Search

Background: Randomized controlled trials have been unable to demonstrate noninferiority of minimally invasive surgery for rectal cancer. The aim of this study was to assess oncologic resection success, short- and long-term morbidity, and overall survival by operative approach in a homogenous early-stage rectal cancer cohort., Methods: This is a multicenter, propensity score-weighted cohort study utilizing deidentified data from the National Cancer Database. Individuals who underwent a formal proctectomy for early-stage rectal cancer (T1-2, N0, M0) from 2010 to 2015 were included. The primary outcome was a composite variable indicating successful oncologic resection stratified by operative approach, defined as negative margins with at least 12 lymph nodes evaluated., Results: Among 3649 proctectomies for rectal adenocarcinoma, 1660 (45%) were approached open, 1461 (40%) laparoscopically, and 528 (15%) robotically. After propensity score weighting, compared to open approach, there were no differences in odds of successful oncologic resection (OR adj  = 1.07, 95% CI 0.9, 1.28 and OR adj  = 1.28, 95% CI 0.97, 1.7). Open approach was associated with longer mean (± SD) length of stay compared to laparoscopic (7.7 ± 0.18 vs. 6.5 ± 0.25 days, p < 0.001) and robotic (7.7 ± 0.18 vs. 6.3 ± 0.35 days, p < 0.001) approaches. In regard to 90-day mortality, compared to open approach, laparoscopic (OR adj  = 0.56, 95% CI 0.36, 0.88) and robotic (OR adj  = 0.45, 95% CI 0.22, 0.94) approaches were associated with a reduced odd of 90-day mortality. This mortality benefit persists in the long-term for laparoscopic approach (p = 0.003)., Conclusion: For individuals with early-stage rectal cancer treated with proctectomy, successful oncologic resection can be achieved irrespective of technical approach. Minimally invasive approaches provide short-term reduction in morbidity. Surgical approach must be tailored to each patient based on surgeon experience and judgement in collaboration with a multi-disciplinary team., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Recent data suggest patients with early-onset rectal cancer (EORC) receive neoadjuvant radiation above recommended doses without oncologic benefit. The use of excessive radiation may lead to worse outcomes and patient harm. We sought to evaluate predictors of aggressive neoadjuvant radiation (A-XRT) use in EORC patients and compare this to late-onset rectal cancer (LORC) patients., Methods: The National Cancer Database from 2004 to 2014 was queried for rectal adenocarcinoma patients undergoing surgical resection. Patients with stage 0 or IV disease, positive margins, and incomplete data were excluded. Standard neoadjuvant radiation (S-XRT) was based upon NCCN guidelines: 25-50.4 Gray for stage II/III patients and none for stage I. Excess radiation was considered A-XRT. Patients diagnosed at age < 50 years were labeled EORC; those ≥ 50 years were LORC. Categorical data were analyzed with chi-square test. Logistic regression was used to analyze clinicodemographic associations with A-XRT., Results: 45,403 patients were included: 7999 (17.6%) EORC and 37,404 (82.4%) LORC. Multivariable logistic regression demonstrated that A-XRT use among stage I patient was associated with male gender, age under 50, urban location, mucinous histology, and poor tumor differentiation. Among stage II and III patients, A-XRT use was associated with male gender, age under 50, higher education and income, and urban location. Cox hazards did not demonstrate a significant association of A-XRT use with survival., Conclusion: Our data reaffirm that EORC patients more frequently receive A-XRT and that use is based on demographic features independent of tumor characteristics. Reasons for A-XRT, particularly in EORC patients, should be clarified to promote adherence to guidelines and minimize patient harm., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite guideline recommendations, some patients still receive care inappropriate for their clinical stage of disease. Identification of factors that contribute to variation in guideline base care may help eradicate disparities in the treatment of early and locally advanced rectal cancer., Methods: The American College of Surgeons National Cancer Database from 2010 to 2015 was analyzed with propensity score weighting to identify factors associated with delivery and omission of neoadjuvant guideline-based chemoradiation (GBC) for those with early and locally advanced rectal cancer., Results: Only 74% of patients with rectal cancer received stage-appropriate neoadjuvant chemoradiation; 4544 (88%) of those with early stage disease and 8675 (68%) in locally advanced disease. Chemotherapy and radiotherapy were not planned in 27% and 34% respectively, of those who did not receive GBC. Factors associated with receipt of non-guideline-based neoadjuvant chemoradiation were age >65 years, Medicare insurance, treatment at a community facility, West-South-Central geography, having locally advanced disease, and Charlson-Deyo score >3. Receipt of ideal guideline-based neoadjuvant chemoradiation conferred a survival benefit at 5 years., Conclusion: Patient and non-patient factors contribute to disparities in guideline-based delivery of neoadjuvant chemoradiation in the treatment of rectal cancer. Identification of these risk factors are important to help standardize care and improve survival outcomes., (© 2021 Wiley Periodicals LLC.)

