An Overview of the Pharmacokinetics and Pharmacodynamics of Landiolol (an Ultra-Short Acting ß1 Selective Antagonist) in Atrial Fibrillation.

Landiolol is an ultra-short-acting, selective ß1-adrenergic receptor blocker that was originally approved in Japan for the treatment of intraoperative tachyarrhythmias. It has gained attention for its use in the management of tachyarrhythmias and perioperative tachycardia, especially atrial fibrillation for both cardiac and non-cardiac surgeries. It can be the ideal agent for heart rate control due to its high ß1-selectivity, potent negative chronotropic effect, a limited negative inotropic potential, and an ultrashort elimination half-life (around 4 min); moreover, it may have a potential therapeutic effects for sepsis and pediatric patients. Landiolol seems to be superior to other short-acting and selective beta-blockers such as esmolol. This review aims to provide a comprehensive overview of landiolol, a new ultra-short-acting ß1 selective antagonist, including its pharmacology, clinical applications, efficacy, safety profile, and future directions in research and clinical data.

Machine Learning-Based Algorithms for Enhanced Prediction of Local Recurrence and Metastasis in Low Rectal Adenocarcinoma Using Imaging, Surgical, and Pathological Data.

(1) Background: Numerous variables could influence the risk of rectal cancer recurrence or metastasis, and machine learning (ML)-based algorithms can help us refine the risk stratification process of these patients and choose the best therapeutic approach. The aim of this study was to assess the predictive performance of 4 ML-based models for the prediction of local recurrence or distant metastasis in patients with locally advanced low rectal adenocarcinomas who underwent neoadjuvant chemoradiotherapy and surgical treatment; (2) Methods: Patients who were admitted at the first Oncologic Surgical Clinic from the Regional Institute of Oncology, Iasi, Romania were retrospectively included in this study between November 2019 and July 2023. Decision tree (DT), naïve Bayes (NB), support vector machine (SVM), and random forest (RF) were used to analyze imagistic, surgical, and pathological data retrieved from the medical files, and their predictive performance was assessed; (3) Results: The best predictive performance was achieved by RF when used to predict disease recurrence (accuracy: 90.85%) or distant metastasis (accuracy: 89.63%). RF was closely followed by SVM (accuracy for recurrence 87.8%; accuracy for metastasis: 87.2%) in terms of predictive performance. NB and DT achieved moderate predictive power for the evaluated outcomes; (4) Conclusions: Complex algorithms such as RF and SVM could be useful for improving the prediction of adverse oncological outcomes in patients with low rectal adenocarcinoma.

Multimodality Imaging in Right Heart Tumors: Proposed Algorithm towards an Appropriate Diagnosis.

A right heart tumor can be identified by transthoracic echocardiography during a routine examination or due to cardiac symptoms. The first step is the assessment by echocardiography, with its multiple techniques, and the obtained information must be judged in a clinical and biological context. The second step comprises one, sometimes even two, of the more complex modality imaging methods. The choice is driven not only by the advantages of each imaging technique but also by local expertise or the preferred imaging modality in the center. This step is followed by staging, follow-up, and/or imaging-guided excision or biopsy, which is performed in selected cases in order to obtain anatomopathological confirmation. In the presence of features suggestive of malignancy or causing hemodynamic impairment, a transvenous biopsy is essential before the more complex imaging modalities (which are still relevant in the staging process). Using a structured imaging approach, it is possible to reach an appropriate diagnosis without a biopsy. Frequently, these imaging techniques have a complementary role, so an integrated imaging approach is recommended. This proposed algorithm for appropriate diagnosis of right heart tumors could serve as a practical guide for clinicians (not only imaging specialists).

Predicting the Feasibility of Curative Resection in Low Rectal Cancer: Insights from a Prospective Observational Study on Preoperative Magnetic Resonance Imaging Accuracy.

