RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport. RCC1 RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. RCC1 silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. RCC1 knockdown (KD) reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) tumors. Mechanistically, RCC1 KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. RCC1 KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in Rcc1 KD KPC-tumor-derived cells and several altered metabolic biosynthesis pathways. In vivo, RCC1 KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, RCC1 KD sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of RCC1 in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.

Gastroenterologist and surgeon perceptions of recommendations for optimal endoscopic localization of colorectal neoplasms.

National consensus recommendations have recently been developed to standardize colorectal tumour localization and documentation during colonoscopy. In this qualitative semi-structured interview study, we identified and contrast the perceived barriers and facilitators to using these new recommendations according to gastroenterologists and surgeons in a large central Canadian city. Interviews were analyzed according to the Consolidated Framework for Implementation Research (CFIR) through directed content analysis. Solutions were categorized using the Expert Recommendations for Implementing Change (ERIC) framework. Eleven gastroenterologists and ten surgeons participated. Both specialty groups felt that the new recommendations were clearly written, adequately addressed current care practice tensions, and offered a relative advantage versus existing practices. The new recommendations appeared appropriately complex, applicable to most participants, and could be trialed and adapted prior to full implementation. Major barriers included a lack of relevant external or internal organizational incentives, non-existing formal feedback processes, and a lack of individual familiarity with the evidence behind some recommendations. With application of the ERIC framework, common barriers could be addressed through accessing new funding, altering incentive structures, changing record systems, educational interventions, identifying champions, promoting adaptability, and employing audit/feedback processes. Future research is needed to test strategies for feasibility and effectiveness.

Early Surveillance Endoscopy Should Be Performed Selectively After Transanal Endoscopic Microsurgery for Rectal Lesions.

Introduction Local recurrence (LR) rates after transanal endoscopic microsurgery (TEM) are unclear, and the utility of early postoperative surveillance for low-risk lesions is unknown. This study aimed to define LR after TEM for benign polyps and invasive adenocarcinoma, describe risk factors for LR, and evaluate the utility of early surveillance endoscopy. Methods This retrospective cohort study was conducted at two hospitals in Winnipeg, Manitoba, Canada. Adult patients who underwent TEM between 2009 and 2020 were evaluated for inclusion. The primary outcome was the rate of LR on surveillance endoscopy. Other outcomes included risk factors for LR and diagnostic yield of surveillance endoscopy. Results Among 357 patients who underwent TEM for benign polyps, LR was 10.5% (95% confidence interval (CI) 5.8-15.2) at three years. Positive margin was correlated with LR on multivariate analysis (hazard ratio (HR) 8.01, 95% CI 2.78-23.08). TEM defect closure was associated with lower LR on multivariate analysis (HR 0.19, 95% CI 0.06-0.59). Among 124 patients who underwent TEM for rectal adenocarcinoma, LR was 15.0% (95% CI 6.0-24.0) at three years. The first surveillance endoscopy had a 1.4% yield for low-risk patients (benign lesion, negative margins, and closed TEM defect) and 6.9% for all others. Conclusions LR at three years after TEM was 10.5% for benign polyps and 15.0% for adenocarcinomas. Early surveillance endoscopy can be considered low yield in some patients after TEM, which can be informative for shared decision-making regarding whether to proceed with early endoscopy in a low-risk subgroup of patients.

Targeting guanine nucleotide exchange factors for novel cancer drug discovery.

INTRODUCTION: Guanine nucleotide exchange factors (GEFs) regulate the activation of small GTPases (G proteins) of the Ras superfamily proteins controlling cellular functions. Ras superfamily proteins act as 'molecular switches' that are turned 'ON' by guanine exchange. There are five major groups of Ras family GTPases: Ras, Ran, Rho, Rab and Arf, with a variety of different GEFs regulating their GTP loading. GEFs have been implicated in various diseases including cancer. This makes GEFs attractive targets to modulate signaling networks controlled by small GTPases. AREAS COVERED: In this review, the roles and mechanisms of GEFs in malignancy are outlined. The mechanism of guanine exchange activity by GEFs on a small GTPase is illustrated. Then, some examples of GEFs that are significant in cancer are presented with a discussion on recent progress in therapeutic targeting efforts using a variety of approaches. EXPERT OPINION: Recently, GEFs have emerged as potential therapeutic targets for novel cancer drug development. Targeting small GTPases is challenging; thus, targeting their activation by GEFs is a promising strategy. Most GEF-targeted drugs are still in preclinical development. A deeper biological understanding of the underlying mechanisms of GEF activity and utilizing advanced technology are necessary to enhance drug discovery for GEFs in cancer.

