Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase 3 CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase 3 trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1:1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n= 103 without upfront PTR, n=101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (IQR 59-71). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% CI 16.0-22.2) compared to 20.1 months (95% CI 17.0-25.1) in the upfront PTR arm (p = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (p=0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSION: of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Implementation of robotic rectal cancer surgery: a cross-sectional nationwide study.

AIM: An increasing number of centers have implemented a robotic surgical program for rectal cancer. Several randomized controls trials have shown similar oncological and postoperative outcomes compared to standard laparoscopic resections. While introducing a robot rectal resection program seems safe, there are no data regarding implementation on a nationwide scale. Since 2018 robot resections are separately registered in the mandatory Dutch Colorectal Audit. The present study aims to evaluate the trend in the implementation of robotic resections (RR) for rectal cancer relative to laparoscopic rectal resections (LRR) in the Netherlands between 2018 and 2020 and to compare the differences in outcomes between the operative approaches. METHODS: Patients with rectal cancer who underwent surgical resection between 2018 and 2020 were selected from the Dutch Colorectal Audit. The data included patient characteristics, disease characteristics, surgical procedure details, postoperative outcomes. The outcomes included any complication within 90 days after surgery; data were categorized according to surgical approach. RESULTS: Between 2018 and 2020, 6330 patients were included in the analyses. 1146 patients underwent a RR (18%), 3312 patients a LRR (51%), 526 (8%) an open rectal resection, 641 a TaTME (10%), and 705 had a local resection (11%). The proportion of males and distal tumors was higher in the RR compared to the LRR. Over time, the proportion of robotic procedures increased from 15% (95% confidence intervals (CI) 13-16%) in 2018 to 22% (95% CI 20-24%) in 2020. Conversion rate was lower in the robotic group [4% (95% CI 3-5%) versus 7% (95% CI 6-8%)]. Anastomotic leakage rate was similar with 16%. Defunctioning ileostomies were more common in the RR group [42% (95% CI 38-46%) versus 29% (95% CI 26-31%)]. CONCLUSION: Rectal resections are increasingly being performed through a robot-assisted approach in the Netherlands. The proportion of males and low rectal cancers was higher in RR compared to LRR. Overall outcomes were comparable, while conversion rate was lower in RR, the proportion of defunctioning ileostomies was higher compared to LRR.

Long-term oncological outcomes after local excision of T1 rectal cancer.

BACKGROUND: A growing proportion of patients with early rectal cancer is treated by local excision only. The aim of this study was to evaluate long-term oncological outcomes and the impact of local recurrence on overall survival for surgical local excision in pT1 rectal cancer. METHODS: Patients who only underwent local excision for pT1 rectal cancer between 1997 and 2014 in two Dutch tertiary referral hospitals were included in this retrospective cohort study. The primary outcome was the local recurrence rate. Secondary outcomes were distant recurrence, overall survival and the impact of local recurrence on overall survival. RESULTS: A total of 150 patients (mean age 68.5 ± 10.7 years, 57.3% males) were included in the study. Median length of follow-up was 58.9 months (range 6-176 months). Local recurrence occurred in 22.7% (n = 34) of the patients, with a median time to local recurrence of 11.1 months (range 2.3-82.6 months). The vast majority of local recurrences were located in the lumen. Five-year overall survival was 82.0%, and landmark analyses showed that local recurrence significantly impacted overall survival at 6 and 36 months of follow-up (6 months, p = 0.034, 36 months, p = 0.036). CONCLUSIONS: Local recurrence rates after local excision of early rectal cancer can be substantial and may impact overall survival. Therefore, clinical decision-making should be based on patient- and tumour characteristics and should incorporate patient preferences.

Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study).

BACKGROUND: This prospective multicentre study was performed to quantify the number of patients with minimal residual disease (ypT0-1) after neoadjuvant chemoradiotherapy and transanal endoscopic microsurgery (TEM) for rectal cancer. METHODS: Patients with clinically staged T1-3 N0 distal rectal cancer were treated with long-course chemoradiotherapy. Clinical response was evaluated 6-8 weeks later and TEM performed. Total mesorectal excision was advocated in patients with residual disease (ypT2 or more). RESULTS: The clinical stage was cT1 N0 in ten patients, cT2 N0 in 29 and cT3 N0 in 16 patients. Chemoradiotherapy-related complications of at least grade 3 occurred in 23 of 55 patients, with two deaths from toxicity, and two patients did not have TEM or major surgery. Among 47 patients who had TEM, ypT0-1 disease was found in 30, ypT0 N1 in one, ypT2 in 15 and ypT3 in one. Local recurrence developed in three of the nine patients with ypT2 tumours who declined further surgery. Postoperative complications grade I-IIIb occurred in 13 of 47 patients after TEM and in five of 12 after (completion) surgery. After a median follow-up of 17 months, four local recurrences had developed overall, three in patients with ypT2 and one with ypT1 disease. CONCLUSION: TEM after chemoradiotherapy enabled organ preservation in one-half of the patients with rectal cancer.

