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/.

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.

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.

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.

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.

Gene expression profiling of pancreatic ductal adenocarcinomas in response to neoadjuvant chemotherapy.

AIM: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. METHODS: Archived formalin-fixed paraffin-embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi- and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%-30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy-responders. RESULTS: Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good- and poor-chemotherapy responders. There were 396 genes that were significantly (p < 0.05) downregulated (200 genes) or upregulated (196 genes) in tumors from good responders compared to poor responders. Further supervised multivariate analysis of significant genes by partial least square (PLS) demonstrated a highly distinct gene expression profile between good- and poor responders. A gene biomarker of panel (IL18, SPA17, CD58, PTTG1, MTBP, ABL1, SFRP1, CHRDL1, IGF1, and CFD) was selected based on PLS model, and univariate regression analysis of individual genes was performed. The identified biomarker panel demonstrated a very high ability to diagnose good-responding PDAC patients (AUROC: 0.977, sensitivity: 82.4%; specificity: 87.0%). CONCLUSION: A distinct tumor biological profile between PDAC patients who either respond or not respond to chemotherapy was identified.

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.

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/.

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.

Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

Small Bowel Obstruction As a Consequence of Peritoneal Tuberculosis.

Peritoneal tuberculosis (PTB) is a rare subset of extrapulmonary tuberculosis which account for only 0.5-1% of all cases. PTB diagnosis can be challenging due to nonspecific clinical manifestations. We present a known case of pulmonary tuberculosis that admitted to the surgery ward due to the major complaint of abdominal pain since ten days before admission. In imaging studies, positive findings favoring mechanical obstruction were detected. There were also several hypodense lesions in the liver suggestive of visceral tuberculosis. An adhesion was noted during exploratory laparotomy prior to the ileocecal valve responsible for intestinal obstruction, which was released. Pathology reports of excised tissues were consonant with the PTB diagnosis. PTB diagnosis can be challenging because of its presentation. This can delay the treatment of patients and thus increase morbidity and mortality. As a result, physicians should always be aware of the PTB diagnosis in patients with nonspecific abdominal involvement.

What are the problems with the current staging of discontinuous tumour nodules (DTNs) in colorectal carcinoma? Is there a better way?

Discontinuous extramural tumour nodules (DTNs) are deposits of metastatic carcinoma in soft tissue not associated with lymph nodes. Although they are established as an adverse prognostic factor in colorectal carcinoma (CRC), under the AJCC eighth edition staging system their presence does not upstage patients who also have lymph node metastases. Counterintuitively, in some situations the presence of lymph node metastases may in effect downstage a patient with DTNs from pN1c to pN1a/b. Therefore, we sought to critically assess the significance of DTNs in a large unselected single institution cohort of patients undergoing surgical resection for CRC. Of 3822 CRC patients undergoing surgical resection from 2005 to 2021, DTNs were present in 686 (18.0%). In univariate (HR=2.687, 95CI 2.355-3.065; p<0.001) and multivariate analysis (HR=1.805, 95CI 1.529-2.132; p<0.001) in a model including age, gender, stage, grade, location, lymph node ratio and apical lymph node status, DTNs were associated with worse overall survival (OS). N1c patients (DTN present but no nodal metastasis) demonstrated worse OS compared to the current pN1a group (p<0.001) and were least different to the current pN2a group (p=0.571). Within the current N1a (p=0.013), N1b (p=0.004) and N2a (p=0.002) groups, patients who also had DTNs had worse OS. DTNs were associated with worse OS for all stage III CRCs combined (p<0.001), and for stage IIIB (p<0.001) and stage IIIC (p=0.007) individually. We conclude that DTNs are an independent adverse prognostic factor that should be considered in the staging system in a way that is additional to (rather than integrated with) the number of involved lymph nodes. We then assess a simple suggestion for how this could be achieved by increasing the overall stage by one group in the presence of DTNs (requiring the creation of a new stage IIID).

Accuracy of Paris 2016 System for Non-invasive Diagnosis Bladder Malignancy.

Background & Objective: The Paris System for Reporting Urinary Cytology (TPS) is a new method for evaluating urinary cytology designed to reduce unreproducible reports. The aim of this study was to reclassify and compare urinary cytology reports with TPS criteria to determine the frequency of unreproducible reports compared to the previous system. Methods: In this study, the laboratory electronic registration system analyzed patients' urine samples taken by voided or washing and brushing methods. The cytological evaluation was performed considering the previous system and TPS by a pathologist. The results of the two systems were compared, and the sensitivity and specificity of TPS were calculated. Results: Urine samples were taken from 876 patients. The mean age of patients was 63.36 ± 12.62. Comparing the routine classification system and TPS, it was observed that the number of atypical reports in the TPS system decreased by 12%, and all of these cases were downgraded to the negative group in the new classification. The sensitivity and specificity of TPS were 29.4% and 95.1%, respectively, if suspected malignancy and positive reports for malignancy were considered. Finally, if positive reports for malignancy were selected, sensitivity and specificity changed to 11.8% and 100%, respectively. Conclusion: Although the TPS system has low sensitivity for the diagnosis of urothelial malignancies, due to its high specificity, it is possible to consider and use this classification for screening patients.

Anxiety and Stress Seem Temporary during the Pneumonia COVID-19 Pandemic: A Survey on the Mental Health Status of Healthcare Workers.