Adjuvant chemotherapy in patients with clinically node-negative but pathologically node-positive rectal cancer in the Netherlands: A retrospective analysis.

INTRODUCTION: Accurate clinical staging of rectal cancer is hampered by suboptimal sensitivity of MRI in the detection of regional lymph node metastases. Consequently, some patients may be understaged and have been withheld neoadjuvant (chemo)radiotherapy in retrospect. Although Dutch guidelines do not advocate adjuvant chemotherapy (ACT) in rectal cancer, some of these clinically understaged patients receive ACT according to local policy. We aim to assess the benefit of ACT in these patients. METHODS: Population-based data from patients with clinically node-negative (cN0) but pathologically node-positive (pN+) rectal cancer that underwent total mesorectal excision (TME) without neoadjuvant treatment between 2008 and 2018 were obtained from the Netherlands Cancer Registry. Missing data were handled by multiple imputation. Stabilised inverse probability treatment weighting (sIPTW) was used to balance clinical characteristics. Overall survival (OS) was compared in ACT and non-ACT patients. RESULTS: Of 34,724 patients, 13,861 had cN0 disease of whom 3016 were pN+ (21.8%). 1466 (48.6%) of these patients underwent upfront TME and were included. Median follow-up was 84 months (95% confidence interval [CI] 76-97) versus 79 months (95% CI 77-81) in patients that did (n = 290, 19.8%) and did not (n = 1176, 80.2%) receive ACT, respectively. After sIPTW adjustment, ACT was associated with improved OS (hazard ratio 0.70; 95% CI 0.49-0.99; p = 0.04). The estimated 5-year OS rate was 74.2% versus 65.3%, respectively. CONCLUSION: In this population-based cohort of patients with cN0 but pN+ rectal cancer who underwent upfront TME, ACT was associated with a significant OS benefit. These data support to discuss ACT in this population.

Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model.

BACKGROUND: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient-derived tumours, and had promising activity in a phase I study. METHODS: Here, we investigated the impact of selinexor-gemcitabine-nab-paclitaxel (Sel-GemPac) combination on LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx1-Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). RESULTS: Sel-GemPac synergistically inhibited the growth of the KPC tumour-derived cell line. The Sel-GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub-maximum tolerated dose (sub-MTD) , Sel-GemPac enhanced the survival of treated mice compared to controls (p < .05). Immunohistochemical analysis of residual KPC tumours showed re-organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase-like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'-kinase-Akt (PI3K-AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel-GemPac-treated mice tumours including the CD44+ stem cell population. CONCLUSION: Taken together, these results demonstrate that the Sel-GemPac treatment caused broad perturbation of PDAC-supporting signalling networks in the KPC mouse model. HIGHLIGHTS: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac). Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse derived cell line and enhanced the survival of mice. Digital spatial profiling shows that Sel-GemPac causes broad perturbation of PDAC-supporting signalling in the KPC model.

Effectiveness of educational materials on levels of knowledge of thyroid associated orbitopathy in an endocrinology clinic.

Objective: We aim to assess and quantify basic knowledge about TAO in patients presenting to an endocrinology clinic and the effect of different educational materials on patients' knowledge. Methods: This study was conducted in a tertiary care center involving 255 patients presenting to an endocrinology clinic. The study was divided into three consecutive phases: 1. a control phase without any educational materials in the waiting room, 2. exposure to educational posters, and 3. exposure to educational pamphlets. Results: In the control population, only 16.5% of patients reported having knowledge of TAO, with a low average TAO-K score of 29.8 (out of 100). After the poster and pamphlet interventions, the percentage of patients having any knowledge of TAO increased across the control, poster and pamphlet phases: 16.5%, 25.9%, 63.5% respectively (p < 0.001). Similarly, the mean TAO-K score increased: 29.8, 45.8, 63.2 respectively (p < 0.001). Conclusion: This study confirms that patients with thyroid dysfunction have a low level of awareness and depth of knowledge of TAO. Innovation: We suggest the dissemination of educational material to increase the knowledge of TAO in thyroid patients. This will help with early symptom detection and ensure proper management of this interdisciplinary condition.

Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

Ophthalmic injuries from the beirut blast: Managing long-term consequences.

