Discordance in Total Mesorectal Excision Specimen Grading in a Prospective Phase 2 Multicenter Rectal Cancer Trial: Are We Overestimating the Quality of Our Resections?

OBJECTIVES: To report the results of a rigorous quality control (QC) process in the grading of total mesorectal excision (TME) specimens during a multicenter prospective phase 2 trial of transanal TME. BACKGROUND: Grading of TME specimens is based on the macroscopic assessment of the mesorectum and standardized through synoptic pathology reporting. TME grade is a strong predictor of outcomes with incomplete (IC) TME associated with increased rates of local recurrence relative to complete or near complete (NC) TME. Although TME grade serves as an endpoint in most rectal cancer trials, in protocols incorporating centralized review of TME specimens for quality assurance, discordance in grading and the management thereof has not been previously described. METHODS: A phase 2 prospective transanal TME trial was conducted from 2017 to 2022 across 11 North American centers with TME quality as the primary study endpoint. QC measures included (1) training of site pathologists in TME protocols, (2) blinded grading of de-identified TME specimen photographs by central pathologists, and (3) reconciliation of major discordance before trial reporting. Cohen Kappa statistic was used to assess agreement in grading. RESULTS: Overall agreement in grading of 100 TME specimens between site and central reviewer was rated as fair, (κ = 0.35; 95% CI: 0.10-0.61; P < 0.0001). Concordance was noted in 54%, with minor and major discordance in 32% and 14% of cases, respectively. Upon reconciliation, 13/14 (93%) major discordances were resolved. Pre versus postreconciliation rates of complete or NC and IC TME are 77%/16% and 7% versus 69%/21% and 10%. Reconciliation resulted in a major upgrade (IC-NC; N = 1) or major downgrade (NC/C-IC, N = 4) in 5 cases overall (5%). CONCLUSIONS: A 14% rate of major discordance was observed in TME grading between the site and central reviewers. The resolution resulted in a major change in final TME grade in 5% of cases, which suggests that reported rates or TME completeness are likely overestimated in trials. QC through a central review of TME photographs and reconciliation of major discordances is strongly recommended.

How reliable is restaging MRI after neoadjuvant therapy in rectal cancer?

BACKGROUND: Despite the pivotal role of magnetic resonance imaging (MRI) in rectal cancer staging and evaluation, the reliability of restaging MRI after neoadjuvant therapy is still debatable. This study aimed to assess the accuracy of restaging MRI by comparing post-neoadjuvant MRI findings with those of the final pathology. METHODS: This study was a retrospective review of the medical records of adult rectal cancer patients who had restaging MRI following neoadjuvant therapy and prior to rectal cancer resection in a NAPRC-certified rectal cancer centre between 2016 and 2021. The study compared findings of preoperative, post-neoadjuvant MRI with final pathology relative to T stage, N stage, tumour size, and circumferential resection margin (CRM) status. RESULTS: A total of 126 patients were included in the study. We found fair concordance (kappa -0.316) for T stage between restaging MRI and pathology report, and slight concordance for N stage and CRM status (kappa -0.11, kappa = 0.089, respectively). Concordance rates were lower for patients following total neoadjuvant treatment (TNT) or with a low rectal tumour. In total, 73% of patients with positive N pathology status had negative N status in the restaging MRI. Sensitivity and specificity regarding positive CRM in post-neoadjuvant treatment MRI were 45.45% and 70.4%, respectively. CONCLUSION: We found low concordance levels between restaging MRI and pathology regarding TN stage and CRM status. Concordance levels were even lower for patients after TNT regimen and with a low rectal tumour. In the era of TNT and watch-and-wait approach, we should not rely solely on restaging MRI to make post-neoadjuvant treatment decisions.

Multicenter phase II trial of transanal total mesorectal excision for rectal cancer: preliminary results.

