Anatomic Basis of Rectal Cancer Staging: Clarifying Controversies and Misconceptions.

Rectal MRI provides a detailed depiction of pelvic anatomy; specifically, the relationship of the tumor to key anatomic structures, including the mesorectal fascia, anterior peritoneal reflection, and sphincter complex. However, anatomic inconsistencies, pitfalls, and confusion exist, which can have a strong impact on interpretation and treatment. These areas of confusion include the definition of the rectum itself, specifically differentiation of the rectum from the anal canal and the sigmoid colon, and delineation of the high versus low rectum. Other areas of confusion include the relative locations of the mesorectal fascia and peritoneum and their significance in staging and treatment, the difference between the mesorectal fascia and circumferential resection margin, involvement of the sphincter complex, and evaluation of lateral pelvic lymph nodes. The impact of these anatomic inconsistencies and sources of confusion is significant, given the importance of MRI in depicting the anatomic relationship of the tumor to critical pelvic structures, to triage surgical resection and neoadjuvant chemoradiotherapy with the goal of minimizing local recurrence. Evolving treatment paradigms also place MRI central in management of rectal cancer. ©RSNA, 2024.

Efficacy and Safety of Atezolizumab and Bevacizumab in Appendiceal Adenocarcinoma.

PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously. EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted. SIGNIFICANCE: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study.

PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.

The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. IMPLICATIONS: PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma.

Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma. Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma. Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023. Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival). Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9. Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-omics Approach Using Patient-Derived Xenografts.

Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including MKI67 and EXO1. Peritoneal tumors were also enriched for proliferative gene sets, including E2F and Myc Targets. Proteomic studies found a 2.5-fold increased ratio of active-to-inactive phosphoforms of the YAP oncoprotein in peritoneal tumors, indicating downregulation of Hippo signaling. IMPLICATIONS: The peritoneal microenvironment promotes growth of appendiceal tumors and expression of proliferative pathways in PDXs.

Repeat Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Mucinous Appendiceal Adenocarcinoma: A Viable Treatment Strategy with Demonstrable Benefit.

INTRODUCTION: Many patients with mucinous appendiceal adenocarcinoma experience peritoneal recurrence despite complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prior work has demonstrated that repeat CRS/HIPEC can prolong survival in select patients. We sought to validate these findings using outcomes from a high-volume center. PATIENTS AND METHODS: Patients with mucinous appendiceal adenocarcinoma who underwent CRS/HIPEC at MD Anderson Cancer Center between 2004 and 2021 were stratified by whether they underwent CRS/HIPEC for recurrent disease or as part of initial treatment. Only patients who underwent complete CRS/HIPEC were included. Initial and recurrent groups were compared. RESULTS: Of 437 CRS/HIPECs performed for mucinous appendiceal adenocarcinoma, 50 (11.4%) were for recurrent disease. Patients who underwent CRS/HIPEC for recurrent disease were more often treated with an oxaliplatin or cisplatin perfusion (35%/44% recurrent vs. 4%/1% initial, p < 0.001), had a longer operative time (median 629 min recurrent vs. 511 min initial, p = 0.002), and had a lower median length of stay (10 days repeat vs. 13 days initial, p < 0.001). Thirty-day complication and 90-day mortality rates did not differ between groups. Both cohorts enjoyed comparable recurrence free survival (p = 0.82). Compared with patients with recurrence treated with systemic chemotherapy alone, this select cohort of patients undergoing repeat CRS/HIPEC enjoyed better overall survival (p < 0.001). CONCLUSIONS: In appropriately selected patients with recurrent appendiceal mucinous adenocarcinoma, CRS/HIPEC can provide survival benefit equivalent to primary CRS/HIPEC and that may be superior to that conferred by systemic therapy alone in select patients. These patients should receive care at a high-volume center in the context of a multidisciplinary team.

Rectal Adenocarcinoma Presenting as a Cervical Mass: A Case Report.

