Blood Transfusions and Adverse Events after Colorectal Surgery: A Propensity-Score-Matched Analysis of a Hen-Egg Issue

Blood transfusions are considered a risk factor for adverse outcomes after colorectal surgery. However, it is still unclear if they are the cause (the hen) or the consequence (the egg) of adverse events. A prospective database of 4529 colorectal resections gathered over a 12-month period in 76 Italian surgical units (the iCral3 study), reporting patient-, disease-, and procedure-related variables, together with 60-day adverse events, was retrospectively analyzed identifying a subgroup of 304 cases (6.7%) that received intra- and/or postoperative blood transfusions (IPBTs). The endpoints considered were overall and major morbidity (OM and MM, respectively), anastomotic leakage (AL), and mortality (M) rates. After the exclusion of 336 patients who underwent neo-adjuvant treatments, 4193 (92.6%) cases were analyzed through a 1:1 propensity score matching model including 22 covariates. Two well-balanced groups of 275 patients each were obtained: group A, presence of IPBT, and group B, absence of IPBT. Group A vs. group B showed a significantly higher risk of overall morbidity (154 (56%) vs. 84 (31%) events; OR 3.07; 95%CI 2.13-4.43; p = 0.001), major morbidity (59 (21%) vs. 13 (4.7%) events; OR 6.06; 95%CI 3.17-11.6; p = 0.001), and anastomotic leakage (31 (11.3%) vs. 8 (2.9%) events; OR 4.72; 95%CI 2.09-10.66; p = 0.0002). No significant difference was recorded between the two groups concerning the risk of mortality. The original subpopulation of 304 patients that received IPBT was further analyzed considering three variables: appropriateness of BT according to liberal transfusion thresholds, BT following any hemorrhagic and/or major adverse event, and major adverse event following BT without any previous hemorrhagic adverse event. Inappropriate BT was administered in more than a quarter of cases, without any significant influence on any endpoint. The majority of BT was administered after a hemorrhagic or a major adverse event, with significantly higher rates of MM and AL. Finally, a major adverse event followed BT in a minority (4.3%) of cases, with significantly higher MM, AL, and M rates. In conclusion, although the majority of IPBT was administered with the consequence of hemorrhage and/or major adverse events (the egg), after adjustment accounting for 22 covariates, IPBT still resulted in a definite source of a higher risk of major morbidity and anastomotic leakage rates after colorectal surgery (the hen), calling urgent attention to the implementation of patient blood management programs

Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or raltitrexed.

Despite the introduction of several novel anticancer agents almost 50% of colorectal cancer (CRC) patients die for cancer suggesting the necessity of new therapeutical approaches. In this study we demonstrated that the HDAC inhibitor vorinostat exerted potent antiproliferative effect in a panel of mut- and wt-p53 human CRC cell lines. Moreover, in combination with 5-fluorouracil modulated by folinic acid (5FU-FA) or with Raltitrexed (RTX), both commonly used in the treatment of this disease, it showed a clear schedule-dependent synergistic antiproliferative interaction as demonstrated by calculating combination indexes. Only simultaneous, or 24 h pretreatment with vorinostat followed by either agent, produced synergistic effect paralleled by evident cell cycle perturbations with major S-phase arrest. Moreover, we provided for the first time evidences that vorinostat can overcome resistance to both 5FU and RTX. Downmodulation of Thymidilate synthase (TS) protein induced by vorinostat within 24 h, represented a key factor in enhancing the effects of both drugs in sensitive as well as resistant tumor cells. Furthermore, p53, whose wild-type expression is critical for sensitivity to 5FU and RTX, was upregulated by vorinostat in wt- and downregulated in mut-p53 cells, suggesting an additional mechanism of the antiproliferative synergistic interactions observed. Overall these data add new insights in the mechanism of vorinostat antitumor effect and suggested that the association of vorinostat plus 5FU-FA and/or RTX should be clinically explored

ERAS program adherence-institutionalization, major morbidity and anastomotic leakage after elective colorectal surgery: the iCral2 multicenter prospective study

