A comprehensive evaluation of 80 consecutive robotic low anterior resections: impact of not mobilizing the splenic flexure alongside low-tie vascular ligation as a standardized technique.

Rectal cancer surgery represents challenges due to its location. To overcome them and minimize the risk of anastomosis-related complications, some technical maneuvers or even a diverting ileostomy may be required. One of these technical steps is the mobilization of the splenic flexure (SFM), especially in medium/low rectal cancer. High-tie vascular ligation may be another one. However, the need of these maneuvers may be controversial, as especially SFM may be time-consuming and increase the risk of iatrogenic. The objective is to present the short- and long-term outcomes of a low-tie ligation combined with no SFM in robotic low anterior resection (LAR) for mid- and low rectal cancer as a standardized technique. A retrospective observational single-cohort study was carried out at Reina Sofia University Hospital, Cordoba, Spain. 221 robotic rectal resections between Jul-18th-2018 and Jan-12th-2023 were initially considered. After case selection, 80 consecutive robotic LAR performed by a single surgeon were included. STROBE checklist assessed the methodological quality. Histopathological, morbidity and oncological outcomes were assessed. Anastomotic stricture occurrence and distance to anal verge were evaluated after LAR by rectosigmoidoscopy. Variables related to the ileostomy closure such as time to closure, post-operative complications or hospital stay were also considered. The majority of patients (81.2%) presented a mid-rectal cancer and the rest, lower location (18.8%). All patients had adequate perfusion of the anastomotic stump assessed by indocyanine green. Complete total mesorectal excision was performed in 98.8% of the patients with a lymph node ratio < 0.2 in 91.3%. The anastomotic leakage rate was 5%. One patient (1.5%) presented local recurrence. Anastomosis stricture occurred in 7.5% of the patients. The limitations were small cohort and retrospective design. The non-mobilization of the splenic flexure with a low-tie ligation in robotic LAR is a feasible and safe procedure that does not affect oncological outcomes.

Transition from laparoscopic to robotic approach in rectal cancer: a single-center short-term analysis based on the learning curve.

As a novel procedure becomes more and more used, knowledge about its learning curve and its impact on outcomes is useful for future implementations. Our aim is (i) to identify the phases of the robotic rectal surgery learning process and assess the safety and oncological outcomes during that period, (ii) to compare the robotic rectal surgery learning phases outcomes with laparoscopic rectal resections performed before the implementation of the robotic surgery program. We performed a retrospective study, based on a prospectively maintained database, with methodological quality assessment by STROBE checklist. All the procedures were performed by the same two surgeons. A total of 157 robotic rectal resections from June 2018 to January 2022 and 97 laparoscopic rectal resections from January 2018 to July 2019 were included. The learning phase was completed at case 26 for surgeon A, 36 for surgeon B, and 60 for the center (both A & B). There were no differences in histopathological results or postoperative complications between phases, achieving the same ratio of mesorectal quality, circumferential and distal resection margins as the laparoscopic approach. A transitory increase of major complications and anastomotic leakage could occur once overcoming the learning phase, secondary to the progressive complexity of cases. Robotic rectal cancer surgery learning curve phases in experienced laparoscopic surgeons was completed after 25-35 cases. Implementation of a robotic rectal surgery program is safe in oncologic terms, morbidity, mortality and length of stay.

Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer: A Phase 3 Randomized Clinical Trial.

Importance: Peritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. Objective: To assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0). Interventions: Patients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex. Main Outcomes and Measures: The primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects. Results: A total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio [HR], 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed. Conclusions and Relevance: In this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02614534.