BACKGROUND Invasive cervical tumors are often seen in clinical practice. However, there are multiple structures within the pelvis, and invasion of the cervix from another site must be included in the differential diagnosis. In such cases, a multidisciplinary approach is needed to define the organ of tumor origin. Ensuring proper staging and histologic analysis are critical for optimal management. CASE REPORT We present a case of a 68-year-old woman who presented to her gynecologist with painless post-menopausal vaginal bleeding. She was diagnosed with a locally aggressive cervical adenocarcinoma, which was histologically confirmed by an in-office biopsy. She was referred to the gynecologic oncology service at a tertiary care hospital for definitive management, where a thorough clinical workup was performed. Physical exam revealed that the mass had invaded the anterior rectal wall. Through a multidisciplinary approach and a repeat biopsy, she was correctly diagnosed with an invasive rectal adenocarcinoma. She was treated with neoadjuvant chemoradiotherapy and underwent curative surgery. Had she been incorrectly treated as having a primary cervical adenocarcinoma, there would have been no role for surgery. The change in the organ of primary drastically altered the patient's management and outcome. She is currently undergoing surveillance with cross-sectional imaging. CONCLUSIONS Cervical masses originating from non-gynecologic organs can be difficult to differentiate on physical exam and histologic analysis. When a mass involves the rectum, an invasive primary rectal adenocarcinoma must be included in the differential. This will have a significant impact on patient management and ultimately on patient survival.

Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers.

Objective: Lynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity. Design: We collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions. Results: On multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P<0.001). We observed a non-statistically significant trend for Hispanics having a higher and earlier cumulative incidence of adenomas compared to non-Hispanics (P=0.073). No MMR carrier was more likely to develop advanced adenomas. No difference in the incidence of CRC by MMR gene (P=0.198). Conclusion: Screening recommendations for CRC in LS patients should be based on specific MMR variants and should also be tailored to consider patient demographics.

Rectal cancer lexicon 2023 revised and updated consensus statement from the Society of Abdominal Radiology Colorectal and Anal Cancer Disease-Focused Panel.

The Society of Abdominal Radiology's Colorectal and Anal Cancer Disease-Focused Panel (DFP) first published a rectal cancer lexicon paper in 2019. Since that time, the DFP has published revised initial staging and restaging reporting templates, and a new SAR user guide to accompany the rectal MRI synoptic report (primary staging). This lexicon update summarizes interval developments, while conforming to the original lexicon 2019 format. Emphasis is placed on primary staging, treatment response, anatomic terminology, nodal staging, and the utility of specific sequences in the MRI protocol. A discussion of primary tumor staging reviews updates on tumor morphology and its clinical significance, T1 and T3 subclassifications and their clinical implications, T4a and T4b imaging findings/definitions, terminology updates on the use of MRF over CRM, and the conundrum of the external sphincter. A parallel section on treatment response reviews the clinical significance of near-complete response and introduces the lexicon of "regrowth" versus "recurrence". A review of relevant anatomy incorporates updated definitions and expert consensus of anatomic landmarks, including the NCCN's new definition of rectal upper margin and sigmoid take-off. A detailed review of nodal staging is also included, with attention to tumor location relative to the dentate line and locoregional lymph node designation, a new suggested size threshold for lateral lymph nodes and their indications for use, and imaging criteria used to differentiate tumor deposits from lymph nodes. Finally, new treatment terminologies such as organ preservation, TNT, TAMIS and watch-and-wait management are introduced. This 2023 version aims to serve as a concise set of up-to-date recommendations for radiologists, and discusses terminology, classification systems, MRI and clinical staging, and the evolving concepts in diagnosis and treatment of rectal cancer.

Prognostic significance of acellular mucin in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for appendiceal neoplasms.

INTRODUCTION: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients. METHODS: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed. RESULTS: Median age was 51 years, 70% were female, and 75% White. Sixty-four patients had M1a disease and 100 M1b,G1 disease. M1a disease had a lower median PCI score (11 vs. 20, p = .0001) and a higher rate of complete CRS (62% vs. 50%, p = .021). Median follow-up was 7.6 years (IQR 5.6-10.5 years). For M1a disease, there were no recurrences and only one patient died during the study interval. In comparison, for M1b disease, 66/100 (66%) recurred with a 5-year RFS of 40.5% (HR 8.0, 95% CI 4.9-15.1, p < .0001), and 31/100 (31%) died with a 5-year OS of 84.8% (HR 4.5, 95% CI 2.2-9.2, p < .0001). CONCLUSIONS: Acellular mucin (M1a disease) after CRS/HIPEC for appendiceal neoplasm is associated with longer OS and RFS compared to M1b, G1 disease. Current AJCC staging does not accurately reflect the differing outcomes of these two patient populations. The presence of acellular mucin in the peritoneal cavity should not be perceived as a metastatic equivalent.

