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

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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/.

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.

Ki67 proliferation index in medullary thyroid carcinoma: a comparative study of multiple counting methods and validation of image analysis and deep learning platforms.

AIMS: The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time-consuming task. METHODS AND RESULTS: We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning-based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near-perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease-specific survival and distant metastasis-free survival. CONCLUSIONS: We herein validate a machine learning-based deep-learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3-7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.

Exploring the varied manifestations of structural violence in the lives of children on the autism spectrum and their families: a qualitative longitudinal study in Kurdistan, Iran.

BACKGROUND: There are many dimensions regarding autism that are closely connected to social structures, policies, and power dynamics, silently impacting the well-being of individuals within the autism spectrum. This research aims to explore these overlooked aspects using a theoretical framework called "structural violence." METHODS: The study was conducted in Kurdistan, Iran, and a qualitative longitudinal approach was chosen. A purposive sampling method was employed to select the participants, with 11 parents taking part. The study data comprised 29 interviews using a topic guide conducted over a span of 2 years. Thematic analysis and a matrix-based approach were utilized for data analysis. To enhance the scientific rigor of this research, four criteria, including Guba and Lincoln's principles, were implemented to ensure methodological accuracy. RESULTS: The research findings highlight four primary forms through which structural violence impacts children on the autism spectrum and their families: access to healthcare, geographic disparities, awareness and stigma, and poverty and financial burden. Additionally, the study identified 11 subthemes related to structural violence in the context of autism and families. CONCLUSIONS: We illustrated how structural forces create barriers to accessing adequate healthcare services, exacerbate discrimination based on ethnicity and geography, perpetuate stigma, and contribute to poverty and the inability to meet basic needs. These factors not only worsen health issues but also deepen existing disparities in healthcare access and outcomes for children on the autism spectrum and families. We emphasize the urgent need for systemic changes to address these issues. It is essential to promote public awareness, provide better access to health and support services, and address economic and political factors that contribute to these inequalities.

Effect of COVID-19 pneumonia infection control protocols on nosocomial infection incidence in trauma patients.

PURPOSE: Nosocomial infection is a major threat to the health care system and patient welfare. After the pandemic, new protocols were established in hospitals and communities to protect against the transmission of COVID-19, which may have changed the incidence of nosocomial transmission. This study was conducted to compare the incidence of nosocomial infection before and after the COVID-19 pandemic. METHODS: This was a retrospective cohort study performed on trauma patients who were admitted, from May 22, 2018 to November 22, 2021, to the largest level-1 trauma center in Shiraz, Iran (Shahid Rajaei Trauma Hospital). All the trauma patients over 15 years old admitted during the study time were included in this study. Individuals who were declared dead upon arrival were excluded. Patients were evaluated in 2 periods: before the pandemic (May 22, 2018 - February 19, 2020) and after the pandemic (February 19, 2020 - November 22, 2021). Patients were assessed based on demographic information (age, gender, length of hospital stay, and patient outcome), the occurrence of hospital infection, and the type of infection. The analysis was done using SPSS version 25. RESULTS: Overall, 60,561 patients were admitted, with a mean age of 40 years. Nosocomial infection was diagnosed in 4.00% (n = 2423) of all admitted patients. The incidence rate of post-COVID-19 hospital-acquired infections decreased by 16.28% (p < 0.001) when compared to before the pandemic; in contrast, surgical site infection (p < 0.001) and urinary tract infection (p = 0.043) were responsible for this change, while hospital-acquired pneumonia (p = 0.568) and bloodstream infection (p = 0.156) were not significantly different. Overall mortality was 1.79%, while 28.52% of all patients with nosocomial infections died. During the pandemic, there was a 25.78% increase (p < 0.001) in the overall incidence rate of mortality, which was also observed among patients with nosocomial infections (17.84%). CONCLUSION: The incidence of nosocomial infection has decreased during the pandemic, possibly due to the use of more personal protective equipment and modified protocols after the outbreak. This also explains the difference in the change in incidence rates of nosocomial infection subtypes.

