperative Pathologic Diagnosis and Implications for Clinical Outcomes.

The diagnostic accuracy of preoperative radiologic findings in predicting the tumor characteristics and clinical outcomes of papillary thyroid microcarcinoma (PTMC) was evaluated across all risk groups. In total, 939 PTMC patients, comprising both low-risk and non-low-risk groups, who underwent surgery were enrolled. The preoperative tumor size and lymph node metastasis (LNM) were evaluated by ultrasonography within 6 months before surgery and compared with the postoperative pathologic findings. Discrepancies between the preoperative and postoperative tumor sizes were analyzed, and clinical outcomes were assessed. The agreement rate between radiological and pathological tumor size was approximately 60%. Significant discrepancies were noted, including an increase in tumor size in 24.3% of cases. Notably, in 10.8% of patients, the postoperative tumor size exceeded 1 cm, despite being initially classified as 0.5 to 1.0 cm based on preoperative imaging. A postoperative tumor size >1 cm was associated with aggressive pathologic factors such as multiplicity, microscopic extrathyroidal extension, and LNM, as well as a higher risk of distant metastasis. In 30.1% of patients, LNM was diagnosed after surgery despite not being suspected before the procedure. This group was characterized by smaller metastatic foci and lower risks of distant metastasis or recurrence than patients with LNM detected both before and after surgery. Among all risk groups of PTMCs, a subset showed an increase in tumor size, reaching 1 cm after surgery. These cases require special consideration due to their association with adverse clinical outcomes, including an elevated risk of distant metastasis.

Correlation of microscopic tumor extension with tumor microenvironment in esophageal cancer patients

ObjectiveIn the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is a challenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE.MethodsFormalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible.ResultsIn tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm.ConclusionOur findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis.Trial registration number and dateBO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886.

Clinicopathological Characteristic of Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma at Dr. Hasan Sadikin Hospital 2016-2021

Background Initial therapy for differentiated thyroid carcinoma (DTC) is thyroidectomy with or without cervical lymph node dissection. Furthermore, radioactive iodine (RAI) is given to patients by considering risk stratification and other patient factors. Although most cases of DTC have a good prognosis after standard therapeutic approaches, the risks of local recurrence and distant metastases can be as high as 20% and 10%. Among these patients, two-thirds showed RAI-refractory. This is concerning because 10-year survival rate is less than 10%. This study aimed to analyze the clinicopathological characteristics of RAI-refractory DTC. Methods This is a case-control study. Data was collected from the Department of Nuclear Medicine and Molecular Theranostics and Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin Hospital, Bandung period 1 January 2016 - 31 December 2021. Results Clinicopathological factors associated with RAI-refractory DTC are age, sex, aggressive histologic subtype, LVI (lymphovascular invasion), m-ETE (microscopic extrathyroid extension), TNM (tumor, nodal, metastasis) stage, and ENE (extranodal extension), with p-value &lt;0.05. Meanwhile, there was no significant difference in the histologic type between RAI-refractory and non-RAI-refractory groups. Conclusion In the pathology report, it is necessary to include prognostically relevant tumor histopathological characteristics. In addition to histologic type, histologic subtype, and tumor size, other features such as presence and extent of capsular invasion, LVI, microscopic and macroscopic ETE, ENE, and number and size of metastatic lymph nodes, have been shown to provide additional prognostic information and are required in standard pathology reports for DTC.

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.