The 2020 Beirut Port explosion was one of the largest non-nuclear urban explosions in history, and resulted in a plethora of oculofacial injuries. In this retrospective study, we present the two year follow up ophthalmic outcomes of the survivors of the blast. Only 16 out of 39 patients continued follow up at our center, with 13 having delayed complications and 7 requiring further surgery. The most common delayed complications related to the eyelid, lacrimal system, and orbit. Treatment of disfiguring facial and peri-ocular scarring with laser-assisted drug delivery of topical 5-fluorouracil showed great promise and significantly improved patients' functional and well as cosmetic outcomes.

Total neoadjuvant therapy for rectal cancer: a guide for surgeons.

The modern management of rectal cancers continues to evolve. With the release of data from new landmark randomized controlled trials (RAPIDO, PRODIGE-23), total neoadjuvant therapy (TNT) has moved to the forefront of locally advanced rectal cancer treatment and is considered a standard option in selected patients. Total neoadjuvant therapy promises enhanced systemic disease control, better treatment adherence and less time with an ostomy. However, TNT as currently described encompasses a number of different potential treatment options that differ significantly in terms of their radiation dosage, chemotherapy regimen and order of treatments administered. Being familiar with TNT regimens will be important for rectal cancer surgeons to appropriately advocate for their patients and optimize their outcomes. This article serves as a primer for the general surgeon and offers a pragmatic overview of the indications, realistic expected benefits and potential downsides of each TNT regimen.

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers.

KRASG12C inhibitors have revolutionized the treatment landscape for cancer patients harboring the G12C mutant isoform of KRAS. With the recent FDA approval of sotorasib and adagrasib, patients now have access to more promising treatment options. However, patients who receive these agents as a monotherapy usually develop drug resistance. Thus, there is a need to develop logical combination strategies that can delay or prevent the onset of resistance and simultaneously enhance the antitumor effectiveness of the treatment regimen. In this study, we aimed at pharmacologically targeting PAK4 by KPT9274 in combination with KRASG12C inhibitors in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and nonâ€"small cell lung cancer (NSCLC) preclinical models. PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We assessed the cytotoxicity of PAK4 and KRASG12C inhibitors combination in KRASG12C mutant 2D and 3D cellular models. KPT9274 synergized with both sotorasib and adagrasib in inhibiting the growth of KRASG12C mutant cancer cells. The combination was able to reduce the clonogenic potential of KRASG12C mutant PDAC cells. We also evaluated the antitumor activity of the combination in a KRASG12C mutant PDAC cell line-derived xenograft (CDX) model. Oral administration of a sub-optimal dose of KPT9274 in combination with sotorasib (at one-fourth of MTD) demonstrated significant inhibition of the tumor burden ( p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment ( p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes. Significance: KRASG12C inhibitors demonstrate limited durable response in patients with KRASG12C mutations. In this study, combining PAK4 inhibitor KPT9274 with KRASG12C inhibitors has resulted in potent antitumor effects in preclinical cancer models of PDAC and NSCLC. Our results bring forward a novel combination therapy for cancer patients that do not respond or develop resistance to KRASG12C inhibitor treatment.

Optimal endoscopic localization of colorectal neoplasms: a comparison of rural versus urban documentation practices.

BACKGROUND: Colonoscopy is the gold standard for diagnosing colorectal neoplasms. However, colonoscopy is often repeated preoperatively due to non-standard documentation and inconsistent practices by index endoscopists. Repeat endoscopies result in treatment delays and can increase risks of complications. National consensus recommendations were recently developed for optimal endoscopic colorectal lesion localization. We aimed to assess baseline colonoscopy practice differences from the new recommendations with a focus on geographical variability in report quality between urban and rural referral sites. METHODS: We performed a retrospective review of patients who underwent elective surgery for colorectal neoplasms at a single institution in Winnipeg between 2007-2020. We compared endoscopy report quality to the national recommendations with charts stratified by endoscopy location. Our primary outcomes were overall report documentation completeness and use of recommended practices. RESULTS: One hundred ninety-four patients were included (97 rural, 97 urban). The mean overall compliance with the recommendations for urban endoscopies was marginally better compared to rural endoscopies (50% vs. 48%, p = 0.04). Sixty-eight percent of the reports complied with tattoo indications (72% urban; 63% rural, p = 0.16). On average, reports included 29% of recommended tattoo information (30% urban; 28% rural, p = 0.25) and demonstrated 74% appropriate tattoo technique (70% urban; 81% rural, p = 0.10). Twenty-one percent of reports included photographs of lesions in accordance with the national recommendations (28% urban; 13% rural, p = 0.01). CONCLUSIONS: Endoscopists frequently omit recommended practices for optimal colorectal lesion localization. Rural reports miss more recommended information compared to urban reports. Future research is needed to facilitate province-wide high-quality endoscopy reporting for patients regardless of endoscopy location.

