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ObjectiveSessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma.DesignA cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAFand KRASmutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT).ResultsThe median polyp size was 9 mm and 86.5% were proximal. Most were BRAFmutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status.ConclusionsSSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these ‘caught in the act’ lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.

A new prostate cancer (PCa) prognostic grading system [Gleason groups (GGs)] has been proposed based on the contemporary Gleason scores (GSs), which has five simplified prognostic categories. The objective of this study was to evaluate the agreement between the GGs of prostate biopsy and radical prostatectomy specimens and to identify predictive factors for upgrading GGs.

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.

ABSTRACTPurpose: To assess fatigue severity in World Trade Center (9/11) responders 13 years later. Methods: The participant pool consisted of male 9/11 responders enrolled in the Stony Brook World Trade Center Health Program (WTC-HP), one of five centers of excellence established by the Centers for Disease Control and Prevention. Fatigue severity was assessed with the Fatigue Severity Scale. WTC-related medical conditions were certified by a physician and diagnoses of 9/11-related post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) were determined with the Structured Clinical Interview for DSM-IV (SCID). Results: High fatigue severity was reported by 20.8% of the sample (N = 1079) and was significantly associated with PTSD, major depressive disorder, sleep apnea, gastro-esophageal reflux disease, upper respiratory disease, and lower respiratory disease. These associations remained significant for PTSD, major depressive disorder and lower respiratory disease when adjusted for medications, age and BMI. Only 17.3% of the high fatigue subgroup did not have an identified medical or psychiatric diagnosis. Fewer fatigued (21.1%) than non-fatigued (72.0%) responders rated their physical health as ‘good’ or ‘very good.’ Also fewer fatigued (33.9%) than non-fatigued (54.1%) responders were employed full-time (p < .0001). Conclusions: This study found clinically elevated fatigue in a high percentage of a male WTC responder cohort that prior to 9/11/2001 would be considered a ‘healthy worker cohort.’ To better understand the pathophysiology of fatigue, newer methodologies such as symptom provocation (e.g. exercise) designs may be useful.

The identification of prostate cancer (PC) is important in men aged ≤ 65 years. We examined complete transurethral resection of prostate (TURP) specimens to quantify the incidence and nature of PC in men aged ≤ 65 years.

The interplay between the inflammatory infiltrate and tissue resident cell populations invokes fibrogenesis. However, the temporal and mechanistic contributions of these cells to fibrosis are obscure. To address this issue, liver inflammation, ductular reaction (DR), and fibrosis were induced in C57BL/6 mice by thioacetamide administration for up to 12 weeks. Thioacetamide treatment induced two phases of liver fibrosis. A rapid pericentral inflammatory infiltrate enriched in F4/80+monocytes co-localized with SMA+myofibroblasts resulted in early collagen deposition, marking the start of an initial fibrotic phase (1 to 6 weeks). An expansion of bone marrow–derived macrophages preceded a second phase, characterized by accelerated progression of fibrosis (>6 weeks) after DR migration from the portal tracts to the centrilobular site of injury, in association with an increase in DR/macrophage interactions. Although chemokine (C-C motif) ligand 2 (CCL2) mRNA was induced rapidly in response to thioacetamide, CCL2 deficiency only partially abrogated fibrosis. In contrast, colony-stimulating factor 1 receptor blockade diminished C-C chemokine receptor type 2 [CCR2neg(Ly6Clo)] monocytes, attenuated the DR, and significantly reduced fibrosis, illustrating the critical role of colony-stimulating factor 1–dependent monocyte/macrophage differentiation and linking the two phases of injury. In response to liver injury, colony-stimulating factor 1 drives early monocyte-mediated myofibroblast activation and collagen deposition, subsequent macrophage differentiation, and their association with the advancing DR, the formation of fibrotic septa, and the progression of liver fibrosis to cirrhosis.