Partial Thyroidectomy With Incidental Metastatic Lymph Nodes

The need for completion thyroidectomy in patients with incidental metastatic lymph nodes after partial thyroidectomy is unclear. To investigate the outcomes of patients with incidental metastatic lymph nodes following partial thyroidectomy. A retrospective review of a prospectively maintained thyroid cancer database from 1985 to 2015 was carried out at a head and neck surgery practice at a tertiary referral cancer center. A total of 74 patients who underwent thyroid lobectomy or thyroid isthmusectomy between 1985 and 2015 and were found to have incidental metastatic lymph nodes on final pathologic analysis and were selected to be observed without immediate completion thyroidectomy were included. A separate group of additional 11 patients who underwent immediate completion thyroidectomy was also identified and reviewed. Analysis took place from February to May 2022. Recurrence-free survival outcomes of patients found to have incidental metastatic lymph nodes on final pathologic analysis following partial thyroidectomy with no immediate completion thyroidectomy. A total of 74 patients were observed, with a median (IQR) age of 39 (28-49) years; 44 (59%) were women. Sixty-four patients underwent thyroid lobectomy and 10 patients had isthmusectomy. Classic papillary thyroid carcinoma was the most common histologic type (34 [46%]). Vascular invasion and microscopic extrathyroidal extension were present in 11 patients (16%) and 22 patients (30%), respectively. Positive margins were identified in 5 patients (7.8%). Size of metastatic lymph nodes ranged between 0.07 cm and 1.2 cm. No extranodal extension was reported. A total of 52 patients (70%) were classified as intermediate risk for recurrence based on the American Thyroid Association risk stratification system. The median (IQR) follow up was 48.15 (15.4-86.1) months, during which only 1 patient had a regional recurrence. Another patient underwent delayed completion thyroidectomy for a contralateral lobe malignant abnormality. Recurrence-free survival, disease-specific survival, and overall survival were 97.4%, 100%, and 96.2%, respectively. A separate group of 11 patients who underwent immediate completion thyroidectomy were reviewed. These patients were more likely to have tall-cell papillary thyroid carcinoma (6 [55%] vs 13 [18%]), multifocality (9 [82%] vs 28 [41%]), microscopic extrathyroidal extension (8 [73%] vs 22 [30%]), and positive margins (3 [30%] vs 5 [7.8%]) compared with patients who were under observation only. Completion thyroidectomy may not be necessary in appropriately selected patients who are found to have incidental metastatic lymph nodes (N1a) after partial thyroidectomy for localized well-differentiated thyroid cancer.

ATA risk stratification in papillary thyroid microcarcinoma has low positive predictive value when identifying recurrence

BackgroundRising incidence of papillary thyroid microcarcinomas (PTMC) has raised concerns for overdiagnosis. Utility of the American Thyroid Association Risk Stratification System (ATA-RSS) 2015 in predicting risk of disease recurrence in patients with PTMC was assessed. MethodsElectronic health records of patients who underwent total thyroidectomy were queried. ATA-RSS 2015 risk stratification was performed on those with PTMC, and validity for predicting disease recurrence was calculated. ResultsWith 10-year median follow up, recurrence was higher in PTMC patients with high/intermediate vs low ATA risk (33 % vs 4 %, p = 0.002). Sensitivity of ATA-RSS for detecting recurrence was 60 %, specificity 90 %, PPV 33.3 %, NPV 96.6 %, and accuracy 88 %. When microscopic extrathyroidal extension (ETE) was excluded as an intermediate risk criterion, PPV improved to 50 % and accuracy improved to 92.5 % ConclusionsATA-RSS 2015 predicts recurrence in PTMC with high NPV but low PPV. Exclusion of microscopic ETE improved PPV, which may help prevent overtreatment.

A multicenter prospective study of lateral neck lymph node mapping in papillary thyroid cancer.

Despite the high incidence of lateral neck lymph node (LN) metastasis in papillary thyroid cancer (PTC), the management of the lateral neck remains controversial. We aimed to map the draining LNs in the lateral neck using carbon nanoparticles and explore its potential in neck evaluation. We conducted a multicenter, prospective study in PTC patients who had non-palpable yet suspicious metastatic lateral LNs on ultrasound and/or computed tomography (CT) but could not be confirmed by fine needle aspiration. Carbon nanoparticle suspension was injected peritumorally into the thyroid and modified lateral neck dissection was subsequently performed. A total of 154 patients were enrolled for analysis. And 5,070 lateral LNs were removed, of which 1,079 (21.3%) were dyed. The median of dyed LNs was 6 per case (range, 1-33). The distribution of dyed LNs in neck compartments was IV > III > IIA > IIB/V, independent of tumor size, location, multifocality or microscopic extra-thyroidal extension (ETE). Compared with undyed LNs, the probabilities of metastasis in dyed LNs were significantly increased in compartment III, IV, V, and II-V (III: 29.3% vs. 15.4%, P<0.001; IV: 26.3% vs. 14.5%, P<0.001; V: 16.7% vs. 3.3%, P=0.005; II-V: 26.3% vs. 10.0%, P<0.001). The relative risks of metastasis in dyed LNs compared with undyed LNs were 1.90, 1.82, 5.04 and 2.62 in compartment III, IV, V, and II-V, respectively. It was the first prospective multicenter study to map the lateral neck LNs with carbon nanoparticles, which could help surgeons visualize the suspicious LNs during surgery. Instead of unguided LN biopsy, this method has a potential role in lateral neck assessment for indeterminate lateral LNs in PTC.

A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called “BRAF-like” atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.

Real-world use of endoscopic and histological indices in ulcerative colitis: Results of a global survey.