Background Enhanced recovery after surgery (ERAS) programs influence morbidity rates and length of stay after colorectal surgery (CRS), and may also impact major complications and anastomotic leakage rates. A prospective multicenter observational study to investigate the interactions between ERAS program adherence and early outcomes after elective CRS was carried out. Methods Prospective enrolment of patients submitted to elective CRS with anastomosis in 18 months. Adherence to 21 items of ERAS program was measured upon explicit criteria in every case. After univariate analysis, independent predictors of primary endpoints [major morbidity (MM) and anastomotic leakage (AL) rates] were identified through logistic regression analyses including all significant variables, presenting odds ratios (OR). Results Institutional ERAS protocol was declared by 27 out of 38 (71.0%) participating centers. Median overall adherence to ERAS program items was 71.4%. Among 3830 patients included in the study, MM and AL rates were 4.7% and 4.2%, respectively. MM rates were independently influenced by intra- and/or postoperative blood transfusions (OR 7.79, 95% CI 5.46-11.10; p < 0.0001) and standard anesthesia protocol (OR 0.68, 95% CI 0.48-0.96; p = 0.028). AL rates were independently influenced by male gender (OR 1.48, 95% CI 1.06-2.07; p = 0.021), intra- and/or postoperative blood transfusions (OR 4.29, 95% CI 2.93-6.50; p < 0.0001) and non-standard resections (OR 1.49, 95% CI 1.01-2.22; p = 0.049). Conclusions This study disclosed wide room for improvement in compliance to several ERAS program items. It failed to detect any significant association between institutionalization and/or adherence rates to ERAS program with primary endpoints. These outcomes were independently influenced by gender, intra- and postoperative blood transfusions, non-standard resections, and standard anesthesia protocol

Sequential PET/CT with [18F]-FDG Predicts Pathological Tumor Response to Preoperative Short Course Radiotherapy with Delayed Surgery in Patients with Locally Advanced Rectal Cancer Using Logistic Regression Analysis.

UNLABELLED: Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone. METHODS: Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS. RESULTS: We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies. CONCLUSIONS: This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence

High adherence to enhanced recovery pathway independently reduces major morbidity and mortality rates after colorectal surgery: a reappraisal of the iCral2 and iCral3 multicenter prospective studies

Background: Enhanced recovery after surgery (ERAS) offers lower overall morbidity rates and shorter hospital stay after colorectal surgery (CRS); high adherence rates to ERAS may significantly reduce major morbidity (MM), anastomotic leakage (AL), and mortality (M) rates as well. Methods: Prospective enrollment of patients submitted to elective CRS with anastomosis in two separate 18- and 12-month periods among 78 surgical centers in Italy from 2019 to 2021. Adherence to ERAS pathway items was measured upon explicit criteria in every case. After univariate analysis, independent predictors of primary endpoints (MM, AL, and M rates) were identified through logistic regression analyses, presenting odds ratios (OR) and 95% confidence intervals. Results: An institutional ERAS status was declared by 48 out of 78 (61.5%) participating centers. The median overall adherence to ERAS was 75%. Among 8,359 patients included in both studies, MM, AL, and M rates were 6.3%, 4.4%, and 1.0%, respectively. Several patient-related and treatment-related variables showed independently higher rates for primary endpoints: male gender, American Society of Anesthesiologists class III, neoadjuvant treatment, perioperative steroids, intra- and/or postoperative blood transfusions, length of the operation >180’, surgery for malignancy. On the other hand, ERAS adherence >85% independently reduced MM (OR, 0.91) and M (OR, 0.25) rates, whereas no mechanical bowel preparation independently reduced AL (OR, 0.68) rates. Conclusions: Among other patient- or treatment-related variables, ERAS adherence >85% independently reduced MM and M rates, whereas no mechanical bowel preparation independently reduced AL rates after CRS

New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer

he chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial

The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection

Survival analysis of a multicentre, randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in patients with metastatic colorectal cancer (mCRC)

n/