Variability in Communication and Reporting Practices Between Gastroenterologists and General Surgeons Contributes to Repeat Preoperative Endoscopy for Colorectal Neoplasms: A Qualitative Analysis.

BACKGROUND: Surgeons commonly repeat preoperative endoscopy before planned colorectal resections. The reasons for this are not entirely clear, and repeat endoscopy may lead to delays in curative resection, increased costs, and patient discomfort. OBJECTIVE: This study aimed to determine practice patterns, localization techniques, and processes of communication undertaken by endoscopy specialists in a high-volume regional health authority. DESIGN: This was a qualitative study involving standardized, semi-structured, in-depth interviews that were conducted in person. Data were analyzed using a thematic analysis approach. SETTINGS: The study was conducted at Canadian tertiary and community facilities. PARTICIPANTS: Ten general surgeons and 10 gastroenterologists were included using a convenience sampling technique. MAIN OUTCOME MEASURES: Interview questions were developed to understand the perspectives and practice patterns of endoscopists when approaching patients diagnosed with colorectal lesions requiring surgical resection. The decision-making process to perform a repeat preoperative endoscopy was assessed. RESULTS: Three key themes emerged: 1) patterns of communication, 2) feedback, and 3) trust. Thematic analysis revealed that poor communication and ambiguous documentation increased the likelihood of performing repeat preoperative endoscopy. Inconsistencies in tattooing practices and lesion location were important factors. Negative experiences and factors related to interprofessional trust emerged as key contributors to repeat preoperative endoscopy. LIMITATIONS: The transferability of findings to health care systems outside Canada may be limited and requires further study. CONCLUSIONS: Suboptimal endoscopic reporting contributes to gaps in communication among endoscopists. In addition, lack of consistent feedback and mutual trust may increase the likelihood of performing repeat preoperative lower endoscopy. Inconsistent tattooing practices pose significant concerns for accurate intraoperative lesion localization. Establishing collaborative work environments through joint educational initiatives may enhance communication and mitigate unnecessary repeat procedures. These results support the need for standardized guidelines and endoscopic reporting in the management of colorectal lesions. See Video Abstract at http://links.lww.com/DCR/B879 . LA VARIABILIDAD EN LAS PRCTICAS DE COMUNICACIN Y PRESENTACIN DE INFORMES ENTRE GASTROENTERLOGOS Y CIRUJANOS GENERALES CONTRIBUYE A REPETIR LA ENDOSCOPIA PREOPERATORIA PARA LAS NEOPLASIAS COLORRECTALES UN ANLISIS CUALITATIVO: ANTECEDENTES:Los cirujanos suelen repetir la endoscopia preoperatoria antes de las resecciones colorrectales planificadas. Las razones de esto no están del todo claras y la repetición de la endoscopia puede provocar retrasos en la resección curativa, aumento de los costos y malestar del paciente.OBJETIVO:Nuestro objetivo fue determinar patrones de práctica, técnicas de localización y procesos de comunicación realizados por especialistas en endoscopia, en una autoridad sanitaria regional, de alto volumen.DISEÑO:Este fue un estudio cualitativo, que involucró entrevistas estandarizadas, semiestructuradas y en profundidad que se llevaron a cabo en persona. Los datos se analizaron mediante un enfoque de análisis temático.ENTORNO CLINICO:El estudio se llevó a cabo en instalaciones comunitarias y terciarias canadienses.PARTICIPANTES:Se incluyeron 10 cirujanos generales y 10 gastroenterólogos, utilizando una técnica de muestreo por conveniencia.PRINCIPALES MEDIDAS DE VALORACION:Las preguntas de la entrevista se desarrollaron para comprender las perspectivas y los patrones de práctica de los endoscopistas, cuando se acercan a pacientes diagnosticados con lesiones colorrectales que requieren resección quirúrgica. Se evaluó el proceso de toma de decisiones para realizar una nueva endoscopia preoperatoria.RESULTADOS:Surgieron tres temas clave: 1) patrones de comunicación, 2) retroalimentación y 3) confianza. El análisis temático reveló que la pobre comunicación y la ambigua documentación aumentaron la probabilidad de realizar una nueva endoscopia preoperatoria. Las inconsistencias en las prácticas de tatuaje y la ubicación de las lesiones fueron factores importantes. Las experiencias pasadas negativas y los factores relacionados con la confianza interprofesional surgieron como contribuyentes clave para repetir la endoscopia preoperatoria.LIMITACIONES:La transferibilidad de los hallazgos a los sistemas de atención médica fuera de Canadá, puede ser limitada y requiere más estudios.CONCLUSIONES:Los informes endoscópicos subóptimos contribuyen a las brechas en la comunicación entre los endoscopistas. Además, la falta de retroalimentación consistente y la confianza mutua pueden aumentar la probabilidad de realizar una nueva endoscopia baja preoperatoria. Las prácticas inconsistentes de tatuaje, plantean preocupaciones importantes para la localización precisa de las lesiones intraoperatorias. El establecimiento de entornos de trabajo colaborativo a través de iniciativas educativas conjuntas pueden mejorar la comunicación y mitigar la repetición de procedimientos innecesarios. Estos resultados apoyan la necesidad de pautas estandarizadas e informes endoscópicos en el tratamiento de las lesiones colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B879 . (Traducción-Dr. Fidel Ruiz Healy ).