Interobserver Variability and Challenges in Intraoperative Frozen Section Evaluation of Pancreatic Margins in Pancreatectomy Specimens.

OBJECTIVE: Frozen-section evaluation of the pancreatic margin is challenging. We aimed to determine interobserver variability among gastrointestinal pathologists for the assessment of frozen sections of pancreatic margins with marked chronic pancreatitis and to determine the challenging histological features in discrepant cases. METHODS: We identified 45 patients who underwent pancreas resection for pancreatic ductal adenocarcinoma and showed marked chronic pancreatitis at pancreatic margin. Deidentified first levels of frozen-sections of the pancreatic margins from all cases were independently reviewed by 5 experienced gastrointestinal pathologists for the presence of carcinoma and/or high-grade dysplasia. RESULTS: Interobserver agreement among pathologists was calculated as kappa coefficients ([Formula: see text]). A consensus diagnosis for discordant cases was obtained after group review and discussion. Interobserver agreement for adenocarcinoma diagnosis was 87%, and there was "substantial agreement" (Fleiss [Formula: see text]=0.78, P<0.01) and "almost perfect agreement" (Brennan-Prediger [Formula: see text]=0.86, P<0.01). Using the final diagnosis based on frozen and permanent sections as the gold standard and the concordant read of at least 3 of 5 pathologists for comparison, the diagnosis of adenocarcinoma was made in frozen-sections of pancreas margins, with accuracy 98%, sensitivity 83%, specificity 100%, negative predictive value 97%, positive predictive value 100%, false negative rate 9%, and false positive rate 0%. CONCLUSIONS: We showed excellent interobserver agreement among gastrointestinal pathologists for diagnosis of adenocarcinoma on frozen sections of pancreatic margins with marked chronic pancreatitis. Missed adenocarcinoma at the margin was mainly caused by freezing or cautery artifacts or by overlooking a tiny focus of perineural invasion in a background of marked chronic pancreatitis. The evaluation of deeper levels led to perfect agreement.

Magnetic Resonance Imaging Directed Surgical Decision Making for Lateral Pelvic Lymph Node Dissection in Rectal Cancer After Total Neoadjuvant Therapy (TNT).

OBJECTIVE: Lateral pelvic lymph node (LPLN) metastases are an important cause of preventable local failure in rectal cancer. The aim of this study was to evaluate clinical and oncological outcomes following magnetic resonance imaging (MRI)-directed surgical selection for lateral pelvic lymph node dissection (LPLND) after total neoadjuvant therapy (TNT). METHODS: A retrospective consecutive cohort analysis was performed of rectal cancer patients with enlarged LPLN on pretreatment MRI. Patients were categorized as LPLND or non-LPLND. The main outcomes were lateral local recurrence rate, perioperative and oncological outcomes and factors associated with decision making for LPLND. RESULTS: A total of 158 patients with enlarged pretreatment LPLN and treated with TNT were identified. Median follow-up was 20 months (interquartile range 10-32). After multidisciplinary review, 88 patients (56.0%) underwent LPLND. Mean age was 53 (SD±12) years, and 54 (34.2%) were female. Total operative time (509 vs 429 minutes; P =0.003) was greater in the LPLND group, but median blood loss ( P =0.70) or rates of major morbidity (19.3% vs 17.0%) did not differ. LPLNs were pathologically positive in 34.1%. The 3-year lateral local recurrence rates (3.4% vs 4.6%; P =0.85) did not differ between groups. Patients with LPLNs demonstrating pretreatment heterogeneity and irregular margin (odds ratio, 3.82; 95% confidence interval: 1.65-8.82) or with short-axis ≥5 mm post-TNT (odds ratio 2.69; 95% confidence interval: 1.19-6.08) were more likely to undergo LPLND. CONCLUSIONS: For rectal cancer patients with evidence of LPLN metastasis, the appropriate selection of patients for LPLND can be facilitated by a multidisciplinary MRI-directed approach with no significant difference in perioperative or oncologic outcomes.

Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Unusual staining of immunohistochemical markers PAX8 and CDX2 in breast carcinoma: a potential diagnostic pitfall.