Background and Objectives: A positive pathological circumferential resection margin is a key prognostic factor in rectal cancer surgery. The point of this prospective study was to see how well different MRI parameters could predict a positive pathological circumferential resection margin (pCRM) in people who had been diagnosed with rectal adenocarcinoma, either on their own or when used together. Materials and Methods: Between November 2019 and February 2023, a total of 112 patients were enrolled in this prospective study and followed up for a 36-month period. MRI predictors such as circumferential resection margin (mCRM), presence of extramural venous invasion (mrEMVI), tumor location, and the distance between the tumor and anal verge, taken individually or combined, were evaluated with univariate and sensitivity analyses. Survival estimates in relation to a pCRM status were also determined using Kaplan-Meier analysis. Results: When individually evaluated, the best MRI predictor for the detection of a pCRM in the postsurgical histopathological examination is mrEMVI, which achieved a sensitivity (Se) of 77.78%, a specificity (Sp) of 87.38%, a negative predictive value (NPV) of 97.83%, and an accuracy of 86.61%. Also, the best predictive performance was achieved by a model that comprised all MRI predictors (mCRM+ mrEMVI+ anterior location+ < 4 cm from the anal verge), with an Se of 66.67%, an Sp of 88.46%, an NPV of 96.84%, and an accuracy of 86.73%. The survival rates were significantly higher in the pCRM-negative group (p < 0.001). Conclusions: The use of selective individual imaging predictors or combined models could be useful for the prediction of positive pCRM and risk stratification for local recurrence or distant metastasis.

Can the ADC Value Be Used as an Imaging "Biopsy" in Endometrial Cancer?

BACKGROUND: The tumor histological grade is closely related to the prognosis of patients with endometrial cancer (EC). Multiparametric MRI, including diffusion-weighted imaging (DWI), provides information about the cellular density that may be useful to differentiate between benign and malignant uterine lesions. However, correlations between apparent diffusion coefficient (ADC) values and histopathological grading in endometrial cancer remain controversial. MATERIAL AND METHODS: We retrospectively evaluated 92 patients with endometrial cancers, including both endometrioid adenocarcinomas (64) and non-endometrioid adenocarcinomas (28). All patients underwent DWI procedures, and mean ADC values were calculated in a region of interest. These values were then correlated with the tumor grading offered by the histopathological examination, which was considered the gold standard. In this way, the patients were divided into three groups (G1, G2, and G3). The ADC values were then compared to the results offered by the biopsy to see if the DWI sequence and ADC map could replace this procedure. We also compared the mean ADC values to the myometrial invasion (50%) and lymphovascular space invasion. RESULTS: We have divided the ADC values into three categories corresponding to three grades: >0.850 × 10-3 mm2/s (ADC1), 0.730-0.849 × 10-3 mm2/s (ADC2) and <0.730 × 10-3 mm2/s (ADC3). The diagnostic accuracy of the ADC value was 85.71% for ADC1, 75.76% for ADC2, and 91.66% for ADC3. In 77 cases out of 92, the category in which they were placed using the ADC value corresponded to the result offered by the histopathological exam with an accuracy of 83.69%. For only 56.52% of patients, the biopsy result included the grading system. For each grading category, the mean ADC value showed better results than the biopsy; for G1 patients, the mean ADC value had an accuracy of 85.71% compared to 66.66% in the biopsy, G2 had 75.76% compared to 68.42%, and G3 had 91.66 compared to 75%. For both deep myometrial invasion and lymphovascular space invasion, there is a close, inversely proportional correlation with the mean ADC value. CONCLUSIONS: Mean endometrial tumor ADC on MR-DWI is inversely related to the histological grade, deep myometrial invasion and lymphovascular space invasion. Using this method, the patients could be better divided into risk categories for personalized treatment.

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

The Applicability of Artificial Intelligence in Predicting the Depth of Myometrial Invasion on MRI Studies-A Systematic Review.

(1) Objective: Artificial intelligence (AI) has become an important tool in medicine in diagnosis, prognosis, and treatment evaluation, and its role will increase over time, along with the improvement and validation of AI models. We evaluated the applicability of AI in predicting the depth of myometrial invasion in MRI studies in women with endometrial cancer. (2) Methods: A systematic search was conducted in PubMed, SCOPUS, Embase, and clinicaltrials.gov databases for research papers from inception to May 2023. As keywords, we used: "endometrial cancer artificial intelligence", "endometrial cancer AI", "endometrial cancer MRI artificial intelligence", "endometrial cancer machine learning", and "endometrial cancer machine learning MRI". We excluded studies that did not evaluate myometrial invasion. (3) Results: Of 1651 screened records, eight were eligible. The size of the dataset was between 50 and 530 participants among the studies. We evaluated the models by accuracy scores, area under the curve, and sensitivity/specificity. A quantitative analysis was not appropriate for this study due to the high heterogeneity among studies. (4) Conclusions: High accuracy, sensitivity, and specificity rates were obtained among studies using different AI systems. Overall, the existing studies suggest that they have the potential to improve the accuracy and efficiency of the myometrial invasion evaluation of MRI images in endometrial cancer patients.

