Systematic Review of Patient-Reported Outcome Measures in Locally Recurrent Rectal Cancer.

BACKGROUND: The availability of high-quality patient-reported outcome (PRO) data is crucial to guiding shared decision-making in the context of locally recurrent rectal cancer (LRRC), where potential treatment benefits must be balanced against the impact of both the disease and treatment on PROs, such as quality of life. This review aimed to identify the patient-reported outcome measures (PROMs) currently being reported in LRRC and to appraise the methodological quality of studies using these measures. METHODS: PubMed, Embase and CINAHL databases were searched, including studies published up until 14th September 2022. Studies in adults with LRRC reporting PROMS as a primary or secondary outcome measure were included. Data were extracted concerning the methodological quality of the reporting of PROMs using criteria informed by the CONSORT-PRO checklist and the psychometric properties of the PROMs identified using the COSMIN Risk of Bias checklist. RESULTS: Thirty-five studies including 1914 patients with LRRC were identified. None of the studies included in the review met all eleven criteria for the quality of reporting of PROMs. Seventeen PROMs and two clinician-reported outcome measures were identified, none of which have been validated for use in patients with LRRC. CONCLUSIONS: None of the PROMs which are currently being used to report PROs in LRRC have been validated for use in this cohort of patients. Future studies in this disease area should focus on utilising PROMs that have undergone a robust development process including patients with LRRC, to produce data which is high quality, accurate and relevant.

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.

Foreign bodies in sigmoid colon diverticulosis.

This review addresses the management of sigmoid colon diverticular disease associated with foreign bodies. In addition, two novel cases are presented. One case describes the management of diverticular bleeding secondary to a chicken bone and the other case reports retrieval of a retained EndoRings™ Device. The review identified 40 relevant publications including 50 subjects. Foreign bodies within sigmoid diverticular disease may be associated with inflammation, perforation, abscess and fistula. In current practice, diagnosis is often achieved with CT scan. Patients with colonic perforation or fistula generally require colonic resection. Patients with inflammation may merit conservative management, including colonoscopic foreign body retrieval. Chicken bones, tooth picks, and biliary stents have been reported in patients with inflammation, perforation and fistula, whereas all published patients with fish bone related diverticulosis complications experienced inflammation. Treatment might be best guided by the consequences of the foreign body rather than the nature of the underlying retained object. Diverticular bleeding secondary to a chicken bone was diagnosed at CT angiography and treated with colonoscopic snare retrieval of the bone and clipping of the bleeding diverticulum. The EndoRings™ Device was retrieved with a colonoscopic balloon.

Sorting nexin 5 selectively regulates dorsal-ruffle-mediated macropinocytosis in primary macrophages.

The regulation of macropinocytosis, a specialised endocytosis pathway, is important for immune cell function. However, it is not known whether the biogenesis of macropinosomes involves one or more distinct pathways. We previously identified sorting nexin 5 (SNX5) as a regulator of macropinocytosis in macrophages. Here, we show that bone-marrow-derived macrophages from SNX5-knockout mice had a 60-70% reduction in macropinocytic uptake of dextran or ovalbumin, whereas phagocytosis and retrograde transport from the plasma membrane to the Golgi was unaffected. In contrast, deficiency of SNX5 had no effect on macropinocytosis or antigen presentation by dendritic cells. Activation of macrophages with CSF-1 resulted in a localisation of SNX5 to actin-rich ruffles in a manner dependent on receptor tyrosine kinases. SNX5-deficient macrophages showed a dramatic reduction in ruffling on the dorsal surface following CSF-1 receptor activation, whereas peripheral ruffling and cell migration were unaffected. We demonstrate that SNX5 is acting upstream of actin polymerisation following CSF-1 receptor activation. Overall, our findings reveal the important contribution of dorsal ruffing to receptor-activated macropinocytosis in primary macrophages and show that SNX5 selectively regulates macropinosomes derived from the dorsal ruffles.

Helios defines T cells being driven to tolerance in the periphery and thymus.

