Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

BACKGROUND: Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. METHODS: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. RESULTS: 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). CONCLUSION: This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort.

BACKGROUND: It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. PATIENTS AND METHODS: In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. RESULTS: Median RFS was 11.1 months [95% confidence interval (CI) 8.5-41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1-9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38-0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. CONCLUSION: Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.

Prognostic value of Lynch syndrome, BRAFV600E , and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

BACKGROUND: Current knowledge on prognostic biomarkers (especially BRAFV600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. METHODS: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. RESULTS: In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. CONCLUSION: BRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

Spontaneous Complete Regression of Colon Cancer Liver Metastases in a Lung Transplant Patient: A Case Report.

Background: Cancer has become an important cause of death in solid organ transplant patients. The cause of malignancies in patients with solid organ transplants is multifactorial, but the use of intensive immunosuppression is regarded as an important factor. We describe the spontaneous, complete regression of colon cancer liver metastases, without initiation of antitumor therapy, in a solid organ transplant patient after modulation of immunosuppressants. Case Presentation. A 59-year-old female was admitted with fever, general discomfort, and elevated liver enzymes. She had received a single lung transplant, five years prior, for end-stage chronic obstructive pulmonary disease. Abdominal ultrasound and a computed tomography scan showed extensive liver lesions, and liver biopsy determined that the lesions were liver metastases originating from a colonic adenocarcinoma. Histopathologic analysis revealed that the primary tumor and liver metastases were mismatch repair-deficient (BRAFV600E mutant and MLH1/PMS2-deficient), also known as a microsatellite instable tumor. The patient's clinical condition deteriorated rapidly, and she was discharged home with palliative care. No antitumor treatment was initiated. Additionally, there was a short period without any immunosuppressants. Unexpectedly, her clinical condition improved, and complete regression of liver metastases was observed on imaging two months later. Unfortunately, the patient developed rejection of her lung transplant and succumbed to pulmonary disease six months following her cancer diagnosis. The autopsy confirmed the primary colon tumor location and complete regression of >40 liver metastases. Conclusions: Disinhibition and reset of the host immune response could have led to immune destruction of the liver metastases of this patient's immunogenic dMMR colon carcinoma. This case underscores the huge impact that temporary relief from immunosuppressive therapy could have on tumor homeostasis. Balanced management of care for organ transplant recipients with malignancies requires a multidisciplinary approach involving medical oncologists and transplant physicians to reach the best quality of care in these complex cases.

An Anatomical Study to the Branching Pattern of the Posterior Interosseous Nerve on the Dorsal Side of the Hand.

Partial denervation of the wrist can benefit patients with chronic wrist pain. A complication of partial denervation is loss of proprioception and hypesthesia on the dorsal side of the hand. Our aim is to evaluate whether the sensory branches of the posterior interosseous nerve could contribute to the loss of proprioception and sensation. The branching pattern of the posterior interosseous nerve was studied in 20 cadaveric hands. The terminal branches of the posterior interosseous nerve reached the metacarpophalangeal joints in three specimens (15%), the midshaft of the metacarpals in three specimens (15%), carpometacarpal joints in 11 specimens (55%), and the scapholunate joint in three specimens (15%). The finding that terminal branches of the posterior interosseous nerve can reach the metacarpals and the metacarpophalangeal joints indicates that the posterior nerve may contribute to the proprioception and sensation of the dorsal side of the hand. Clin. Anat., 33:678-682, 2020. © 2019 Wiley Periodicals, Inc.

Does Mechanical Bowel Preparation Reduce the Risk of Developing Infectious Complications in Pediatric Colorectal Surgery? A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate whether the application of mechanical bowel preparation (MBP) before colorectal surgery reduces the risk of developing infectious complications in children. STUDY DESIGN: In this systematic review and meta-analysis, PubMed, Embase, and the Cochrane Library were systematically searched to identify all articles comparing pediatric patients receiving MBP with pediatric patients not receiving MBP before colorectal surgery. Results are presented with weighted risk differences based on the number of events and sample size per study. RESULTS: Six original studies were included comparing MBP (n = 810) and no MBP (n = 1167). The overall risk of developing infectious complications was 10.1% in patients with MBP, compared with 9.1% in patients without MBP, resulting in a nonsignificant risk difference of -0.03% (95% CI, -0.09% to 0.03%). Concerning the number of wound infections and anastomotic leaks, we found nonsignificant risk differences of -0.03% (95% CI, -0.08% to 0.02%) and 0.01% (95% CI, -0.01% to 0.02%), respectively. CONCLUSION: Based on the current literature, there is insufficient evidence to indicate that the use of MBP leads to a significant difference in the risk of developing infectious complications in pediatric colorectal surgery.

An easy-to-use scoring index to determine severity of mitral regurgitation by 2D echocardiography in clinical practice.

PURPOSE: Mitral regurgitation (MR) grading by two-dimensional transthoracic echocardiography is challenging, but important to determine the best treatment strategy in patients with MR. Current guidelines advocate an integrative approach, although no recommendation is provided on how to do so. An easy-to-use index will be helpful for standardized and reproducible MR grading. METHODS: Eleven echocardiographic parameters were retrospectively evaluated in 145 patients with moderate or severe MR. Parameters were scored positive or negative for severe MR, where expert panel consensus reading was considered as the reference standard. Logistic regression was performed, and adjusted coefficients were used to create a risk score for severe MR per patient (ROSE-index). The best cutoff with corresponding predictive values was determined. RESULTS: Eighty-two percent of all parameters could be determined. Multivariable analysis revealed five parameters that remained significant predictors for severe MR: morphology, jet characteristics, vena contracta, systolic reversal, and left ventricular dimensions. With different weighing, a total score of 8 could be obtained. Median total ROSE-index score for moderate (2.0) and severe MR (5.0) did significantly differ. The cutoff score (≥4) revealed sensitivity 0.84 and specificity 0.83 to diagnose severe MR. Negative predictive value was 100% for score 0 and 1; score 6-8 showed a 100% positive predictive value. Inter- and intra-observer agreements were excellent (K-values >0.80). CONCLUSION: Here, we propose an easy-to-use tool for integrated analysis of guideline parameters to assess MR severity. Using this so-called ROSE-index revealed reliable and reproducible assessment of severe MR (cutoff≥4) that may be helpful for clinical decision making.