Breast Sarcomas-How Different Are They from Breast Carcinomas? Clinical, Pathological, Imaging and Treatment Insights.

Breast sarcoma (BS) is a very rare and poorly studied condition. This has led to a lack of studies with a high level of evidence and to low efficacy of current clinical management protocols. Here we present our experience in treating this disease in the form of a retrospective case series study including discussion of clinical, imaging, and pathological features and treatment. We also compare the main clinical and biological features of six cases of BS (phyllodes tumors were excluded) with a cohort of 184 patients with unilateral breast carcinoma (BC) from a previous study performed at our institution. Patients with BS were diagnosed at a younger age, presented no evidence of lymph node invasion or distant metastases, had no multiple or bilateral lesions, and underwent a shorter length of hospital stay versus the breast carcinoma group. Where recommended, adjuvant chemotherapy consisted of an anthracycline-containing regimen, and adjuvant external radiotherapy was delivered in doses of 50 Gy. The comparison data obtained from our BS cases and the ones with BC revealed differences in diagnosis and treatment. A correct pathological diagnosis of breast sarcoma is essential for the right therapeutic approach. We still have more to learn about this entity, but our case series could add value to existing knowledge in a meta-analysis study.

Mesenchymal Stem Cell-Derived Exosomes Modulate Angiogenesis in Gastric Cancer.

Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant changes in chronic gastritis. The successful use of transplanted mesenchymal stem cells (MSCs) for gastric ulcer healing has raised interest in studying their effects on tumor neovascularization and in potential antiangiogenic therapies that could use mesenchymal stem cell secretion into extracellular vesicles-such as exosomes-in GC cells. The use of MSCs isolated from bone marrow in order to achieve angiogenic modulation in the tumor microenvironment could exploit the inherent migration of MSCs into GC tissues. Bone marrow-derived MSCs naturally present in the stomach have been reported to carry a malignancy risk, but their effect in GC is still being researched. The pro- and antiangiogenic effects of MSCs derived from various sources complement their role in immune regulation and tissue regeneration and provide further understanding into the heterogeneous biology of GC, the aberrant morphology of tumor vasculature and the mechanisms of resistance to antiangiogenic drugs.

Robotic-Assisted Pelvic Surgery: Early Outcomes in a Single Institution.

Introduction: This article reports the authors' experience with their first 50 consecutive robotic pelvic procedures, aiming to determine the feasibility and safety of adopting robotic pelvic surgery. Robotic surgery offers several benefits for minimally invasive surgery, but its applicability is hindered by cost and limited regional experience. This study aimed to evaluate the feasibility and safety of robotic pelvic surgery. Material and Methods: This is a retrospective review of our initial experience with robotic surgery for colorectal, prostate, and gynaecologic neoplasia, between June and December 2022. The surgical outcomes were evaluated in terms of perioperative data, such as operative time, estimated blood loss, and length of hospital stay. Intraoperative complications were recorded, and postoperative complications were evaluated at 30 days and 60 days after surgery. The feasibility of the roboticassisted surgery was assessed by measuring the conversion rate to laparotomy. The safety of the surgery was evaluated by recording the incidence of intraoperative and postoperative complications. Results: Fifty robotic surgeries were performed over 6 months, including 21 interventions for digestive neoplasia, 14 gynaecologic cases, and 15 prostatic cancers. Operative time ranged from 90 to 420 minutes, with two minor complications and two grade II Clavien-Dindo complications. One patient required prolonged hospitalization and an end-colostomy, deriving from an anastomotic leakage requiring reintervention. No thirty-day mortality or readmissions were reported. Conclusion: The study found that robotic-assisted pelvic surgery is safe and has a low rate of transfer to open surgery, making it a suitable addition to conventional laparoscopy.