Switch/sucrose-non-fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)-deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas.

AIMS: Loss of expression of mammalian switch/sucrose-non-fermentable (SWI/SNF) [BRG1/BRM-associated factor (BAF)] complex subunits, including SMARCA4, SMARCA2 and INI1/SMARCB1 (termed SWI/SNF complex deficiency), has been reported in colorectal carcinomas (CRCs) but its frequency and clinical significance are uncertain. METHODS AND RESULTS: We performed immunohistochemistry for SMARCA4, SMARCA2 and SMARCB1 on 4508 consecutive resected CRCs. Loss of SMARCA4 expression was found in 13 cases (0.3%), loss of SMARCA2 expression was found in 59 cases (1.3%), and loss of SMARCB1 expression was found in 21 cases (0.4%). Some CRCs showed loss of expression of more than one subunit, so that 84 CRCs (1.7%) were deficient for at least one component. SWI/SNF complex deficiency was associated with higher grade, a right-sided location, mismatch repair deficiency, and BRAF V600E mutation (P < 0.05); 5.8% of mismatch repair-deficient (MMRd) cases and 5.4% of BRAF V600E-mutant cases were SWI/SNF complex-deficient, as compared with 0.9% and 0.4% of mismatch repair-proficient and BRAF-wild-type cases (P < 0.001). Any loss of SMARCB1 expression and global loss of SMARCA2 expression were associated with statistically significant worse overall survival, whereas SMARCA4-deficient cases showed a trend only towards poor overall survival (P = 0.121). In multivariate analysis, any loss of SMARCA4 expression and global loss of SMARCA2 expression were associated with worse survival [odds ratio (OR) 3.33, P = 0.019; and OR 3.39, P < 0.001]. Of particular note, among the subgroup of cases that were MMRd and BRAF V600E-mutated (otherwise considered to be a good prognostic group), loss of SMARCA4 expression was associated with much worse median survival (10.5 months versus 110.9 months; P = 0.003). CONCLUSIONS: SWI/SNF complex deficiency is rare in CRC but is enriched in MMRd cases. Identifying these cases has morphological associations and prognostic significance, and in the future may have potential therapeutic implications.

The Anatomy of Nerve Transfers Used in Tetraplegic Hand Reconstruction.

PURPOSE: To evaluate the anatomy of nerve transfers used to reconstruct wrist extension, hand opening, and hand closing in tetraplegic patients. METHODS: Nerve transfers were completed on 18 paired cadaveric upper limbs. The overlap of donor and recipient nerves was measured, as well as the distance to the target muscle. Axons were counted in each nerve and branch, with the axon percentage calculated by dividing the donor nerve count by that of the recipient. RESULTS: Transfers with overlap of the donor and recipient nerve were from the radial nerve branch to extensor carpi radialis brevis to anterior interosseous nerve (AIN) and from the branch(es) to supinator to posterior interosseous nerve. The extensor carpi radialis brevis to AIN had the shortest distance to the target, with the branch to brachialis to AIN being the longest. The nerve transfers for wrist extension had the highest axon percentage. Of the transfers for hand closing, the brachialis to AIN had the highest axon percentage, and the branch to brachioradialis to AIN had the lowest. CONCLUSIONS: The anatomical features of nerve transfers used in tetraplegic hand reconstruction are variable. Differences may help explain clinical outcomes. CLINICAL RELEVANCE: This study demonstrates which nerve transfers may be anatomically favorable for restoring hand function in tetraplegic patients.

Molecular Features of Lymph Node Metastasis in T1/2 Colorectal Cancer from Formalin-Fixed Paraffin-Embedded Archival Specimens.