BACKGROUND: Transanal TME (taTME) combines abdominal and transanal dissection to facilitate sphincter preservation in patients with low rectal tumors. Few phase II/III trials report long-term oncologic and functional results. We report early results from a North American prospective multicenter phase II trial of taTME (NCT03144765). METHODS: 100 patients with stage I-III rectal adenocarcinoma located ≤ 10 cm from the anal verge (AV) were enrolled across 11 centers. Primary and secondary endpoints were TME quality, pathologic outcomes, 30-day and 90-day outcomes, and stoma closure rate. Univariable regression analysis was performed to assess risk factors for incomplete TME and anastomotic complications. RESULTS: Between September 2017 and April 2022, 70 males and 30 females with median age of 58 (IQR 49-62) years and BMI 27.8 (IQR 23.9-31.8) kg/m2 underwent 2-team taTME for tumors located a median 5.8 (IQR 4.5-7.0) cm from the AV. Neoadjuvant radiotherapy was completed in 69%. Intersphincteric resection was performed in 36% and all patients were diverted. Intraoperative complications occurred in 8% including 3 organ injuries, 2 abdominal and 1 transanal conversion. The 30-day and 90-day morbidity rates were 49% (Clavien-Dindo (CD) ≥ 3 in 28.6%) and 56% (CD ≥ 3 in 30.4% including 1 mortality), respectively. Anastomotic complications were reported in 18% including 10% diagnosed within 30 days. Higher anastomotic risk was noted among males (p = 0.05). At a median follow-up of 5 (IQR 3.1-7.4) months, 98% of stomas were closed. TME grade was complete or near complete in 90%, with positive margins in 2 cases (3%). Risk factors for incomplete TME were ASA ≥ 3 (p = 0.01), increased time between NRT and surgery (p = 0.03), and higher operative blood loss (p = 0.003). CONCLUSION: When performed at expert centers, 2-team taTME in patients with low rectal tumors is safe with low conversion rates and high stoma closure rate. Mid-term results will further evaluate oncologic and functional outcomes.

Interactive Training Program Improves Surgeon and Pathologist Comfort Level With Total Mesorectal Excision Grading for Rectal Cancer.