The expression of the Ikaros transcription factor family member, Helios, has been shown to be associated with T-cell tolerance in both the thymus and the periphery. To better understand the importance of Helios in tolerance pathways, we have examined the expression of Helios in TCR-transgenic T cells specific for the gastric H(+) /K(+) ATPase, the autoantigen target in autoimmune gastritis. Analysis of H(+) /K(+) ATPase-specific T cells in mice with different patterns of H(+) /K(+) ATPase expression revealed that, in addition to the expression of Helios in CD4(+) Foxp3(+) regulatory T (Treg) cells, Helios is expressed by a large proportion of CD4(+) Foxp3(-) T cells in both the thymus and the paragastric lymph node (PgLN), which drains the stomach. In the thymus, Helios was expressed by H(+) /K(+) ATPase-specific thymocytes that were undergoing negative selection. In the periphery, Helios was expressed in H(+) /K(+) ATPase-specific CD4(+) T cells following H(+) /K(+) ATPase presentation and was more highly expressed when T-cell activation occurred in the absence of inflammation. Analysis of purified H(+) /K(+) ATPase-specific CD4(+) Foxp3(-) Helios(+) T cells demonstrated that they were functionally anergic. These results demonstrate that Helios is expressed by thymic and peripheral T cells that are being driven to tolerance in response to a genuine autoantigen.

Functional outcomes after limb-salvage surgery and endoprosthetic reconstruction with an expandable prosthesis: a report of 4 cases.

OBJECTIVE: To determine the functional outcomes of skeletally immature patients after replacement of the femur and tibia performed by using noninvasive expandable endoprostheses. DESIGN: Case series. SETTING: A hospital-based ambulatory care center. PARTICIPANTS: Pediatric patients (N=4) with primary bone tumors of the distal femur and proximal tibia who underwent surgical replacement performed by using the Repiphysis noninvasive expandable endoprosthesis (Wright Medical Technology, Memphis, TN). INTERVENTIONS: Wide resection of bone sarcoma and placement of expandable endoprosthesis. MAIN OUTCOME MEASURES: Musculoskeletal Tumor Society (MSTS) scores were assessed at the beginning of the study and at each follow-up visit. Medical Outcomes Study 36-Item Short-Form Health Survey, Version 2 (SF-36); gait; sit-to-stand transition; and range of motion (ROM) were assessed at an average follow-up of 31.5 months. RESULTS: At an average of 31.5 months postoperative, the SF-36 physical component summary scores lagged behind the national mean, whereas the mental component summary scores were satisfactory. MSTS scores indicated low levels of pain and supports use with high emotional acceptance and walking ability but persisting difficulties with function and gait. Patients also showed altered patterns of sit-to-stand transition including decreased peak vertical force in the operated limb and increased center of mass momentum in a shorter amount of time. Parts of gait functioning were found to be decreased, including gait velocity, stride length, and cadence. Some patients displayed alternate weight-bearing strategies that accompanied increased double-limb support and stance phase during walking. ROM and strength were diminished at both the hip and knee joints in the operated limb and in the nonoperated limb. CONCLUSIONS: Reconstruction with a noninvasive expandable endoprosthesis produces satisfactory functional outcomes in pediatric patients with primary tumors of the bone. Patients in our study displayed some persisting physical difficulties including decreased ROM and strength and altered gait and sit-to-stand patterns, yet they maintained high levels of emotional acceptance and coping.

Postoperative gait velocity and mean knee flexion in stance of ambulatory children with spastic diplegia four years or more after multilevel surgery.

Factors associated with longer-term outcomes of multilevel orthopaedic surgery in ambulatory children with cerebral palsy using a multivariate approach were evaluated using a retrospective pretest-posttest design. The population included 20 ambulatory children with spastic diplegia who had undergone multilevel orthopaedic surgery with a minimum of 4-year interval between a preoperative and a postoperative gait assessment. Multiple regression analysis was used to identify factors associated with postoperative velocity and mean knee flexion in stance. Independent variables included in the regression models were velocity, mean knee flexion in stance, age at preoperative evaluation, Gross Motor Function Classification System level, use of ankle-foot orthoses, leg length, age-adjusted body mass index, number of surgical procedures, and range of motion of hip and knee. Children who demonstrated faster postoperative gait velocity 4 years or more after surgery were younger at the time of initial evaluation, had undergone fewer surgical procedures, had faster preoperative gait velocity, used ankle-foot orthoses postoperatively, and had increased hip extension range of motion postoperatively (R = 0.55). Children who demonstrated greater knee flexion in stance 4 years or more after surgery had undergone more surgical procedures, greater postoperative popliteal angle, and less knee extension range of motion (R = 0.73). This study demonstrates the usefulness of a multivariate approach toward understanding and predicting outcomes. The results of this study will provide clinicians and researchers more information about those factors associated with maintained improvements in the longer term and may be useful for treatment planning.