Objective: To evaluate the presence/severity of depression, anxiety, and stress among health care workers (HCWs) who work on the specially allocated COVID-19 ward (Group A) and HCWs on the other wards (Group B). Methods: This questionnaire-based study was conducted from January 25 to February 28, 2021. The mental status was assessed using the Persian version of the 42-item Depression, Anxiety, and Stress score (DASS-42). Gathered data was analyzed using SPSS version 25. The independent T-test and Chi-square tests were used to compare quantitative and qualitative variables. Results: Two-hundred and twenty two questionnaires were eligible for analysis. Group A consisted of 33 HCWs, and 189 (85.1%) individuals were working on the other wards. No statistically significant differences were seen regarding the Socio-demographic features except for the marital status (p=0.005). The depressions' mean score was comparable between group A and B (p=0.102). The mean scores of anxiety and stress were significantly lower in group A than group B (p=0.006), although the frequency of DASS-42 parameters did not differ between these two groups (p>0.05). Conclusion: Contrary to our assumptions, this study showed that the DASS-42 parameters were not higher in HCWs working on the COVID-19 wards. This might be justified by developing coping mechanisms, being on the honeymoon phase of the disaster, compassion satisfaction, promising vaccine news, and working on the less impacted hospital.

Necrosis is an independent predictor of disease-free and overall survival in pancreatic well-differentiated neuroendocrine tumours (NETs): a proposal to include it in grading systems.

Pancreatic neuroendocrine tumours (NETs) are currently graded using the World Health Organization (WHO) 2019 system, which is based solely on mitotic count and Ki-67 proliferative index. Although necrosis is a well recognised adverse prognostic feature that is included in the grading systems of NETs of certain types such as pulmonary carcinoid and medullary thyroid carcinoma, there is currently insufficient evidence to support its inclusion in the grading of pancreatic NETs. Therefore, we sought to investigate the prognostic significance of tumour necrosis in our cohort of resected pancreatic NETs, with a view to providing evidence to support its incorporation into the WHO grading scheme. Under our proposal, pancreatic NETs without necrosis would continue to be graded based solely on mitotic count and Ki-67 index using the established WHO cut-offs, while NETs with tumour necrosis would be classified as grade 3, irrespective of proliferative activity. Using this system in our cohort of 110 resected pancreatic NETs, overall survival (OS) was 250, 198, and 151 months (p=0.039) and disease-free survival (DFS) was 180 months, 117 months, and 38 months (p<0.0001) for grades 1, 2, and 3, respectively. In contrast, there was no significant difference in OS (p=0.231) or DFS (p=0.058) between low grade (grade 1) and intermediate-high grade (grade 2/3) tumours using the current WHO system which does not consider necrosis. Interobserver concordance for assessment of necrosis was excellent. In conclusion, necrosis is an independent predictor of OS and DFS for pancreatic NETs, and our findings strongly support its addition to the grading scheme for this tumour.

Successful Treatment of Central Nervous System Histiocytic Sarcoma With Craniectomy and Adjuvant Radiotherapy.

Histiocytic sarcoma (HS) is a rare, aggressive non-Langerhans histiocytic cell neoplasm of hematopoietic origin. Histiocytic sarcoma is prone to early systemic metastasis, rendering early diagnosis and treatment critical determinants for patient outcome. Primary HS originating from the central nervous system (CNS) is exceptionally rare and portends a poor prognosis. This grim clinical course is further complicated by the challenging diagnosis and the lack of standard treatment guidelines for the disease. This is due to the exceptionally rare nature of primary CNS histiocytic sarcoma and the limited data available on the successful management of the disease, prompting the therapeutic approach to be guided by retrospective data from case reports or single-institutional studies with a limited number of patients. Here, we report a case of a young Middle Eastern male who was diagnosed with primary CNS histiocytic sarcoma, successfully treated with frontotemporal craniotomy and adjuvant radiation therapy. We also elucidate the role of the CD163 biomarker in diagnosing HS and using surgery and adjuvant radiotherapy (RT) as a successful treatment approach for primary CNS histiocytic sarcoma.

Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens.

Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are rare and greatly under-represented in large-scale genomic mapping projects. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4 to 77.2/Mb sequenced. No stage-related mutational differences were observed, consistent with reanalysis of The Cancer Genome Atlas (TCGA) Stage I and IIIA datasets. We next examined mutational burdens and observed that the top five cancers were microsatellite stable (MSS) genotypes (mean TMB 49.3/Mb), while the other 16 MSS cancers had a mean TMB of 5.9/Mb. To facilitate comparison with TCGA hypermutator CRC, we included four microsatellite instability-high (MSI-H) samples with the high mutation burden MSS cases to form a TMB-High group. Comparison of TMB-High with TMB-Low groups revealed differences in mutational frequency of ATM, ALK, NSD1, UBR5, BCL9, CARD11, KDM5C, MN1, PTPRT and PIK3CA, with ATM and UBR5 validated in reanalysis of TCGA hypermutator Stages I and IIIA samples. Variants in ATM were restricted to the TMB-High group, and in four of five MSS specimens, we observed the co-occurrence of mutations in homologous recombination repair (HRR) genes in either two of ATM, CDK12, PTEN or ATR, with at least one of these being a likely pathogenic truncating mutation. No MSI-H specimens carried nonsense mutations in HRR genes. These findings add to our knowledge of early T stage CRC and highlight a potential therapeutic vulnerability in the HRR pathway of TMB-H MSS CRC.