BACKGROUND: Total mesorectal excision for rectal cancer has been shown to decrease local recurrence and improve survival, and specimen grading is recommended as a best practice. However, specimen grading remains underutilized in the United States potentially because of the lack of surgeon and pathologist training in the technique. OBJECTIVE: This study aimed to determine whether an interactive webinar improves physician comfort with mesorectal grading. DESIGN: To test the effect of the program, participants completed a survey before and after participating. SETTINGS: Twelve Michigan Surgical Quality Collaborative hospitals volunteered to participate in a Total Mesorectal Excision Project. PARTICIPANTS: Total mesorectal excision grading training program participants were surgeons, surgery residents, pathologists, and pathology assistants from 12 hospitals. MAIN OUTCOME MEASURES: Comfort with grading total mesorectal excision specimens was our main outcome measure. Prewebinar surveys also measured familiarity, previous experience, and training in grade assignment, as well as interest in the training program. Postwebinar surveys measured webinar relevance and effectiveness as well as participant intention to use content in practice. RESULTS: A total of 34 participants completed the prewebinar survey and 28 participants completed the postwebinar survey. The postwebinar overall median comfort level with specimen grading of 3.64 was significantly higher than the prewebinar overall median comfort level of 2.94 (95% CI, 3.32-3.96 versus 95% CI 2.56-3.32; p = 0.007). When evaluated separately, both surgeons and pathologists reported significantly higher comfort levels with total mesorectal excision grading after the webinar. LIMITATIONS: Six participants did not complete the postwebinar survey. Surgery residents and pathology assistants were analyzed with practicing surgeons and pathologists. The pre- and postwebinar surveys were deidentified, so paired analysis was not possible. CONCLUSIONS: Our total mesorectal excision grading training program improved the comfort level of both surgeons and pathologists with specimen grading. Survey results also demonstrate that providers are interested in receiving training in rectal cancer specimen grading. See Video Abstract at http://links.lww.com/DCR/B766.PROGRAMA DE ENTRENAMIENTO INTERACTIVO MEJORA EL NIVEL DE COMODIDAD DEL CIRUJANO Y DEL PATÓLOGO CON LA CLASIFICACIÓN DE LA ESCISIÓN TOTAL DEL MESORRECTO PARA EL CÁNCER DE RECTO. ANTECEDENTES: Se ha demostrado que la escisión total del mesorrecto para el cáncer de recto disminuye la recurrencia local y mejora la supervivencia, y se recomienda la clasificación de la muestra como buena práctica de rutina. Sin embargo, sigue siendo poco utilizado en los Estados Unidos debido principalmente a la falta de formación en la técnica de cirujanos y patólogos. OBJETIVO: Determinar si un seminario interactivo en línea mejora la comodidad del médico con la clasificación mesorrectal. DISEO: Para probar el efecto del programa, los participantes completaron una encuesta antes y después de haber participado de la misma. MARCO: Doce hospitales en cooperación sobre la calidad quirúrgica de Michigan se ofrecieron como voluntarios para participar en el proyecto de Escisión Total de Mesorrecto. PARTICIPANTES: Los participantes del programa de entrenamiento en la clasificación de escisión total de mesorrecto fueron cirujanos, residentes de cirugía, patólogos y asistentes de patología de doce hospitales. PRINCIPALES RESULTADOS MEDIDOS: La comodidad con la clasificación de las muestras de escisión total de mesorrecto fue nuestro principal resultado de medición. Las encuestas previas al seminario en línea también midieron la familiaridad, la experiencia y entrenamiento previo en la clasificación, así como el interés en el programa de entrenamiento. Las encuestas posteriores midieron la relevancia y la eficacia del seminario web, así como la intención de los participantes de utilizar en la practica el contenido. RESULTADOS: Un total de 34 participantes completaron la encuesta previa, y 28 de ellos la completaron con posterioridad al seminario en línea.La mediana del nivel de comodidad general, posterior al seminario en línea, con respecto a la clasificación de la pieza de 3,64 fue significativamente mayor con respecto al valor de 2,94 previo al seminario (IC del 95%: 3,32 - 3,96 versus IC 2,56 - 3,32, respectivamente; valor de p = 0,007).Cuando fueron evaluados de manera separada, tanto los cirujanos como los patólogos reportaron niveles de comodidad significativamente más altos con la clasificación de escisión total de mesorrecto (TME) después del seminario en línea. LIMITACIONES: Seis participantes no completaron la encuesta posterior al seminario en línea. Los residentes de cirugía y los asistentes de patología fueron analizados conjuntamente con los cirujanos y patólogos en ejercicio, respectivamente. Las encuestas previas y posteriores al seminario en línea fueron anónimas, anulándose la identificación, por lo que no fue posible realizar un análisis por pares. CONCLUSIONES: Nuestro programa de entrenamiento en la clasificación de escisión total de mesorrecto mejoró el nivel de comodidad tanto de los cirujanos como de los patólogos con la clasificación de las muestras. Los resultados de la encuesta también demuestran que el personal involucrado está interesado en recibir capacitación en la clasificación de muestras de cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/B766. (Traducción-Dr Osvaldo Gauto).

How Reliable Is CT Scan in Staging Right Colon Cancer?