Recommendations for Optimal Endoscopic Localization of Colorectal Neoplasms: A Delphi Consensus of National Experts.

BACKGROUND: Colonoscopy is the standard of care for diagnosis and evaluation of colorectal cancers before surgery. However, varied practices and heterogenous documentation affects communication between endoscopists and operating surgeons, hampering surgical planning. OBJECTIVE: This study aimed to develop recommendations for the use of standardized localization and reporting practices for colorectal lesions identified during lower GI endoscopy. DESIGN: A systematic review of existing endoscopy guidelines and thorough narrative review of the overall endoscopy literature were performed to identify existing practices recommended globally. SETTING: An online Delphi process was used to establish consensus recommendations based on a literature review. PATIENTS: Colorectal surgeons and gastroenterologists from across Canada who had previously demonstrated leadership in endoscopy, managed large endoscopy programs, produced high-impact publications in the field of endoscopy, or participated in the development of endoscopy guidelines were selected to participate. PRIMARY OUTCOME MEASURES: The primary outcomes measured were colorectal lesion localization and documentation practice recommendations important to planning surgical or advanced endoscopic excisions. RESULTS: A total of 129 of 197 statements achieved consensus after 3 rounds of voting by 23 experts from across Canada. There was more than 90% participation in each round. Recommendations varied according to lesion location in the cecum, colon, or rectum and whether the referral was planned for surgical or advanced endoscopic resection. Recommendations were provided for appropriate documentation, indications, location, and method of tattoo placement, in addition to photograph and real-time 3-dimensional scope configuration device use. LIMITATIONS: Because of a paucity of evidence, recommendations are based primarily on expert opinion. There may be bias, as all representatives were based in Canada. CONCLUSIONS: Best practices to optimize endoscopic lesion localization and communication are not addressed in previous guidelines. This consensus involving national experts in colorectal surgery and gastroenterology provides a framework for efficient and effective colorectal lesion localization. See Video Abstract at http://links.lww.com/DCR/C71 . RECOMENDACIONES PARA LA LOCALIZACIN ENDOSCPICA PTIMA DE LAS NEOPLASIAS COLORRECTALES UN CONSENSO DELPHI DE EXPERTOS NACIONALES: ANTECEDENTES:La colonoscopia es el estándar de atención para el diagnóstico y la evaluación de los cánceres colorrectales antes de la cirugía. Sin embargo, las prácticas variadas y la documentación heterogénea afectan la comunicación entre los endoscopistas y los cirujanos operadores, lo que dificulta la planificación quirúrgica.OBJETIVO:Este estudio tuvo como objetivo desarrollar recomendaciones para el uso de prácticas estandarizadas de localización y notificación de lesiones colorrectales identificadas en la endoscopia gastrointestinal inferior.DISEÑO:Se realizó una revisión sistemática de las pautas de endoscopia existentes y una revisión narrativa exhaustiva de la literatura general sobre endoscopia para identificar las prácticas existentes recomendadas a nivel mundial. Se utilizó un proceso Delphi en línea para establecer recomendaciones de consenso basadas en la revisión de la literatura.PARTICIPANTES:Se seleccionaron para participar cirujanos colorrectales y gastroenterólogos de todo Canadá que previamente habían demostrado liderazgo en endoscopia, manejado grandes programas de endoscopia, producido publicaciones de alto impacto en el campo de la endoscopia o que habían participado en el desarrollo de pautas de endoscopia.RESULTADOS:Localización de lesiones colorrectales y recomendaciones prácticas de documentación importantes para planificar escisiones quirúrgicas o endoscópicas avanzadas.RESULTADOS:129 de 197 declaraciones lograron consenso después de tres rondas de votación de 23 expertos de todo Canadá. Hubo >90% de participación en cada ronda. Las recomendaciones variaron según la ubicación de la lesión en el ciego, colon o recto, y si se planificó la derivación para resección quirúrgica o endoscópica avanzada. Se proporcionaron recomendaciones para la documentación adecuada, las indicaciones, la ubicación y el método de colocación del tatuaje, además de la fotografía y el uso del dispositivo de configuración del alcance 3D en tiempo real.LIMITACIONES:Debido a la escasez de evidencia, las recomendaciones se basan principalmente en la opinión de expertos. Puede haber sesgo, ya que los representantes tenían su sede en Canadá.CONCLUSIONES:Las mejores prácticas para optimizar la localización y comunicación de lesiones endoscópicas no se abordan en las guías anteriores. Este consenso que involucra a expertos nacionales en cirugía colorrectal y gastroenterología proporciona un marco para la localización eficiente y efectiva de lesiones colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/C71 . (Traducción-Dr. Mauricio Santamaria ).