A Proposal for Modification of the PSOGI Classification According to the Ki-67 Proliferation Index in Pseudomyxoma Peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignancy, classified according to the Peritoneal Surface Oncology Group International (PSOGI) classification, whose response to treatment remains highly heterogeneous within the high-grade (HG) category. Molecular profiling of PMP cases might help to better categorize patients and predict treatment responses. METHODS: We studied the Ki-67 proliferation rate and P53 overexpression in tissue samples from our historical cohort of HG-PMP patients. We established as cut-off levels the third quartile of each marker to perform univariate and multivariate Cox regression survival analyses. According to these results, the HG-PMP category was divided into subcategories and a new survival analysis was performed. RESULTS: A total of 90/117 patients with PMP undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) were selected for secondary analysis. The survival analysis of the HG-PMP category for preoperative variables showed that a proliferation index defined by Ki-67 >15% is a bad prognostic factor, with a hazard ratio (HR) of 3.20 (95% confidence interval [CI] 1.24-8.25). Accordingly, the HG-PMP group was divided using the Ki-67 15% cut-off. The new PSOGI/Ki-67 variable was an independent prognostic factor for overall survival (OS), with an HR of 3.74 (95% CI 1.88-7.47), and disease-free survival (DFS), with an HR of 4.184 (95% CI 1.79-9.75). The estimated 5-year OS rate was 100%, 70% and 24% for the LG-PMP, HG-PMP ≤15% and HG-PMP >15% groups, respectively (p = 0.0001), while the 5-year DFS rate was 90%, 44% and 0%, respectively (p = 0.0001). CONCLUSION: Division of the HG-PMP category of the PSOGI classification, according to the Ki-67 proliferation index, provides two well-defined subcategories, with significant differences in terms of OS and DFS, and hence high prognostic value.

From the Ronnett to the PSOGI Classification System for Pseudomyxoma Peritonei: A Validation Study.

BACKGROUND: Several classifications have been used for pseudomyxoma peritonei (PMP), and among these, the Ronnett classification is the most commonly used. However, a new consensual Peritoneal Surface Oncology Group International (PSOGI) classification has recently been proposed. Nonetheless, to date, the ability of the PSOGI classification to predict survival based on its different disease histologic categories has not been validated. METHODS: This study enrolled 117 patients with PMP who had undergone cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) between 1997 and 2020. Cox proportional hazards regression models and time-dependent curve receiver operating characteristic (ROC) analyses were used to assess the predictive capacity of both classification systems for the overall survival (OS) and disease-free survival (DFS) of these patients. RESULTS: Significant differences in the 5-year OS rate were found for the different histologic grades according to each of the classifications. The completeness of cytoreduction score (CCS) was identified as a factor that predicted patient OS prognosis (p = 0.006). According to the time-dependent ROC curves at the "100" time point, adjusted by the CCS and DFS, the capacity to predict OS was optimal and achieved an area under the curve (AUC) of about 69% for OS and approximately 62% for DFS. CONCLUSIONS: Both the Ronnett and PSOGI classifications were able to predict survival optimally for this patient cohort. However, when the classifications were adjusted by the CCS, the predictive availability for OS was better with the PSOGI classification than with the Ronnett classification.

Rituximab levels are associated with the B cell homeostasis but not with the clinical response in patients with rheumatoid arthritis.

OBJECTIVE: To study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis. METHODS: Thirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements. RESULTS: RTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment. CONCLUSION: Our findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months.

Impact of barium enema on acute diverticulitis recurrence: A retrospective cohort study of 349 patients.

OBJECTIVE: Acute diverticulitis (AD) is becoming a health concern with its increasing incidence. One of the accepted theories of the possible causes of diverticular perforation is the impaction of fecal residuals into some diverticula. We aimed to evaluate whether barium impaction had a negative effect by promoting diverticular inflammation or rupture and thereby AD recurrence. METHODS: A retrospective cohort study (January 2005-December 2015) was conducted at the Reina Sofia University Hospital of Cordoba, Spain with follow-up for patients received barium enema or not after their first episode of AD. Factors related to disease recurrence and its severity were analyzed. RESULTS: In total, 349 patients were included and subdivided into the barium enema group (n = 141) and control group (n = 208), respectively. In the studied cohort, 72 (20.6%) patients suffered recurrence of AD, which was almost twice as frequent in the barium enema group than in the control group (27.7% vs 15.9%, P = 0.008). Patients who had undergone barium enema were more likely to present a higher Hinchey grade at recurrence than that observed in the index presentation (30.8% vs 9.1%, P = 0.024). Age <50 years, female sex, absence of treatment with rifaximin and especially barium enema, showed a trend to a higher probability of AD recurrence over time. However, no statistically significant differences were found. CONCLUSIONS: We failed to conclude that barium enema increased AD recurrence. Patients undergo barium enema are more likely to show a higher Hinchey grade at recurrence than that observed in their index presentation.