Outcomes Following Surgery for Locally Advanced Pancreatic Cancer - Single Center Experience. A Retrospective Study.

Background: Pancreatic cancer represents one of the most frequent cancers with an increased incidence. Most cases on initial diagnosis are considered to be locally advanced and surgery remains the most important therapeutic option. The aim of this study was to evaluate postoperative morbidity that can impair the association of adjuvant therapy. Methods: We performed a retrospective study on a prospective database that includes all the patients diagnosed with pancreatic cancer in which surgery was performed between 2012 and 2021. We divided the patients in advanced tumours and localized tumours and we compared the outcomes after surgery. Results: On 58 patients with pancreatic tumours surgery was performed: 28(48.3%) pancreaticoduodenectomies and 30 (51.7%) distal pancreatectomies. Localized tumours (T1 and T2) were encountered in 32 patients (55.2%) and more advanced tumours (T3 and T4) were present in 26 cases (44.8%). Although there was no significant difference either for major complications, we observed a tendency for patients with advanced tumours to develop a major complication (15.6% vs 34.6%, p=0.09). The occurrence of major complication, such as pancreatic fistula and postoperative hemorrhage, there was no significant difference (6.25% vs 7.69% and 6.25% vs. 23.1%). On multivariate analysis of preoperative factors associated with the occurrence of a severe complication only the CA19-9 levels were associated with an increased risk (odds ratio 0.666, 95% CI 0.5-1.01; p= 0.04) Conclusions: This study showed no significant differences in terms of postoperative complications between the two subgroups. CA 19-9 is an accurate biomarker for the prediction of postoperative complications.

The Prediction of Peritoneal Carcinomatosis in Patients with Colorectal Cancer Using Machine Learning.

The incidence of colon, rectal, and colorectal cancer is very high, and diagnosis is often made in the advanced stages of the disease. In cases where peritoneal carcinomatosis is limited, patients can benefit from newer treatment options if the disease is promptly identified, and they are referred to specialized centers. Therefore, an essential diagnostic benefit would be identifying those factors that could lead to early diagnosis. A retrospective study was performed using patient data gathered from 2010 to 2020. The collected data were represented by routine blood tests subjected to stringent inclusion and exclusion criteria. In order to determine the presence or absence of peritoneal carcinomatosis in colorectal cancer patients, three types of machine learning approaches were applied: a neuro-evolutive methodology based on artificial neural network (ANN), support vector machines (SVM), and random forests (RF), all combined with differential evolution (DE). The optimizer (DE in our case) determined the internal and structural parameters that defined the ANN, SVM, and RF in their optimal form. The RF strategy obtained the best accuracy in the testing phase (0.75). Using this RF model, a sensitivity analysis was applied to determine the influence of each parameter on the presence or absence of peritoneal carcinomatosis.

Evaluation of Immediate Inflammatory Response in Thoracoscopic Esophageal Resection versus Open Approach - A Prospective Study.

Introduction: There is an immune response after major surgery and inflammatory complications following complex surgery have a direct impact on morbidity and mortality. Currently, we do not have clinical tools to predict in which subset of patients a major complication will occur. The aim of this study was to evaluate the immediate dynamics of C-reactive protein (CRP), presepsin and procalcitonin in patients in which esophagectomy was performed either through video assisted thoracic surgery (VATS) or open approach. Methods: We conducted a prospective study on 27 patients with a mean age of 61.48 +-6.80 years, 13 patients with VATS and 14 with open approach, most of the patients were on stage III esophageal cancer (81%) and in all cases neoadjuvant treatment was performed. Results: There were increased levels of CRP, presepsin and procalcitonin after both arms of the study with significantly higher values for the open approach and with the same dynamic curves. In 3 cases there were extremely elevated levels of procalcitonin in the absence of a septic complication, in all cases a major complication occurred. Conclusion: Video assisted thoracoscopic esophageal mobilization induces a less immune response, even with the association of laparotomy. An elevated postoperative procalcitonin level can be an early indicator of a major postoperative complication.

Diagnosis of Peritoneal Carcinomatosis of Colorectal Origin Based on an Innovative Fuzzy Logic Approach.