Routine pathologic evaluation of circular stapler anastomotic rings is not useful after resection for colorectal cancer: retrospective study and systematic review with meta-analysis.

BACKGROUND: Circular staplers are commonly used for reconstruction after radical resection for colorectal cancer. Pathological analysis of the anastomotic rings is common practice, although the benefits are unclear. The purpose of this study was to evaluate the usefulness of routine histopathological analysis of anastomotic rings in an original series and in a systematic review of the literature. METHOD: The retrospective study was performed at two university-associated academic hospitals in Winnipeg, Canada, including patients investigated for colorectal cancers (within 30 cm of the anal verge) who underwent resection between 2007 and 2020. The systematic review involved Ovid MEDLINE, Embase, Scopus, and Web of Science databases, selecting for adult human studies involving analysis of anastomotic rings in elective colorectal cancer resections. The main outcome measure was the proportion of patients with cancer in the anastomotic ring specimens. The frequency of benign pathology findings and changes to patient management were also examined. RESULTS: Out of 673 eligible patients, 487 were included in the retrospective analysis. No patients had cancer within the anastomotic ring specimens. Twenty-five patients (5.1 per cent) had benign pathological findings within the anastomotic ring specimens, and patient management was never affected. In the systematic review, 27 articles were included in the final analysis out of 5848 records reviewed. The rate of cancer within anastomotic ring specimens was 0.34 per cent, and the rate of change in patient management was 0.19 per cent. CONCLUSION: The likelihood of finding cancer within anastomotic rings is rare and their histopathological examination seldom changes patient management.

Role of noncoding RNAs in pancreatic ductal adenocarcinoma associated cachexia.

Cachexia is an acute syndrome that is very commonly observed in patients with cancer. Cachexia is the number one cause of death in patients with metastatic disease and is also the major factor for physical toxicity and financial burden. More importantly, the majority of patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) cancer undergo cachexia. Pancreatic cancer causes deaths of ∼50,000 Americans and about 400,000 people worldwide every year. The high mortality rates in metastatic PDAC are due to systemic pathologies and cachexia, which quickens death in these patients. About 90% of all patients with PDAC undergo wasting of muscle causing mobility loss and leading to a number of additional pathological conditions. PDAC-associated cancer cachexia emanates from complex signaling cues involving both mechanical and biological signals. Tumor invasion is associated with the loss of pancreatic function-induced digestive disorders and malabsorption, which causes subsequent weight loss and eventually promotes cachexia. Besides, systemic inflammation of patients with PDAC could release chemical cues (e.g., cytokine-mediated Atrogin-1/MAFbx expression) that participate in muscle wasting. Our understanding of genes, proteins, and cytokines involved in promoting cancer cachexia has evolved considerably. However, the role of epigenetic factors, particularly the role of noncoding RNAs (ncRNAs) in regulating PDAC-associated cachexia is less studied. In this review article, the most updated knowledge on the various ncRNAs including microRNAs (miRs), long noncoding RNA (lncRNAs), piwi interacting RNAs (PiwiRNAs), small nucleolar RNA (snoRNAs), and circular RNAs (circRNA) and their roles in cancer cachexia are described.

