Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the ...colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1−/− mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.
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•Commensal metabolite butyrate and niacin induce IL-18 in colon via Gpr109a•Butyrate and niacin induce IL-10 and Aldh1a in APCs in a Gpr109a-dependent manner•Niacr1−/− mice exhibit increased risk for colitis and colon cancer•Gpr109a signaling protects colon health during deficiency of gut bacteria and dietary fiber
Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles ...and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b
+
CD33
+
HLA-DR
−
MDSCs from peripheral blood of human colon cancer patients are PD-L1
+
. PD-L1
+
MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1
+
MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1
+
in vivo. In contrast, PD-L1
+
MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1
−
in tumor-bearing mice. IFNγ is highly expressed in cells of the tumor tissues and IFNγ neutralization significantly decreased PD-L1
+
MDSCs in the tumor microenvironment in vivo. However, IFNγ-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.
Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) ...in men with locally advanced prostate cancer. This report summarizes long-term follow-up results.
Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF).
Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events.
The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.
Molecular genetics has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease by the discovery of rare, inherited mutations in gene products that associate with the mitochondria. ...Mutations in PTEN-induced kinase-1 (PINK1), which encodes a mitochondrial kinase, and PARKIN, encoding an E3 ubiquitin ligase, are the most frequent causes of recessive Parkinson's disease. Recent functional studies have revealed that PINK1 recruits PARKIN to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. PINK1 is post-translationally processed into a cleaved form whose levels are tightly regulated, although the significance of this processing is unknown. Here we demonstrate that the mitochondrial protease presenilin-associated rhomboid-like (PARL) can affect the proteolytic processing of PINK1 and that normal PINK1 localization and stability requires PARL's catalytic activity. PARL deficiency impairs PARKIN recruitment to mitochondria, suggesting PINK1's processing and localization are important in determining its interaction with PARKIN. We sequenced the PARL gene in Parkinson's disease patients and discovered a novel missense mutation in a functional domain of PARL's N-terminus. This PARL mutant is not sufficient to rescue PARKIN recruitment, suggesting that impaired mitophagy may be an underlying mechanism of disease pathogenesis in patients with PARL mutations.
To present our single-institution experience with image-guided radiotherapy comparing fiducial markers and cone-beam computed tomography (CBCT) for daily localization of prostate cancer.
From April ...2007 to October 2008, 36 patients with prostate cancer received intensity-modulated radiotherapy with daily localization by use of implanted fiducials. Orthogonal kilovoltage (kV) portal imaging preceded all 1244 treatments. Cone-beam computed tomography images were also obtained before 286 treatments (23%). Shifts in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) dimensions were made from kV fiducial imaging. Cone-beam computed tomography shifts based on soft tissues were recorded. Shifts were compared by use of Bland-Altman limits of agreement. Mean and standard deviation of absolute differences were also compared. A difference of 5 mm or less was acceptable. Subsets including start date, body mass index, and prostate size were analyzed.
Of 286 treatments, 81 (28%) resulted in a greater than 5.0-mm difference in one or more dimensions. Mean differences in the AP, SI, and LR dimensions were 3.4 ± 2.6 mm, 3.1 ± 2.7 mm, and 1.3 ± 1.6 mm, respectively. Most deviations occurred in the posterior (fiducials, 78%; CBCT, 59%), superior (79%, 61%), and left (57%, 63%) directions. Bland-Altman 95% confidence intervals were -4.0 to 9.3 mm for AP, -9.0 to 5.3 mm for SI, and -4.1 to 3.9 mm for LR. The percentages of shift agreements within ±5 mm were 72.4% for AP, 72.7% for SI, and 97.2% for LR. Correlation between imaging techniques was not altered by time, body mass index, or prostate size.
Cone-beam computed tomography and kV fiducial imaging are similar; however, more than one-fourth of CBCT and kV shifts differed enough to affect target coverage. This was even more pronounced with smaller margins (3 mm). Fiducial imaging requires less daily physician input, is less time-consuming, and is our preferred method for prostate image-guided radiotherapy.
To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer.
Patients ...with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided).
Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥ 2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval CI: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively.
The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.
Antigen-presenting cells (APCs) can induce tolerance or immunity. We describe a subset of human APCs that express indoleamine 2,3-dioxygenase (IDO) and inhibit T cell proliferation in vitro. ...IDO-positive APCs constituted a discrete subset identified by coexpression of the cell-surface markers CD123 and CCR6. In the dendritic cell (DC) lineage, IDO-mediated suppressor activity was present in fully mature as well as immature $CD123^+ DCs$. $IDO^+ DCs$ could also be readily detected in vivo, which suggests that these cells may represent a regulatory subset of APCs in humans.
The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death ...(PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa.
Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD.
Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p<0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p<0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p<0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p<0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio HR, 1.56 95% confidence interval CI, 1.43-1.70 p<0.0001) but with decreased metastasis (HR, 0.72 95% CI, 0.63-0.83 p<0.0001) and PCSD (HR, 0.78 95% CI, 0.66-0.92 p<0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated.
These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.
Abstract Most mesenchymal neoplasms of the gastrointestinal tract are currently classified as gastrointestinal stromal tumors (GIST). Gastrointestinal stromal tumors are diagnosed by immunopositivity ...for CD117, CD34, and DOG1.1, with or without molecular analyses. According to the World Health Organization classification, the diagnosis of primary leiomyosarcomas of the gastrointestinal tract is so rare that there are no significant data on demographic, clinical, or gross features of this tumor. A comprehensive literature search was performed to identify gastrointestinal leiomyosarcomas. Searches were limited to the past 12 years because definitive tools to differentiate leiomyosarcomas from GIST were introduced in the late 1990s. Cases were included only if convincing data were presented. Six cases of esophageal leiomyosarcoma and 5 cases of gastric leiomyosarcoma were confirmed. Furthermore, 26 cases of leiomyosarcoma of the small bowel, 11 cases of the colon, and 8 cases arising in the rectum were identified. Finally, 28 cases of infantile and adolescent leiomyosarcoma were reviewed. Although survival analysis is precluded by small case numbers and limited survival data availability, the trend identifies that increased size and mitotic activity portends to a worse prognosis in small bowel leiomyosarcomas. Colonic leiomyosarcomas appear to be aggressive tumors, regardless of tumor size and mitotic activity. Rectal leiomyosarcomas present as smaller tumors with favorable prognosis. Leiomyosarcomas in post-GIST era are rare tumors of the gastrointestinal tract with distinctive clinicopathologic characteristics. Owing to different treatment options, it is necessary to accurately differentiate these from GIST, using a combination of histologic appearance, presence of smooth muscle antigens, and absence of specific GIST immunomarkers.
To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine ...plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%).
A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m(2)/d Monday-Friday) plus irinotecan (50 mg/m(2)/wk × 4); and (2) capecitabine (1650 mg/m(2)/d Monday-Friday) plus oxaliplatin (50 mg/m(2)/wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m(2); leucovorin 400 mg/m(2); 5-fluorouracil 400 mg/m(2); 5-fluorouracil 2400 mg/m(2)) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually.
A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively.
Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an unsuitable surrogate for traditional survival metrics of clinical outcome. Although it remains uncertain whether the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest that further study of irinotecan may be warranted.
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