Knowing the sensitivity and specificity of tissue-specific immunohistochemical markers is crucial for accurate determination of the primary tumor site. PAX8 has been used as a diagnostic marker for carcinomas of the gynecologic tract, kidney, and thyroid gland, and CDX2 has been used as a marker of gastrointestinal carcinoma. Neither is considered a marker for breast carcinoma (BC). However, we have encountered BCs that express PAX8 or CDX2, some of which caused diagnostic confusion. We investigated the immunohistochemical staining frequency of PAX8 and CDX2 in BC. We identified 237 BCs for which PAX8 staining results were reported (102 primary and 135 metastatic BCs); seven primary and four metastatic BCs (4.6%) were positive for PAX8, with various intensities and staining patterns. CDX2 staining results were reported for 271 BCs (78 primary and 193 metastatic); four primary BCs and one metastatic BC (1.8%) were positive for CDX2, ranging from focal and weak to diffuse and strong. We also stained primary invasive BCs with PAX8 and CDX2 using tissue microarrays. None of the 332 PAX8-stained cases was positive, while one of 143 CDX2-stained cases was positive. Four PAX8-positive and three CDX2-positive cases were stained with TRPS1, and all were positive for TRPS1. In addition, we reviewed the literature for PAX8 and CDX2 expression in BCs and found 5.5% PAX8-positive BCs (90/1625) in 17 studies and 0.8% CDX-2 positive BCs (7/909) in 20 studies. PAX8 and CDX2 are infrequently expressed in BC by immunohistochemistry, and in rare cases, the staining can be strong and diffuse. Additional diagnostic markers are necessary and helpful in distinguishing breast from other primary origins.

What is the Risk for Peritoneal Metastases and Survival Afterwards in T4 Colon Cancers?

BACKGROUND: Patients with T4 colon adenocarcinomas have an increased risk of peritoneal metastases (PM) but the histopathologic risk factors for its development are not well-described. OBJECTIVE: The purpose of this study was to determine factors associated with PM, time to recurrence, and survival after recurrence among patients with T4 colon cancer. PATIENTS AND METHODS: Patients with pathologic T4 colon cancer who underwent curative resection from 2005 to 2017 were identified from a prospectively maintained institutional database and classified by recurrence pattern: (a) none - 68.8%; (b) peritoneal only - 7.9%; (c) peritoneal and extraperitoneal - 9.9%; and (d) extraperitoneal only - 13.2%. Associations between PM development and patient, primary tumor, and treatment factors were assessed. RESULTS: Overall, 151 patients were analyzed, with a median follow-up of 66.2 months; 27 patients (18%) developed PM (Groups B and C) and 20 (13%) patients recurred at non-peritoneal sites only (Group D). Median time to developing metastases was shorter for Groups B and C compared with Group D (B and C: 13.7 months; D: 46.7 months; p = 0.022). Tumor deposits (TDs) and nodal stage were associated with PM (p < 0.05), and TDs (p = 0.048) and LVI (p = 0.015) were associated with additional extraperitoneal recurrence. Eleven (41%) patients with PM underwent salvage surgery, and median survival after recurrence was associated with the ability to undergo cytoreduction (risk ratio 0.20, confidence interval 0.06-0.70). CONCLUSION: PM risk after resection of T4 colon cancer is independently associated with factors related to lymphatic spread, such as N stage and TDs. Well-selected patients can undergo cytoreduction with long-term survival. These findings support frequent postoperative surveillance and aggressive early intervention, including cytoreduction.

Prognosis for Poorly Differentiated, High-Grade Rectal Neuroendocrine Carcinomas.

INTRODUCTION: Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. METHODS: Patients captured in the National Cancer Database (NCDB; 2004-2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. RESULTS: The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1 year, 41%; 3 years, 13%; 5 years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60 years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. CONCLUSIONS: Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.

Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 µmol/L) and bexarotene (40 µmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.

Liver Fibrosis Assessment.

Early diagnosis of hepatic fibrosis (HF) is pivotal for management to cease progression to cirrhosis and hepatocellular carcinoma. HF is the telltale sign of chronic liver disease, and confirmed by liver biopsy, which is an invasive technique and inclined to sampling errors. The morphologic parameters of cirrhosis are assessed on conventional imaging such as on ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). Newer imaging modalities such as magnetic resonance elastography and US elastography are reliable and accurate. More research studies on novel imaging modalities such as MRI with diffusion weighted imaging, enhancement by hepatobiliary contrast agents, and CT using perfusion are essential for earlier diagnosis, surveillance and accurate management. The purpose of this article is to discuss non-invasive CT, MRI, and US imaging modalities for diagnosis and stratify HF.