BACKGROUND: The observation of inferior oncologic outcomes after surgery for proximal colon cancers has led to the investigation of alternative treatment strategies, including surgical procedures and neoadjuvant systemic chemotherapy in selected patients. OBJECTIVE: The purpose of this study was to determine the accuracy of CT staging in proximal colon cancer in detecting unfavorable pathologic features that may aid in the selection of ideal candidates alternative treatment strategies, including extended lymph node dissection and/or neoadjuvant chemotherapy. DESIGN: This was a retrospective consecutive series. SETTINGS: Trained abdominal radiologists from 2 centers performed a blinded review of CT scans obtained to locally stage proximal colon cancer according to previously defined prognostic groups, including T1/2, T3/4, N+, and extramural venous invasion. CT findings were compared with histopathologic results as a reference standard. Unfavorable pathologic findings included pT3/4, pN+, or extramural venous invasion. PATIENTS: Consecutive patients undergoing right colectomy in 2 institutions between 2011 and 2016 were retrospectively reviewed from a prospectively collected database. MAIN OUTCOME MEASURES: T status, nodal status, and extramural venous invasion status comparing CT with final histologic findings were measured. RESULTS: Of 150 CT scans reviewed, CT failed to identify primary cancer in 18%. Overall accuracy of CT to identify unfavorable pathologic features was 63% with sensitivity, specificity, positive predictive value, and negative predictive value of 63% (95% CI, 54%-71%), 63% (95% CI, 46%-81%), 87% (95% CI, 80%-94%) and 30% (95% CI, 18%-41%). Only cT3/4 (55% vs 45%; p = 0.001) and cN+ (42% vs 58%; p = 0.02) were significantly associated with correct identification of unfavorable features at final pathology. CT scans overstaged and understaged cT in 23.7% and 48.3% and cN in 28.7% and 53.0% of cases. LIMITATIONS: The study was limited by its retrospective design, relatively small sample size, and heterogeneity of CT images performed in different institutions with variable equipment and technical details. CONCLUSIONS: Accuracy of CT scan for identification of pT3/4, pN+, or extramural venous invasion was insufficient to allow for proper identification of patients at high risk for local recurrence and/or in whom to consider alternative treatment strategies. Locoregional overstaging and understaging resulted in inappropriate treatment strategies in <48%. See Video Abstract at http://links.lww.com/DCR/A935.

The Future of Rectal Cancer Surgery: A Narrative Review of an International Symposium.

Surgery remains the mainstay of curative treatment for primary rectal cancer. For mid and low rectal tumors, optimal oncologic surgery requires total mesorectal excision (TME) to ensure the tumor and locoregional lymph nodes are removed. Adequacy of surgery is directly linked to survival outcomes and, in particular, local recurrence. From a technical perspective, the more distal the tumor, the more challenging the surgery and consequently, the risk for oncologically incomplete surgery is higher. TME can be performed by an open, laparoscopic, robotic or transanal approach. There is a lack of consensus on the "gold standard" approach with each of these options offering specific advantages. The International Symposium on the Future of Rectal Cancer Surgery was convened to discuss the current challenges and future pathways of the 4 approaches for TME. This article reviews the findings and discussion from an expert, international panel.

The Rationale for and Reality of the New National Accreditation Program for Rectal Cancer.

BACKGROUND: The treatment of rectal cancer has greatly evolved because of numerous diagnostic and therapeutic advances. More accurate staging by MRI has allowed more appropriate use of neoadjuvant therapy as well as more standardized high-quality total mesorectal excision. Lower rates of perioperative morbidity, permanent colostomy creation, and improved rates of oncologically acceptable rectal excision have led to lower recurrence and greater disease-free survival rates. The recognition of the need for pathologic assessment of the quality of total mesorectal excision, the status of the circumferential resection margins, and the finding of a minimum of 12 lymph nodes as well as identification of extramural vascular invasion has improved staging. These evolutions in imaging, surgical management, and pathologic specimen assessment are interdependent and have been repeatedly shown on national levels to be best operationalized in a multidisciplinary team environment. OBJECTIVE: The aim of this article is to evaluate the evidence leading to these important changes, including the imminent launch of the National Accreditation Program for Rectal Cancer. DESIGN AND SETTING: Based on the myriad confirmatory experiences in Europe and in the United Kingdom, a multidisciplinary team rectal cancer program was designed by the Consortium for Optimizing Surgical Treatment of Rectal Cancer and subsequently endorsed and accepted by the American College of Surgeons Commission on Cancer. MAIN OUTCOME MEASURES: The primary outcome measured is the adherence to the new program standards. RESULTS: Surgical treatment of rectal cancer consortium membership rapidly increased from 14 centers in August 2011 to more than 350 centers in April 2017. LIMITATIONS: The multidisciplinary team rectal cancer program has not yet launched; thus, its impact cannot yet be assessed. CONCLUSIONS: It is our hope and expectation that the outstanding improvement in quality outcomes repeatedly demonstrated within Europe, and extensively shown as much needed in the United States, will be rapidly achieved.