Adalimumab regulates intracellular TNFα production in patients with rheumatoid arthritis.

INTRODUCTION: Adalimumab is a fully human anti-tumor necrosis factor α (anti-TNFα) monoclonal antibody that specifically blocks the interaction of TNFα with its receptors. It binds both soluble and transmembrane TNFα. We hypothesized that blocking these TNFα signals regulates the altered TNFα production in rheumatoid arthritis (RA) patients. METHODS: We compared, by flow cytometry, Toll-like receptor induction levels of membrane and intracellular TNFα in monocytes (iTNFα + CD14+ cells) from 12 patients before and after adalimumab treatment with those from 5 healthy donors. RESULTS: Before starting the treatment, the percentage of iTNFα+ CD14+ cells in the RA patients was significantly lower than that in healthy donors (mean ± SEM = 33.16 ± 4.82% vs 66.51 ± 2.4%, P < 0.001). When we added in vitro TNFα to healthy donor culture cells, levels of iTNFα+ CD14+ cells decreased, suggesting that the TNFα signal was responsible for the iTNFα+ CD14+ cell downregulation observed in the RA patients. After 2, 6 and 12 adalimumab injections, we observed significant blocking of membrane and soluble TNFα and a progressive increase in iTNFα+ CD14+ cells in ten patients with a good to moderate response as defined by the European League Against Rheumatism (EULAR) criteria. Levels of iTNFα+ CD14+ cells after 12 injections in these 10 patients were comparable to levels in healthy donors. In two patients, iTNFα+ CD14+ cell upregulation was not observed, and their EULAR-defined responses had not improved. The first patient developed antiadalimumab antibodies, explaining why adalimumab was not able to block membrane and soluble TNFα. In the second patient, adalimumab was discontinued because of adverse effects, which led to a decrease in iTNFα+ CD14+ cells to levels measured before treatment. CONCLUSIONS: Our findings suggest that adalimumab treatment in RA patients can return iTNFα levels to those of healthy donors. This effect was not observed in the presence of neutralizing antiadalimumab antibodies.

Rituximab-induced interleukin-15 reduction associated with clinical improvement in rheumatoid arthritis.

Rituximab therapy alters all aspects of B-cell participation in the disturbed immune response of rheumatoid arthritis patients. To determine the impact of B-cell depletion on other immune compartments, we analysed levels of soluble and surface interleukin-15 (IL-15) along with the frequency of IL-15-related subsets after rituximab treatment. We then studied the correlation of observed changes with clinical activity. Heparinized blood samples from 33 rheumatoid arthritis patients were collected on days 0, 30, 90 and 180 after each of three rituximab cycles. Serum cytokine levels were determined by ELISA. Interleukin-15 trans-presentation was analysed by cytometry. Flow cytometry with monoclonal antibodies was performed to analyse circulating cell subsets. Interleukin-15 was detected in the serum of 25 patients before initiating the treatment. Rituximab then progressively reduced serum IL-15 (138 ± 21 pg/ml at baseline, 48 ± 18 pg/ml after third cycle, P = 0·03) along with IL-17 (1197 ± 203 pg/ml at baseline, 623 ± 213 pg/ml after third cycle, P = 0·03) and tended to increase the frequency of circulating regulatory T cells (3·1 ± 1 cells/µl at baseline, 7·7 ± 2 cells/µl after third cycle). Rituximab also significantly decreased IL-15 trans-presentation on surface monocytes of patients negative for IL-15 serum (mean fluorescence intensity: 4·82 ± 1·30 at baseline, 1·42 ± 0·69 after third cycle P = 0·05). Reduction of serum IL-15 was associated with decrease in CD8(+)  CD45RO(+) /RA(+) ratio (1·17 ± 0·21 at baseline, 0·36 ± 0·06 at third cycle, P = 0·02). DAS28, erythrocyte sedimentation rate and C-reactive protein correlated significantly with CD8(+)  CD45RO(+) /RA(+) ratio (R = 0·323, R = 0·357, R = 0·369 respectively, P < 0·001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL-15/memory T-cell-related mechanisms beyond circulating B cells.