•External quality assessment developed to provide independent oversight of molecular acute myeloid leukemia MRD testing globally•Testing and interpretation errors identified that could lead to erroneous treatment and have serious consequences in a clinical setting

Brevicoryne brassicae (Linnaeus), Lipaphis pseudobrassicae (Davis), Acyrthosiphon kondoi (Shinji), Aphis craccivora (Koch) and Rhopalosiphum padi (Linnaeus) are among the most important aphid pests in Australian broadacre systems. In this study a leaf-dip method was used to assay pirimicarb, dimethoate, α-cypermethrin and imidacloprid against field populations collected from Victoria, New South Wales, South Australia, Western Australia and Queensland. This research established toxicity baseline data that will be important for future monitoring of insecticide responses in broadacre crops. It also provided an opportunity to identify any chemical tolerance that may be evolving in these pests. Acyrthosiphon craccivora populations showed differences in their responses to dimethoate, pirimicarb and imidacloprid (but not to α-cypermethrin), indicating possible shifts in field sensitivity to these three chemicals. Rhopalosiphum padi had the lowest sensitivity to all insecticides tested, with two populations (collected from South Australia and Queensland) showing less than 100% mortality when tested at the field rate of α-cypermethrin. There were few differences in insecticide responses between populations of the other three species. Continued screening of A. craccivora and R. padi populations is needed to fully assess the current status of tolerance among field populations and to strengthen resistance management tactics.

IL-17–producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term “inflammatory iTc17” (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.

IL-17–producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term “inflammatory iTc17” (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.

Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective antiviral responses in this setting. Although CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound dendritic cell (DC) defect that led to a failure in the generation of CMV-specific CD8+ T-cell responses. This was accompanied by a defect in antiviral CD8+ T cells. In combination, these defects dramatically limited antiviral T-cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing antiviral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD.

Idiopathic pneumonia syndrome (IPS) is a relatively common, frequently fatal clinical entity, characterized by noninfectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. In this study, we demonstrate that immune suppression with cyclosporin after SCT limits T-helper cell (Th) 1 differentiation and interferon-γ secretion by donor T cells, which is critical for inhibiting interleukin (IL)-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung, and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6−/−recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and is present at very high levels in the plasma of patients with IPS compared with SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were nonresponsive to steroids and anti-tumor necrosis factor therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation, and strategies that target these cytokines represent logical therapeutic approaches for IPS.

The present study aims to determine the risk of early secondary nasal revisions in patients with complete unilateral and bilateral cleft lip and palate (UBCLP) treated with and without nasoalveolar molding (NAM) and examine the associated costs of care. A retrospective cohort study from 1990 to 1999 was performed comparing the risk of early secondary nasal revision surgery in patients with a CLP treated with NAM and surgery (cleft lip repair and primary surgical nasal reconstruction) versus surgery alone in a private practice and tertiary level clinic. The NAM treatment group consisted of 172 patients with UCLP and 71 patients with BCLP, whereas the non-NAM-prepared group consisted of 28 patients with UCLP and 5 with BCLP. The risk of secondary nasal revision for patients with UCLP was 3 in the NAM group and 21 in the non-NAM group. The risk of secondary nasal revision for patients with BCLP was 7 in the NAM group compared with 40 in the non-NAM group. Using multicenter averages, the non-NAM revision rates were calculated at 37.8 and 48.5 for UBCLP, respectively. Applying these risks of revision, NAM treatment led to an estimated savings of between 491 and 4893 depending on the type of cleft. In conclusion, NAM can reduce the number of early secondary nasal revision surgeries and, therefore, reduce the overall cost of care.

The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAFand KRASmutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, β-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAFmutation was present in 67% and KRASmutation in 22%. BRAFmutant traditional serrated adenomas were more frequently proximal (39% versus2%; P≤0.0001), were exclusively associated with a precursor polyp (57% versus0%; P≤0.0001), and were more frequently CpG island methylator phenotype high (60% versus16%; P≤0.0001) than KRASmutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear β-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAFmutant traditional serrated adenomas compared with 10% of the advanced areas of KRASmutant or BRAF/KRASwild-type traditional serrated adenomas. BRAFand KRASmutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A(encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAFmutant traditional serrated adenomas. Thus, the BRAFmutant traditional serrated adenoma represents an important precursor of the aggressive BRAFmutant, microsatellite-stable subtype of colorectal carcinoma.