Variation in Hospital-Specific Rates of Suboptimal Lymphadenectomy and Survival in Colon Cancer: Evidence from the National Cancer Data Base.

BACKGROUND: Little is known about between-hospital differences in the rate of suboptimal lymphadenectomy. This study characterizes variation in hospital-specific rates of suboptimal lymphadenectomy and its effect on overall survival in a national hospital-based registry. METHODS: Stage I-III colon cancer patients were identified from the 2003-2012 National Cancer Data Base. Bayesian multilevel logistic regression models were used to assess the impact of patient- and hospital-level factors on hospital-specific rates of suboptimal lymphadenectomy (<12 lymph nodes), and multilevel Cox models were used to estimate the effect of suboptimal lymphadenectomy at the patient (yes vs. no) and hospital level (quartiles of hospital-specific rates) on overall survival. RESULTS: A total of 360,846 patients across 1345 hospitals in the US met the inclusion criteria, of which 25 % had a suboptimal lymphadenectomy. Wide variation was observed in hospital-specific rates of suboptimal lymphadenectomy (range 0-82 %, median 44 %). Older age, male sex, comorbidity score, no insurance, positive margins, lower tumor grade, lower T and N stage, and sigmoid and left colectomy were associated with higher odds of suboptimal lymphadenectomy. Patients treated at lower-volume and non-academic hospitals had higher odds of suboptimal lymphadenectomy. Patient- and hospital-level factors explained 5 % of the between-hospital variability in suboptimal lymphadenectomy, leaving 95 % unexplained. Higher suboptimal lymphadenectomy rates were associated with worse survival (quartile 4 vs. quartile 1: hazard ratio 1.19, 95 % confidence interval 1.16-1.22). CONCLUSION: Large differences in hospital-specific rates of suboptimal lymphadenectomy were observed, and this variation was associated with survival. Quality improvement initiatives targeting hospital-level adherence to the national standard may improve overall survival among resected colon cancer patients.

High Rate of Positive Circumferential Resection Margins Following Rectal Cancer Surgery: A Call to Action.

OBJECTIVES: To identify predictors of positive circumferential resection margin following rectal cancer resection in the United States. BACKGROUND: Positive circumferential resection margin is associated with a high rate of local recurrence and poor morbidity and mortality for rectal cancer patients. Prior study has shown poor compliance with national rectal cancer guidelines, but whether this finding is reflected in patient outcomes has yet to be shown. METHODS: Patients who underwent resection for stage I-III rectal cancer were identified from the 2010-2011 National Cancer Database. The primary outcome was a positive circumferential resection margin. The relationship between patient, hospital, tumor, and treatment-related characteristics was analyzed using bivariate and multivariate analysis. RESULTS: A positive circumferential resection margin was noted in 2859 (17.2%) of the 16,619 patients included. Facility location, clinical T and N stage, histologic type, tumor size, tumor grade, lymphovascular invasion, perineural invasion, type of operation, and operative approach were significant predictors of positive circumferential resection margin on multivariable analysis. Total proctectomy had nearly a 30% increased risk of positive margin compared with partial proctectomy (OR 1.293, 95%CI 1.185-1.411) and a laparoscopic approach had nearly 22% less risk of a positive circumferential resection margin compared with an open approach (OR 0.882, 95%CI 0.790-0.985). CONCLUSIONS: Despite advances in surgical technique and multimodality therapy, rates of positive circumferential resection margin remain high in the United States. Several tumor and treatment characteristics were identified as independent risk factors, and advances in rectal cancer care are necessary to approach the outcomes seen in other countries.

Histopathologic advantages of compression ring anastomosis healing as compared with stapled anastomosis in a porcine model: a blinded comparative study.