Histological risk factors for lymph node metastasis (LNM) in early-stage colorectal cancers (CRC) have been described, although the predictive utility of these factors varies. Improved LNM risk assessment based on findings in endoscopic colon and rectal excisions is necessary for optimal surgical management of CRC patients with pathologic T1- /T2-staged invasive depth (i.e., tumor not invading beyond the muscularis propria layer); as the current system is overly conservative, and results in many unnecessary radical surgeries. To identify molecular features in early CRC with elevated LNM potential, we carried out proteomic and gene expression profiling to compare T1 lymph node (LN) negative with T1/2 LN positive CRC tumors from formalin-fixed paraffin-embedded (FFPE) specimens. Using a data-independent acquisition mass spectrometry workflow, we detected over 7400 proteins and quantified over 4400 in all 21 specimens. Proteins from tumors with LN metastasis were enriched with effectors of epithelial-mesenchymal transition (EMT) and gene expression profiling confirmed activation of key transcription factors, SNAI1 and ZEB1, as well as a reduction in E-cadherin expression. Toward an implementation pathway, we investigated immunohistochemistry assays targeting four EMT-related proteins. While MS could reliably discern twofold protein abundance changes, we found the semiquantitative nature of IHC scoring limited confirmation of this degree of protein expression difference. This study demonstrated that EMT effectors are associated with locoregional metastasis in T1/T2 CRC and could be used to augment metastatic risk assessment, although further developments are required to enable routine implementation.

DNA damage-inducible transcript 3 immunohistochemistry is highly sensitive for the diagnosis of myxoid liposarcoma but care is required in interpreting the significance of focal expression.

AIMS: Myxoid liposarcoma (MLPS) is characterised by DNA damage-inducible transcript 3 (DDIT3) gene rearrangements, confirmation of which is commonly used diagnostically. Recently, DDIT3 immunohistochemistry (IHC) has been reported to be highly sensitive and, when strict criteria are employed, specific for the diagnosis of MLPS. The aim of this study was to independently investigate DDIT3 IHC as a diagnostic marker for MLPS. METHODS AND RESULTS: DDIT3 IHC was performed on 52 MLPS and on 152 mimics on whole sections, and on 515 non-MLPS sarcomas in tissue microarray format. Only one MLPS (which had undergone acid-based decalcification) was completely negative. With inclusion of this case if any nuclear expression is considered to indicate positivity, the overall sensitivity of DDIT3 is 98% (51 of 52 cases) and the specificity is 94% (633 of 667 non-MLPS cases are negative). If a cut-off of >10% of neoplastic cells is required for positivity, then the sensitivity remains 98% (51/52) and the specificity is 98.5% (657 of 667 non-MLPS cases are negative). If a cut-off of >50% of cells is required for positivity, then the sensitivity is 96% (50 of 52 cases) but the specificity improves to 100%. CONCLUSIONS: Diffuse nuclear DDIT3 expression occurs in the overwhelming majority of MLPSs, and can be used to confirm the diagnosis in most cases without the need for molecular testing. A complete absence of expression argues strongly against MLPS, and almost completely excludes this diagnosis, particularly if there is consideration of technical factors such as decalcification. The significance of focal DDIT3 expression should be interpreted in the morphological and clinical context, although most tumours showing only focal expression are not MLPS.

NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas-a study of 4569 cases.

NTRK gene rearrangements are important to identify as predictors of response to targeted therapy in many malignancies. Only 0.16-0.3% of colorectal carcinomas (CRCs) harbor these fusions making universal screening difficult. We therefore investigated whether pan-Trk immunohistochemistry (IHC), mismatch repair deficiency (MMRd), and BRAFV600E mutation status could be used to triage molecular testing for NTRK gene rearrangements in CRC. CRCs from 4569 unselected patients underwent IHC in TMA format with two different anti-pan-Trk rabbit monoclonal antibodies. All positive cases were confirmed on whole sections and underwent RNA-sequencing. Pan-Trk IHC was positive in 0.2% of CRCs (9/4569). Both antibodies demonstrated similar staining characteristics with diffuse positive staining in all neoplastic cells. Of note 8/9 (89%) IHC positive cases were both MMRd (all showing MLH1/PMS2 loss) and lacked BRAFV600E mutation. That is, IHC was positive in 5.3% (8/152) MLH1/PMS2/BRAFV600E triple negative CRCs, but only 0.02% (1/4417) not showing this phenotype. All nine IHC positive CRCs demonstrated gene rearrangements (LMNA-NTRK1 in 5 CRCs, TPR-NTRK1, STRM-NTRK1, MUC2-NTRK2, and NTRK1 with an unknown partner in one each), suggesting close to 100% specificity for IHC in this sub-population. NTRK fusions were associated with right sided (p = 0.02), larger tumors (p = 0.029) with infiltrative growth (p = 0.021). As a part of universal Lynch syndrome screening many institutions routinely test all CRCs for MMRd, and then proceed to reflex BRAFV600E mutation testing in MLH1/PMS2 negative CRCs. We conclude that performing pan-Trk IHC on this preselected subgroup of MLH1/PMS2/BRAFV600E triple negative CRCs (only 3.3% of all CRC patients) is a resource effective approach to identify the overwhelming majority of CRC patients with NTRK gene fusions.