Functional consequences of platelet binding to T lymphocytes in inflammation.

Expression of the scavenger receptor CD36 on lymphocytes is intriguing. We observed that a minor subpopulation of lymphocytes expressed CD36 on the cell surface. We investigated the source of CD36 and also the proliferation and cytokine production of these CD36(+) CD4(+) lymphocytes. Flow cytometry analysis and immunofluorescence microscopy showed that CD36(+) platelets were responsible for CD36 detection on lymphocytes. CD36 was then used as a tool to characterize lymphocytes with bound platelets. Activation-induced proliferation was lower in CD4(+) lymphocytes with bound platelets than lymphocytes without bound platelets. IL-17 and IFN-γ production was also reduced in lymphocytes with bound platelets. We then studied the presence of CD36(+) CD4(+) lymphocytes in RA patients. We observed that the percentage of CD4(+) lymphocytes with bound platelets was higher on RA patients than in healthy donors. RA patients with higher titers of anti-CCP, RF levels, and cardiovascular risk index presented a lower percentage of CD4(+) lymphocytes with bound platelets. These patients also had higher IL-17 and IFN-γ production. These results suggest that platelet-binding modifies lymphocyte function. This binding could be a regulatory mechanism in RA that confers a less severe phenotype.

Predictors of response to rituximab in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARDs.

OBJECTIVES: Identifying early predictors of response to biological agents is important for both the individual patient and health economics. The aim here was to identify clinical variables that are easily assessed in clinical practice which are associated with a major response to rituximab (moderate to good EULAR response, according to DAS28 values) in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARDs. METHODS: Rituximab (2x1g, two weeks apart) was administered to 108 patients in four different Spanish hospitals. The primary efficacy endpoint was the percentage of patients who achieved a major response at six months. Potential predictors of a major response were identified using multivariate binary logistic regression models. RESULTS: At six months of treatment 75.9% of patients achieved a major response (24% good and 52% moderate). Comparing the clinical features at baseline between patients who did or did not achieve a major response, significant differences were found in rheumatoid factor (RF) and anti-CCP positivity, as well as in the number of failed anti-TNF agents prior to rituximab. While rituximab delivers clinical benefit in seronegative patients, the presence of RF and/or anti-CCP consistently enriches clinical responses. The multivariate analysis showed that the best model for predicting a major EULAR response to rituximab was comprised of the following two variables: the anti-CCP antibody positivity (p=0.045) and the number of previous anti-TNF agents used (p=0.028). Using a cut-off level for CCP of 300 U/ml we found that patients with an anti-CCP titre >300 U/ml were 3-4 times more likely to achieve a major EULAR response [odds ratio (OR): 3.38; 95% CI: 1.025-11.17]. By contrast, those patients who had failed to respond to 2 or more anti-TNF agents had a 72.5% lower probability of achieving a moderate to good EULAR response (OR: 0.275; 95% CI: 0.087-0.871) than did patients who had only failed to respond to one such agent. CONCLUSIONS: A lower number of previously-failed TNF blockers and high anti-CCP titre can help select the best candidates for RTX therapy in patients with RA.