Colorectal cancer represents one of the most important causes worldwide of cancer related morbidity and mortality. One of the complications which can occur during cancer progression, is peritoneal carcinomatosis. In the majority of cases, it is diagnosed in late stages due to the lack of diagnostic tools capable of revealing the early-stage peritoneal burden. Therefore, still associates with poor prognosis and quality of life, despite recent therapeutic advances. The aim of the study was to develop a fuzzy logic approach to assess the probability of peritoneal carcinomatosis presence using routine blood test parameters as input data. The patient data was acquired retrospective from patients diagnosed between 2010-2021. The developed model focuses on the specific quantitative alteration of these parameters in the presence of peritoneal carcinomatosis, which is an innovative approach as regards the literature in the field and validates the feasibility of using a fuzzy logic approach in the noninvasive diagnosis of peritoneal carcinomatosis.

Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.

Rare Case of Smooth Muscle Tumor of Uncertain Malignant Potential - Clinical Case.

Introduction: Smooth muscle tumor of uncertain malignant potential (STUMP) still represents a medical and surgical challenge, being rare and hard to diagnose. Normally STUMP consists in a multitude of uterine tumors that do not meet the current histologic criteria for a specific malignant or benign tumor. Clinical, imagistic and laboratory investigations seem to only raise the presumptive diagnosis in these cases, the diagnosis being confirmed during histological examination of the post hysterectomy/myomectomy specimen. Case report: We present the case of a 50-year-old female patient who was examined for the first time for pelvic pain and sensation of increased pressure in the lower abdomen in June 2020. A gynecology consultation was performed, during which a large uterine mass was felt on vaginal digital examination combined with pelvic palpation. Further pelvic ultrasound examination revealed a voluminous tumor of the left ovary. Then, a magnetic resonance imaging was performed, which showed a large pelvi-abdominal tumor of probable ovarian origin with a mixt tissue type and cystic structure, the presence of pathological abdominal and pelvic lymph nodes, ascites with a suspicion of peritoneal carcinomatosis. The patient was referred to a tertiary center and the multidisciplinary team recommended surgical treatment. A total hysterectomy with bilateral oophorectomy and stadial lymphadenectomy was performed. After surgery, the patient had a favorable evolution and was discharged five days after the intervention in a good health condition. Macroscopic and histological examinations of the biopsy pieces showed morphological aspects of uterine smooth muscles tumors with uncertain malignancy potential/STUMP and multiple uterine leiomyomas. Discussion:Due to the rarity of these tumors, the scientific literature needs to be constantly updated in order to help physicians to correctly identify and treat this pathology. It is highly recommended to identify tumors with a high malignancy potential, so that the follow up will be sufficient to discover and treat recurrences before they become life-threatening. Conclusion:Smooth muscle tumor of uncertain malignant potential remains a difficult diagnosis due to uncertainty between malignancy and benign features. Treatment approaches are difficult in these cases and must always be in accordance with the patients' desire to maintain their reproductive functions and fertility. Recurrence of STUMP has been reported, therefore a close follow up of these patients must always be performed.

Evaluation of circulating tumor cells in colorectal cancer using flow cytometry.

OBJECTIVE: We aimed to evaluate the prognostic value of circulating tumor cells (CTCs) and the impact of intraoperative tumor manipulation on CTCs in colorectal cancer (CRC) patients. METHODS: We performed a prospective study on 40 patients with CRC stages I to IV who received curative surgery using the no-touch technique. Flow cytometry was used to identify CTCs in peripheral blood samples (4 mL/sample) collected at two surgical moments: skin incision (T1) and after surgical resection (T2). A threshold of ≥4 CTCs/4 mL blood was established for considering patients CTC positive. RESULTS: In the univariate analysis, CTC evaluation at T2 was correlated with female sex, vascular invasion, tumor localization in the colon and metastatic lymph nodes. In the multivariate analysis, only female sex and colon cancer maintained statistical significance. At a medium follow-up of 15 months (1-25 months), the mortality rate was 10% (n = 4), with no significant differences between the overall survival of T1 or T2 CTC-positive and CTC-negative patients. CONCLUSIONS: Flow cytometry is a feasible CTC identification technique in CRC, and although surgical manipulation has no influence on CTC numbers, CTCs may serve as a prognostic and predictive factor.

Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy.

BACKGROUND: Multiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive. METHODS: This study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining. RESULTS: Front-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity. CONCLUSIONS: Our results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.