BACKGROUND: The performances of compression and stapled devices were compared previously in porcine colorectal anastomosis. The compression anastomosis was associated with elevated bursting strength and anastomotic patency in this model as compared with the stapled anastomosis. OBJECTIVE: The purpose of this work was to compare the histopathologic features between compression and stapled methods in the healing of colorectal anastomoses using a porcine model. DESIGN: This was a blinded comparison study. SETTINGS: The study was conducted at a single university surgery department. PATIENTS: Fifty crossbred pigs were used in this study. MAIN OUTCOME MEASURES: Fifty crossbred pigs underwent rectal transection 20 cm from the anal verge and end-to-end compression or stapled anastomosis. The anastomotic tissues were harvested 3, 7, 30, and 90 days postoperatively (n = 5-6). Tissue repair parameters associated with the wound healing were analyzed using image analysis morphometry and histological architecture assessments. RESULTS: A different microscopic pattern of the anastomotic area was shown between groups. Foreign body response was rated (p < 0.001) as minimal in the compression and moderate in the stapled group. The scarring area in the compression anastomosis group, on postoperative day 90 (4 ± 3 × 10(5) µm) was lower (p = 0.016) than in the stapled group (2 ± 1 × 10(6) µm). In addition, the anastomotic line was narrower (p = 0.003) 90 days after surgery in the compression samples (0.77 ± 0.20 mm) compared with that in the stapled group (1.86 ± 0.19 mm). Lastly, in terms of inflammatory cells, the compression biopsies showed lower (p < 0.001) numbers of mononuclear cells, polymorphonuclear cells, and lymphocytes in the anastomotic tissues 30 and 90 days from surgery. LIMITATIONS: The long-term effect of the compression technique on the anastomotic patency in colorectal anastomoses should be further investigated in human studies. CONCLUSIONS: Compression anastomotic healing was associated with less foreign body reactions, scarring, and inflammation as compared with stapled anastomoses in a large animal model.

Judging pathological assessment in cancer specimens.

The pathologist plays a critical role in the multidisciplinary team in charge of treating cancer patients, as many of the therapeutic decisions rely on the information conveyed through the pathology reports. The task of the pathologist includes not only an accurate assessment of pathological T and N categories, but also the evaluation of other indicators of prognosis including quality of surgery, margins of resection, as well as additional histopathological and molecular markers that influence prognosis and could predict response to therapy.

Laparoscopic resection of rectal cancer results in higher lymph node yield and better short-term outcomes than open surgery: a large single-center comparative study.

BACKGROUND: Prognosis in rectal cancer is closely related to mesorectal integrity, margin status, and adequate lymph node dissection. The impact of laparoscopy on the pathologic and short-term outcomes remains controversial. OBJECTIVE: We aim to compare the pathologic and short-term outcomes of laparoscopic and open resections for rectal cancer. DESIGN: This is a large single-center retrospective comparative study using a prospective database. PATIENTS: All patients who underwent primary resections for rectal cancer from January 2007 to September 2011 were identified. MAIN OUTCOME MEASURES: Pathologic (nodal harvest, mesorectal integrity, circumferential, and distal margins) and operative outcomes were measured. RESULTS: Two hundred thirty-four (mean age, 61 years; 65% male) patients underwent resections for primary rectal cancer, including 118 laparoscopic (99 restorative proctectomies, 19 abdominoperineal resections) and 116 open (69 restorative proctectomies, 47 abdominoperineal resections) resections. Both groups were similar in demographics, comorbidities, and tumor characteristics. The laparoscopic group had significantly more lymph nodes (26 vs 21, p = 0.02) than the open group, with no differences in circumferential margins, proportion of distal resection margins

Distal Tumor Spread in Rectal Cancer-How Low Should We Go?