Background and Objectives: Right-sided colon cancers (R-CC) are associated with worse outcomes compared to left-sided colon cancers (L-CC). We hypothesize that R-CC with synchronous liver metastases who undergo resection of primary and metastatic sites have worse survival and that survival will vary significantly among R-CC, L-CC, and rectal cancer (ReC)., Methods: The Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2016 was used to identify colorectal cancer patients with liver metastases who underwent surgical resection of both primary and metastatic disease. Survival was analyzed by multivariate Cox regression., Results: A total of 2275 patients were included; 38% R-CC, 46% L-CC, and 16% ReC. R-CC primary tumors tended to be larger than 5 cm, higher grade, and mucinous (all P < .001). Compared to patients with R-CC, both L-CC and ReC had improved overall (HR 0.72; P < .001; HR 0.75, P = .006) and disease-specific (HR 0.71, P < .001; HR 0.73, P = .008) survival. There was no difference in survival between L-CC and ReC., Conclusions: Patients with R-CC have significantly worse survival than L-CC or ReC. This provides additional evidence that R-CC tumors are fundamentally different from L-CC and ReC tumors. Future studies should determine factors responsible for this disparity, and identify targeted treatment based on primary tumor location., (© 2020 Wiley Periodicals LLC.)

Background and Objectives: Sarcopenia is associated with poor long-term outcomes in many gastrointestinal cancers, but its role in anal squamous cell carcinoma (ASCC) is not defined. We hypothesized that patients with sarcopenic ASCC experience worse long-term outcomes., Methods: A retrospective review of patients with ASCC treated at an academic medical center from 2006 to 2017 was performed. Of 104 patients with ASCC, 64 underwent PET/computed tomography before chemoradiation and were included in the analysis. The skeletal muscle index was calculated as total L3 skeletal muscle divided by height squared. Sarcopenia thresholds were 52.4 cm 2 /m 2 for men and 38.5 cm 2 /m 2 for women. Cox regression analysis was performed to assess overall and progression-free survival., Results: Twenty-five percent of the patients were sarcopenic (n = 16). Demographics were similar between groups. There was no difference in the clinical stage or comorbidities between groups. On multivariate analysis, factors associated with worse overall survival were male gender (hazard ratio [HR] 3.7, P = .022) and sarcopenia (HR 3.6, P = .019). Male gender was associated with worse progression-free survival (HR 2.6, P = .016)., Conclusions: Sarcopenia is associated with worse overall survival in patients with anal cancer. Further studies are indicated to determine if survival can be improved with increased attention to nutritional status in sarcopenic patients., (© 2020 Wiley Periodicals, Inc.)

Background: The liver is an immunologic privileged organ; liver allografts are accepted across major histocompatibility complex barriers in many species. However, hepatocyte transplants are acutely rejected, suggesting a role for liver nonparenchymal cells in regulating the immunoresponse. We have shown potent immunoregulatory activity of hepatic stellate cells (HSCs) in mice. The aim of this study was to examine the immunoregulatory activity of human HSCs., Methods: HSCs were isolated from normal human livers for analyses of their impact on T-cell response., Results: HSCs expressed low HLA-DR and costimulatory molecules CD40 and CD80 but constitutively expressed high levels of CD54. Interferon-γ stimulated HSCs to express B7-H1 in a dose-dependent manner and produce the suppressive cytokines interleukin-6, interleukin-10, and transforming growth factor-β but did not affect expression of HLA-DR, CD40, and CD80. Human HSCs did not stimulate allogeneic T-cell proliferative response, indicating that they are not professional antigen-presenting cells. HSCs markedly inhibited T-cell response elicited by either allogeneic antigen-presenting cells or CD3/CD28 beads, which was associated with increases in activated CD4 and CD8 T-cell apoptosis. Addition of anti-B7-H1 blocking antibody significantly reversed the inhibitory effect., Conclusions: Human HSCs demonstrate potent immunoregulatory activity via B7-H1-mediated induction of apoptosis in activated T cells. Understanding of the involved mechanisms may lead to development of novel therapeutic approaches for treatment of liver diseases.