Polyunsaturated fatty acids changes during electroconvulsive therapy in major depressive disorder.

Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as 'early response' (at T12), 'late response' (after ECT-course) and 'no' response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in 'late responders' compared to 'non responders'. For NA, 'late responders' showed significantly higher concentrations compared to 'early'- and 'non responders'. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Treatment of clinical T1 rectal cancer in the Netherlands; a population-based overview of clinical practice.

INTRODUCTION: Local excision is increasingly used as an alternative treatment for radical surgery in patients with early stage clinical T1 (cT1) rectal cancer. This study provides an overview of incidence, staging accuracy and treatment strategies in patients with cT1 rectal cancer in the Netherlands. MATERIALS AND METHODS: Patients with cT1 rectal cancer diagnosed between 2005 and 2018 were included from the Netherlands Cancer Registry. An overview per time period (2005-2009, 2010-2014 and 2015-2018) of the incidence and various treatment strategies used, e.g. local excision (LE) or major resection, with/without neoadjuvant treatment (NAT), were given and trends over time were analysed using the Chi Square for Trend test. In addition, accuracy of tumour staging was described, compared and analysed over time. RESULTS: In total, 3033 patients with cT1 rectal cancer were diagnosed. The incidence of cT1 increased from 540 patients in 2005-2009 to 1643 patients in 2015-2018. There was a significant increased use of LE. In cT1N0/X patients, 9.2% received NAT, 25.5% were treated by total mesorectal excision (TME) and 11.4% received a completion TME (cTME) following prior LE. Overall accuracy in tumour staging (cT1 = pT1) was 77.3%, yet significantly worse in cN1/2 patients, as compared to cN0 patients (44.8% vs 77.9%, respectively, p < 0.001). CONCLUSION: Over time, there was an increase in the incidence of cT1 tumours. Both the use of neoadjuvant therapy and TME surgery in clinically node negative patients decreased significantly. Clinical accuracy in T1 tumour staging improved over time, but remained significantly worse in clinical node positive patients.

Case Report: "Niemann-Pick Disease Type C in a Catatonic Patient Treated With Electroconvulsive Therapy".

We describe a case of an adolescent male with Niemann-Pick Type C (NP-C), a neurodegenerative lysosomal lipid storage disorder, who presented with recurrent catatonia which required repeated treatment with electroconvulsive therapy (ECT). During the ECT-course, seizure threshold increased substantially, leading to questions about the influence of NP-C on neuronal excitability. In this exemplary ECT-patient, NP-C was diagnosed not until after the first ECT-course when initial psychopharmacology for catatonia had failed and antipsychotics and benzodiazepines showed significant side-effects. Clinicians should be aware of NP-C in patients referred for ECT, especially in the case of treatment resistance, neurological symptoms and intolerance of psychopharmacological drugs. As was shown in our NP-C patient, ECT can be repeatedly effective for catatonic features. In the literature, effectiveness of ECT in patients with NP-C has sparsely been reported. This case demonstrates that detection of NP-C is beneficial for patients because more optimal treatment with ECT can be provided earlier without further exposure to side-effects.

The liver-first approach for locally advanced rectal cancer and synchronous liver metastases.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and synchronous liver metastases (sRLM) can be treated according to the liver-first approach. This study aimed to evaluate prognostic factors for completing treatment and in how many patients extensive lower pelvic surgery might have been omitted. METHODS: Retrospective analysis of all patients with LARC and sRLM treated at the Erasmus MC Cancer Institute according to the liver-first between 2003 and 2016. RESULTS: In total 129 consecutive patients were included. In 90 patients (70%) the liver-first was completed. Ten patients had a (near) complete response (ypT0-1N0) of their primary tumour. In 36 out of 39 patients not completing the liver-first protocol palliative rectum resection was withheld. Optimal cut-offs for CEA level (53.15 µg/L), size (3.85 cm) and number (4) of RLMs were identified. A preoperative CEA level above 53.15 µg/L was an independent predictor for non-completion of the liver-first protocol (p = 0.005). CONCLUSION: Ten patients had a (near) complete response of their primary tumour and, in retrospect, rectum sparing therapies could have been considered. Together with 36 patient in whom palliative rectum resection was not necessary this entails that nearly 40% patients with LARC and sRLM might be spared major pelvic surgery if the liver-first approach is applied. A predictor (CEA) was found for non-completion of the liver-first protocol. The majority of patients underwent resection of both primary tumour and hepatic metastasis with curative intent. These findings together entail that the liver-first approach may be considered in patients with LARC and sRLM.