BACKGROUND: Distal tumor spread (DTS) is an adverse prognostic factor in rectal cancer correlating with advanced stage disease. We aimed to assess prevalence and location of distal tumor spread and impact of neoadjuvant chemoradiotherapy (NACRT) in patients who underwent proctectomy for rectal cancer. METHODS: The pathology database at our institution was queried for all patients who underwent proctectomy with curative intent for rectal cancer from 1/2008 to 12/2016. Specimen slides were re-evaluated by a single expert rectal cancer pathologist to verify diagnosis and measure the distance to the distal resection margin. Main outcome measures were 3-year overall and disease-free survival. RESULTS: 275 consecutive patients were identified. 109/111 patients with clinical stage 3 disease received preoperative neoadjuvant chemoradiotherapy. DTS was found in 13 (4.7%) specimens, 6 with intra-mural and 7 with extra-mural distal tumor spread. DTS was found only in patients with clinical stage 3 disease. Length of DTS from the distal end of the tumor ranged from 0 to 30 mm; in only 4 specimens DTS was >10 mm. A positive distal resection margin was found in 5/275 (1.8%) specimens. CONCLUSION: A macroscopically tumor-free margin may suffice in patients with pre-treatment stage 1 or 2 disease. Furthermore, a 1 cm margin is adequate in most patients with stage 3 disease.

Medullary carcinoma of the colon: A comprehensive analysis of the National Cancer Database.

PURPOSE: Medullary carcinomas (MC) of the colon are uncommon tumors. In this study, we analyzed demographic and disease characteristics as well as survival outcomes of MC versus undifferentiated (UDA) and poorly differentiated (PDA) adenocarcinomas (AC) of the colon. MATERIALS AND METHODS: The National Cancer Database (2004-2018) was utilized to identify patients with colon cancer. Patient demographics (including age, gender, race), disease characteristics (including grade, TNM stage, carcinoembryonic levels, perineural and lymphovascular invasion, lymph node status, microsatellite stability, KRAS mutation, and primary tumor site), and facility type and location were evaluated. Chi-square tests were used to compare descriptive data. Cox Regression and Kaplan Meier analyses were used to analyze survival characteristics. RESULTS: 1,041,753 patients with colon cancer were identified of whom 2709 patients had MC and 897,902 had AC (136,597 PDA and 18,042 UDA). MC was seen in older patients (mean age 74 ± 13 years) and women (72.5% vs. 27.5% males). Most MCs were poorly differentiated (63.3%), and 82.4% of patients with MC had microsatellite instability. Fewer patients with MC had perineural invasion (15.6% vs. 22.0% in PDA and 22.4% in UDA, p < 0.001) and positive lymph nodes (38.4% versus 59.9% with PDA and 59.7% with UDA, p < 0.0001). MC diagnosis increased by year (Cochran-Armitage trend test, p < 0.0001). Kaplan Meir analysis revealed a better prognosis for patients with MC when compared to PDA or UDA (p < 0.001). CONCLUSION: Given the rarity, pathologists should maintain a high suspicion for MC when encountering poorly differentiated or undifferentiated right-sided colon cancer with associated MSI-H.

Testosterone and 17ß-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.

Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17ß-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-ß1 signaling pathway. Pretreatment with 17ß-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-ß1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17ß-estradiol. These hormones modulate podocyte damage and apoptosis.

17ß-estradiol modifies diabetic wound healing by decreasing matrix metalloproteinase activity .

UNLABELLED: Postmenopausal women are more susceptible to poor wound healing. This phenomenon can be reversed by estrogen replacement therapy in non-diabetic individuals. Postmenopausal women with type 2 diabetes are more susceptible to wound healing complications, potentially secondary to an estrogen deficiency. Few studies have examined the mechanism of action and effects of estrogens on diabetic wound healing in females. It appears that multiple factors influence delayed wound healing among individuals with diabetes including: an imbalance in cytokines, growth factors, extracellular matrix (ECM) turnover, and oxidant stress (OS). Estrogens have been shown to regulate the expression of genes important for extracellular matrix turnover, including collagen and matrix metalloproteinases (MMP). METHODS: For this reason, the effects of 17ß-estradiol (E2) on MMP-2, MMP-13, and MMP-14 and estrogen receptor alpha and beta (ER-α and -ß) expression in the wound tissue of estrogen-deficient female mice with established type 2 diabetes mellitus (C57BL/6J-m Leprdb/2+) were studied. RESULTS: Topical E2 upregulates ERα in wound tissue thereby improving and accelerating diabetic wound healing in estrogen deficient mice. CONCLUSION: The mechanism appears to decrease MMP-2, MMP-13, and MMP-14 mediated tissue matrix destruction and increasing collagen content. .