Colorectal Surgery in Romania during the COVID-19 Pandemic.

As the COVID-19 pandemic extends, its negative consequences on the effectiveness of therapeutic programs - previously assumed by the medical community and imperatively suspended for a difficult-to-predict period of time - are becoming increasingly worrying. In this context, as the evidence-based recommendations are not possible, most of the national and international scientific societies tried to develop balanced recommendations (1-4). The Romanian Society of Coloproctology (SRCP) and the Romanian Association for Endoscopic Surgery (ARCE) have created a working group that, taking into account recent publications, the statements of international academic societies, the national legislative context and the unique experience of countries severely affected by this pandemic (China, Italy, Spain, USA, etc.) proposes for Romania, the following recommendations for medical practice in colorectal surgery during the COVID-19 pandemic. These recommendations are subjected to continuous review, depending on the global and national situation of the pandemic, the particular needs of each hospital, the recommendations of the competent authorities and the evolution of the literature that publishes the conclusions of ongoing clinical trials.

Clinical, histopathological and immunohistochemical features of brain metastases originating in colorectal cancer: a series of 27 consecutive cases.

INTRODUCTION: Brain metastases (BMs) originating in colorectal cancer (CRC) have a significant importance for patients' survival. Because in literature there are only isolated case reports and only few series published on this issue, we aimed to assess the incidence of BMs from CRC, to identify patient's characteristics and BMs clinical, histopathological (HP) and immunohistochemical (IHC) features, and to compare the data we obtained with those from literature. PATIENTS, MATERIALS AND METHODS: We present a retrospective study of 27 histologically confirmed cases of BMs from CRC among all 1040 patients who received metastasectomy in the Department of Neurosurgery, Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania, in an eight-year period (January 2011 to December 2018). Patients' characteristics (gender, age), primary tumor location, time from primary tumor surgery to BMs surgery and BMs features (number, location and HP characteristics) were investigated. Histochemical [Alcian Blue (AB) and Periodic Acid-Schiff (PAS)] staining and IHC stainings for cytokeratin (CK) 7, CK20, caudal-type homeobox 2 (CDX2) and human epidermal growth factor receptor 2 (HER2)∕neu were performed on all available BMs specimens. RESULTS: There were 27 consecutive patients with BMs from CRC, corresponding to 2.59% of all patients with BMs during the eight-year period we have studied, most of them being diagnosed and treated in 2016. Male:female ratio was 1.45. The mean age for all patients at diagnosis of the BMs was 62.25 years (range: 40-79 years). The origin of the primary cancer was mainly the colon (62.96% of all cases). Of all 27 patients, only two (7.4%) presented neurological symptoms without a diagnosis of CRC. BMs were identified in a period ranging from six months to 70 months after the initial diagnosis. The average time between diagnosis of the primary tumor and of the BMs was 25.92 months. At the moment of the diagnosis of BMs, 17 (62.96%) patients also had other systemic metastases. Most of the cases (55.55%) were situated in the supratentorial compartment. IHC stainings were negative for CK7 and positive for CK20 and CDX2 in all BMs from colonic adenocarcinomas (ADCs), a profile consistent with a non-neuronal and gastric origin. AB and PAS stainings revealed pools of extracellular mucin, especially in cases of mucinous ADC. Ki67 labeling index ranged between 90% and 100%. IHC staining with anti-HER2∕neu antibody showed in 25 (96.15%) cases a strong and diffuse aberrant nuclear staining. CONCLUSIONS: BMs originating in CRC represent a rare pathology and have particular clinical and IHC features that could vary from one series to another series. In a few cases, BMs may be diagnosed in the absence of a known CRC diagnosis and in these situations, the correct diagnosis is of interest. However, a panel of antibodies can help in establishing a correct diagnosis. Our study was among the first to analyze the HER2∕neu expression pattern in BMs from CRC and we found a strong aberrant nuclear expression of this molecular marker on IHC investigation. Related to the data published so far in the literature, it is possible that HER2∕neu aberrant expression in the tumor nuclei of the BMs from our series may express the metastatic tumor cell phenotype that was previously subjected to cytostatics and radiation therapies. As such, we suggest that HER2∕neu aberrant expression in BMs originating in CRC could represent a proof for the worst prognosis of these patients.