Deregulated transcription factors and poor clinical outcomes in cancer patients.

Transcription factors are a group of proteins, which possess DNA-binding domains, bind to DNA strands of promoters or enhancers, and initiate transcription of genes with cooperation of RNA polymerase and other co-factors. They play crucial roles in regulating transcription during embryogenesis and development. Their physiological status in different cell types is also important to maintain cellular homeostasis. Therefore, any deregulation of transcription factors will lead to the development of cancer cells and tumor progression. Based on their functions in cancer cells, transcription factors could be either oncogenic or tumor suppressive. Furthermore, transcription factors have been shown to modulate cancer stem cells, epithelial-mesenchymal transition (EMT) and drug response; therefore, measuring deregulated transcription factors is hypothesized to predict treatment outcomes of patients with cancers and targeting deregulated transcription factors could be an encouraging strategy for cancer therapy. Here, we summarize the current knowledge of major deregulated transcription factors and their effects on causing poor clinical outcome of patients with cancer. The information presented here will help to predict the prognosis and drug response and to design novel drugs and therapeutic strategies for the treatment of cancers by targeting deregulated transcription factors.

Difficult diagnosis of factitious disorder.

Factitious disorder imposed on another, or medical child abuse, has been rarely reported to have primary ocular presentations. We report an unusual and difficult diagnosis of factitious disorder imposed by a mother on her infant resulting in bilateral blindness. An infant was referred with a history of recurrent periorbital cellulitis and sanguineous discharge associated with seizure-like episodes. Symptoms have been going on for more than 14 months, and child had been treated by different physicians from different specialties without a clear ophthalmic diagnosis. The right eye was previously enucleated at an outside hospital for secondary complications of similar symptoms. He was admitted for exhaustive diagnostic tests and multiple surgical treatments, and his hospital stay was complicated with multiple corneal perforations and apnoeic episodes despite optimal treatment. After suspicion of factitious disease, continuous electroencephalography and video monitoring revealed evidence of the mother inflicting physical harm to her child.

Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C-Mutant Cancers.

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. Significance: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

Preoperative stoma site marking for fecal diversions (ileostomy and colostomy): position statement of the Canadian Society of Colon and Rectal Surgeons and Nurses Specialized in Wound, Ostomy and Continence Canada.

BACKGROUND: Every year, about 13 000 Canadians undergo an ostomy procedure, which requires stoma site marking to create a well-constructed stoma and prevent stoma-related complications. The Canadian Society of Colon and Rectal Surgeons (CSCRS) and Nurses Specialized in Wound, Ostomy and Continence Canada (NSWOCC) created a position statement to provide evidence-based guidance and techniques for stoma site selection. METHODS: A task force was formed comprising 20 health care professionals (7 colorectal surgeons from the CSCRS and 13 nurses from NSWOCC) with representation from across Canada. A literature review was performed, with the following databases searched from January 2009 to April 2019: MEDLINE, Embase, Cochrane, PubMed, CINAHL and Google Scholar. After the abstracts were screened, 6 task force members created a draft version of the position statement from the articles retained after full-text review. The draft was submitted to the entire task force for comments, and the ensuing modifications were incorporated. Peer reviewers were then recruited from the CSCRS and NSWOCC; a summary of their comments was reviewed by the task force, and modifications were incorporated to produce the final document. RESULTS: The literature search identified 272 papers, of which 58 were reviewed after duplicates were excluded. After full-text review, 18 papers were included to guide the position statement. From these papers, we created a series of 17 steps for stoma site marking. Four general principles were found to be important for stoma site marking: obtain informed consent, identify important patient factors and landmarks, assess the abdomen and mark the most appropriate location. A 1-page enabler document and video were created as teaching aids and to help with dissemination of the information. CONCLUSION: This position statement, associated enabler document and video provide evidence-based guidance for stoma site marking in both emergency and elective settings, and should be used by surgeons and nurses specialized in wound, ostomy and continence to identify optimal stoma sites preoperatively.