RAF1 rearrangements are common in pancreatic acinar cell carcinomas.

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.

A single nucleotide polymorphism within HOX Transcript Antisense RNA (HOTAIR) is associated with risk of psoriasis.

Recent studies have shown participation of long non-coding RNAs (lncRNAs) in the pathogenesis of psoriasis. Several mechanisms might be involved in the dysregulation of expression of lncRNAs in patients with psoriasis, among them is the presence of single nucleotide polymorphisms (SNPs) which modulate expression or function of these transcripts. In the present work, we genotyped three SNPs (rs12826786, rs1899663 and rs4759314) of the HOX Transcript Antisense RNA (HOTAIR) in 286 patients with psoriasis and 300 control subjects. The rs12826786 was associated with risk of psoriasis in dominant model (TC + TT vs. CC: OR (95% CI) = 1.59 (0.1.14-2.22), adjusted p-value = .02). In the allelic model, T allele of this SNP significantly increased the risk of psoriasis compared with the C allele (OR (95% CI) = 1.35 (1.06-1.71), adjusted p-value = .04). Other SNPs were not associated with risk of psoriasis in any inheritance model. No significant difference was found in haplotype frequencies between cases and controls. The current work shows association between a genomic variant within HOTAIR and risk of psoriasis. The clinical significance of this finding should be assessed in future studies.

Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology.

Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.

Design and rationale for a randomized, open-label, parallel clinical trial evaluating major adverse cardiovascular events (pharmacological treatment versus diet control) in patients with high-normal blood pressure: the PRINT-TAHA9 trial.

BACKGROUND: The distinction between normal and high blood pressure remains a debated topic, with varying guidelines on when to start medication. Contemporary guidelines advocate for the initiation of antihypertensive therapy in individuals who present with high-normal blood pressure, particularly those exhibiting elevated 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores. Despite these recommendations, there is a notable lack of direct evidence supporting the efficacy of treating high-normal blood pressure to prevent major adverse cardiovascular events (MACE). METHODS: The PRINT-TAHA9 trial, a unicentric, randomized, open-label, controlled, parallel clinical study, seeks to explore the effects of intensive blood pressure control on MACE in participants with high-normal blood pressure. We will enroll 1620 adults aged 18 years and above with a systolic blood pressure range of 130-140 mmHg, diastolic blood pressure under 90 mmHg, and atherosclerotic cardiovascular disease (ASCVD) risk score exceeding 7.5%. The study will be executed in five distinct phases, with each phase enrolling between 300 and 400 participants. Participants will be randomly assigned to either the treatment group receiving antihypertensive medication (amlodipine/valsartan) and a low-salt/low-fat diet or to the control group receiving a similar diet. Follow-up visits are scheduled every 6 months over a 3-year period to monitor blood pressure, evaluate medication adherence, document any adverse events, and adjust the intervention as necessary. Cox proportional hazards regression analysis will be employed to examine the disparities between the two arms. DISCUSSION: Despite guidelines promoting early treatment of elevated blood pressure, the debate continues due to insufficient evidence that such interventions significantly reduce the occurrence of MACE. This trial seeks to address this critical evidence gap. TRIAL REGISTRATION: The PRINT-TAHA9 trial was registered in October 2019 with the Iranian Registry of Clinical Trials (IRCT.ir) under the registration number IRCT20191002044961N1. https://irct.behdasht.gov.ir/trial/43092 .