Treatment targets of ulcerative colitis (UC) have evolved to include not only endoscopic but also histologic remission. However, the concept of histological activity is still in its early days. We aimed to capture the attitudes toward UC histology and the uptake of standardized reporting of endoscopy and histology of UC in daily practice. We conducted a cross-sectional survey of physicians involved in the care of inflammatory bowel disease worldwide. The survey included 21 questions divided into three sections. The first recorded demographics, specialty, and level of experience of participants; the second covered clinical practices and attitudes toward the use and reporting of endoscopy; and the third covered histology. In total, 359 participants from 60 countries and all levels of experience completed the survey. UC histology was used by nearly all respondents (90.5%) for initial diagnosis, by 72% to monitor disease course, by 62.4% to determine the microscopic extension, by 59.9% to confirm deep remission when considering to stop treatment, and 42.3% to increase/optimize treatment. Nevertheless 77.2% of participants reported that no standard histological index was available in their daily practice. Instead, endoscopy reports included the Mayo Endoscopic score in 90% of cases. The majority of respondents welcomed as useful or very useful an artificial intelligence system to automate scoring of endoscopy (69%) or histology (73%). UC histology reports are less standard than endoscopy reports, although most physicians consider histological activity useful when managing UC and would welcome artificial intelligence systems to automate endoscopic and histological scoring.

Impact of microscopic extrathyroidal extension on differentiated thyroid cancer post-surgical risk of recurrence: a retrospective analysis

PurposeIn the last edition of the American Joint Committee on Cancer (AJCC) staging system, differentiated thyroid cancers (DTC) showing microscopic extrathyroidal extension (mETE) are considered comparable to intrathyroidal cancers for their clinical behavior and prognosis. The aim of the study is to evaluate the impact of this updated assessment of T, when applied to the postoperative recurrence risk stratification, according to the American Thyroid Association Guidelines (ATA-RR).MethodsOne-hundred DTC patients who underwent total thyroidectomy were retrospectively evaluated. The downstaging of mETE was introduced in the definition of T, and the updated classification defined as modified ATA-RR (ATAm-RR). For each patient, post-surgical basal and stimulated thyroglobulin (Tg) levels, neck ultrasound (US) and post-ablative 131-I whole body scan (WBS) reports were considered. The predictive performance (PP) of disease recurrence was calculated both for each single parameter, as well as for all of them.ResultsAccording to ATAm-RR classification, 19/100 patients (19%) were downstaged. ATA-RR proved a significant PP for disease recurrence (DR) (sensitivity 75.0%, specificity 63.0%, p = 0.023). However, ATAm-RR performed slightly better due to an increased specificity (sensitivity 75.0%, specificity 83.7%, p < 0.001). For both classifications, the PP was optimal when all the above-mentioned predictive parameters were considered.ConclusionOur results suggest that the new assessment of T considering mETE resulted in a downgrading of ATA-RR class in a significant number of patients. This provides a better PP for disease recurrence, and the best PP was obtained when considering the whole predictive variables together.

An Integrated Monte Carlo Model for Heterogeneous Glioblastoma Treated with Boron Neutron Capture Therapy.

Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique for GBM. Previously, a Geant4 BNCT modelling framework was developed for a simplified model of GBM. The current work expands on the previous model by applying a more realistic in silico GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions (ME). Each cell within the GBM model was assigned an α/β value associated with different GBM cell lines and a 10B concentration. Dosimetry matrices corresponding to various MEs were calculated and combined to evaluate cell survival fractions (SF) using clinical target volume (CTV) margins of 2.0 & 2.5 cm. SFs for the BNCT simulation were compared with external X-ray radiotherapy (EBRT) SFs. The SFs within the beam region decreased by more than two times compared to EBRT. It was demonstrated that BNCT results in markedly reduced SFs for both CTV margins compared to EBRT. However, the SF reduction as a result of the CTV margin extension using BNCT was significantly lower than using X-ray EBRT for one MEP distribution, while it remained similar for the other two MEP models. Although the efficiency of BNCT in terms of cell kill is superior to EBRT, the extension of the CTV margin by 0.5 cm may not increase the BNCT treatment outcome significantly.