Cytoprotective functions of a 20S proteasome activator were investigated. Saccharomyces cerevisiae Blm10 and human 20S proteasome activator 200 (PA200) are homologs. Comparative genome-wide analyses of untreated diploid cells lacking Blm10 and growing at steady state at defined growth rates revealed downregulation of numerous genes required for accurate chromosome structure, assembly and repair, and upregulation of a specific subset of genes encoding protein-folding chaperones. Blm10 loss or truncation of the Ubp3/Blm3 deubiquitinating enzyme caused massive chromosomal damage and cell death in homozygous diploids after phleomycin treatments, indicating that Blm10 and Ubp3/Blm3 function to stabilize the genome and protect against cell death. Diploids lacking Blm10 also were sensitized to doxorubicin, hydroxyurea, 5-fluorouracil, rapamycin, hydrogen peroxide, methyl methanesulfonate, and calcofluor. Fluorescently tagged Blm10 localized in nuclei, with enhanced fluorescence after DNA replication. After DNA damage that caused a classic G2/M arrest, fluorescence remained diffuse, with evidence of nuclear fragmentation in some cells. Protective functions of Blm10 did not require the carboxyl-terminal region that makes close contact with 20S proteasomes, indicating that protection does not require this contact or the truncated Blm10 can interact with the proteasome apart from this region. Without its carboxyl-terminus, Blm10((-339aa)) localized to nuclei in untreated, nonproliferating (G(0)) cells, but not during G(1) S, G(2), and M. The results indicate Blm10 functions in protective mechanisms that include the machinery that assures proper assembly of chromosomes. These essential guardian functions have implications for ubiquitin-independent targeting in anticancer therapy. Targeting Blm10/PA200 together with one or more of the upregulated chaperones or a conventional treatment could be efficacious.

Background: Side effects of lifetime immunosuppression for cell transplants often outweigh the benefits; therefore, induction of transplant tolerance is needed. We have shown that cotransplantation with myeloid-derived suppressor cells (MDSC) effectively protect islet allografts from rejection without requirement of immunosuppression. This study was to investigate the underlying mechanisms., Methods: MDSC were generated by addition of hepatic stellate cells from various stain mice into dendritic cell (DC) culture. The quality of MDSC was monitored by phenotype and function analyses. MDSC mixed with islet allografts were transplanted into diabetic recipients. T-cell response was analyzed after transplantation by using flow and histochemical analyses, and was compared with islet alone and islet/DC transplant groups. B7-H1 knockout mice were used to determine the role of B7-H1 on MDSC in regulation of T-cell response., Results: Cotransplantation with MDSC (not DC) effectively protected islet allografts without requirement of immunosuppression. This is associated with attenuation of CD8 T cells in the grafts and marked expansion of regulatory T (Treg) cells, which contributed to MDSC-induced T-cell hyporesponsiveness. Antigen-specific Treg cells were prone to accumulate in lymphoid organs close to the grafts. Both in vitro and in vivo data demonstrated that B7-H1 was absolutely required for MDSC to exert immune regulatory activity and induction of Treg cells., Conclusion: The described approach holds great clinical application potential and may overcome the limitation of requiring chronic administration of immunosuppression in cell transplants. Understanding the underlying mechanisms will facilitate the development of this novel therapeutic strategy.

Organs are composed of parenchymal cells that characterize organ function and nonparenchymal cells that are composed of cells in transit, as well as tissue connective tissue, also referred to as tissue stromal cells. It was originally thought that these tissue stromal cells provided only structural and functional support for parenchymal cells and were relatively inert. However, we have come to realize that tissue stromal cells, not restricted to in the thymus and lymphoid organs, also play an active role in modulating the immune system and its response to antigens. The recognition of these elements and the elucidation of their mechanisms of action have provided valuable insight into peripheral immune regulation. Extrapolation of these principles may allow us to utilize their potential for clinical application. In this article, we will summarize a number of tissue stromal elements/cell types that have been shown to induce hyporesponsiveness to transplants. We will also discuss the mechanisms by which these stromal cells create a tolerogenic environment, which in turn results in long-term allograft survival.