Anaplastic thyroid cancer: A review of recent evidence and summary of an Australian institutional protocol.

Anaplastic thyroid cancer (ATC), a rare and highly aggressive malignancy, is characterized by an exceptionally poor prognosis, where the majority of patients present with extensive local invasion and/or distant metastases. 20-30% of ATCs harbor the BRAF-V600E mutation. Neoadjuvant BRAF-targeted therapy may have the potential to downstage and facilitate surgical resection for patients with locally advanced and unresectable primary tumors with BRAF mutation and may convey a survival advantage in those with metastatic disease. There is emerging evidence to support the use of other targeted agents, including multikinase inhibitors, as well as the incorporation of immunotherapy into the treatment regimen. Rapid molecular and pathological diagnosis and expert multidisciplinary discussion at specialized treatment centers are critical to expedite investigations and initiate treatment for this complex and rapidly progressive disease.

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study.

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

Evaluation of GATA3 and GCDFP15 Expression in Triple Negative Breast Cancers.

Background & Objective: Breast cancer is one of the most common cancers in the world. There are some different types of breast cancer and triple-negative breast cancer is the type in which no receptors for estrogen, progesterone, and human epidermal growth factor receptor-2 are expressed. Identifying factors that can facilitate the diagnosis of triple-negative breast cancer is important. In this study, we decided to investigate the expression of GATA3 and GCDFP15 genes in triple-negative breast cancers. Methods: This is a retrospective descriptive-analytical study that was performed on 50 specimens of samples of triple-negative breast cancer. Data including age and sex, tumor grade, tumor size, types of invasion, GATA-3, and GCDFP-15 were assessed. Results: The mean age of the patients was 48.3±14.17 years. Of the total specimens, 46% were positive for GCDFP15 and 90% were positive for GATA-3. The intensity of GATA3 was evaluated and it was observed that 33(73.3%) of the cells were strongly stained and 12(26.7%) were weakly stained. There were no relationships between GATA-3 and GCDFP-15 with tumor characteristics. Conclusion: GATA-3 and GCDFP-15 may serve as diagnostic markers for triple-negative breast cancers and GATA-3 seems to be more reliable.

A novel prognostic nomogram for predicting survival in diffuse pleural mesothelioma.

Recent advances in the management of diffuse pleural mesothelioma (DPM) have increased interest in prognostication and risk stratification on the basis that maximum benefit of combination immunotherapy appears to be seen in patients who otherwise would have the worst prognosis. Various grading schemes have been proposed, including the recently published Mesothelioma Weighted Grading Scheme (MWGS). However, predictive modelling using deep learning algorithms is increasingly regarded as the gold standard in prognostication. We therefore sought to develop and validate a prognostic nomogram for DPM. Data from 369 consecutive patients with DPM were used as independent training and validation cohorts to develop a prognostic tool that included the following variables: age, sex, histological type, nuclear atypia, mitotic count, necrosis, and BAP1 immunohistochemistry. Patients were stratified into four risk groups to assess model discrimination and calibration. To assess discrimination, the area-under-the-curve (AUC) of a receiver-operator-curve (ROC), concordance-index (C-index), and dissimilarity index (D-index) were calculated. Based on the 5-year ROC analysis, the AUC for our model was 0.75. Our model had a C-index of 0.67 (95% CI 0.53-0.79) and a D-index of 2.40 (95% CI 1.69-3.43). Our prognostic nomogram for DPM is the first of its kind, incorporates well established prognostic markers, and demonstrates excellent predictive capability. As these factors are routinely assessed in most pathology laboratories, it is hoped that this model will help inform prognostication and difficult management decisions, such as patient selection for novel therapies. This nomogram is now freely available online at: https://nomograms.shinyapps.io/Meso_Cox_ML/.