Incidental Node Metastasis as an Independent Factor of Worse Disease-Free Survival in Patients with Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) have high node metastasis rates. Occasionally after thyroidectomy, the pathological report reveals node metastasis unintentionally resected. The present study aimed to evaluate the prognosis of these patients. A retrospective cohort of patients submitted to thyroidectomy with or without central compartment neck dissection (CCND) due to PTC with a minimum follow-up of five years. A total of 698 patients were included: 320 Nx, 264 pN0-incidental, 37 pN1a-incidental, 32 pN0-CCND and 45 pN1a-CCND. Patients with node metastasis were younger, had larger tumors, higher rates of microscopic extra-thyroidal extension, and angiolymphatic invasion and most received radioiodine therapy. Treatment failure was higher in patients pN1a-incidental and pN1a-CCND (32% and 16%, respectively; p < 0.001-Chi-square test). Disease-free survival (DFS) was lower in patients pN1a-incidental compared to patients Nx and pN0-incidental (p < 0.001 vs. Nx and pN0-incidental and p = 0.005 vs. pN0-CCND) but similar when compared to patients pN1a-CCND (p = 0.091)-Log-Rank test. Multivariate analysis demonstrated as independent risk factors: pT4a (HR = 5.524; 95%CI: 1.380-22.113; p = 0.016), pN1a-incidental (HR = 3.691; 95%CI: 1.556-8.755; p = 0.003), microscopic extra-thyroidal extension (HR = 2.560; 95%CI: 1.303-5.030; p = 0.006) and angiolymphatic invasion (HR = 2.240; 95%CI: 1.077-4.510; p = 0.030). Patients that were pN1a-incidental were independently associated with lower DFS.

Thyroid Collision Tumors: The Presence of the Medullary Thyroid Carcinoma Component Negatively Influences the Prognosis.

The retrospective study included 69 cases diagnosed with TCTs (with simultaneous MTC and PTC components), MTC and PTC. All tumors were comparatively assessed for the classical histopathological prognostic features, including a new grading system for MTC. The main component of TCTs had more frequent microscopic extrathyroidal extension (mETE) (p = 0.000), lymphovascular invasion (LVI) (p = 0.000), perineural invasion (PNI) (p = 0.044), and lymph node metastasis (p = 0.042). Additionally, the TCTs' MTC component presented with more frequent LVI (p = 0.010). Comparing TCTs' MTC and PTC components with MTC-only tumors and PTC-only tumors revealed that only the TCTs' MTC components had statistically significant more frequent mETE (p = 0.010) than MTC-only tumors. When applied to the MTC component of TCTs, the pathological parameters of the new grading system of MTC showed no correlations with other microscopic or clinical aspects. Using classical pathological prognostic features, the comparative analysis revealed that the main TCTs' component was more aggressive than the minor one. Contrary to PTCs, in TCTs, the medullary component was more aggressive than the papillary one, but also more aggressive than MTC-only tumors.

Is multifocality a risk factor in low-risk papillary thyroid cancer?

Multifocality in papillary thyroid cancer (PTC) is a common event, ranging from 18% to 87%. Additional multiple foci are frequently very small and generally detected in pathology specimens. The mechanisms of intrathyroidal spread, and its correlation with age, gender, tumour size, and lymph node metastases remain unclear. Moreover, studies assessing the prognostic impact of PTC multifocality have yielded non-univocal results. We aimed to evaluate the following: a) the histopathological and clinical characteristics associated with multifocal PTC; and b) the impact of multifocality on the long-term outcome. We analysed a consecutive series of 2814 PTC patients without evidence of microscopic extrathyroidal extension (T1a, T1b, and T2), all of whom had undergone total thyroidectomy and were followed-up (median 4.7 years) in our thyroid clinic. Females comprised 81.3% and males 18.7% (F/M = 4.4/1), with a median age at diagnosis of 45.0 years. Patients were subdivided into 2 groups: 72.7% unifocal tumour and 27.3% multifocal tumour. Post-surgical radioiodine ablation (RAI) (30-100 mCi of 131-I) was performed in 1425 (50.6%) patients. All patients were periodically followed with thyroglobulin and anti-thyroglobulin antibodies measurements and with neck ultrasonography under L-thyroxine therapy and subjected to additional radioiodine administration or another therapeutic measure if not cured. Patients in the multifocal group were older (median age 46.4 vs. 44.5 years, respectively, p < 0.05) and presented a lower F/M ratio (F/M = 3.7/1 and 4.7/1; p = 0.01). T1a and T1b tumours showed no significant difference in multifocality rate whereas T2 tumours were less frequently multifocal (14.2% vs. 10.9%, p < 0.05). Multifocal tumours were more frequent in N1b (11.3% vs. 7.8%, p < 0.01) and less frequent in Nx (50.5% vs. 56.8%, p < 0.01), with no difference between the N0 and N1a groups. The clinical outcome was similar in the 2 group of patients (88.2 % in the unifocal group vs. 90.2% in the multifocal group). Multifocality is more frequent in older and male patients, in smaller tumours, and in N1b. However, multifocality "per se" was not associated, in our study, with worse clinical outcome in PTC patients.