IntroductionTumorigenesis is associated with a wide array of both genetic and epigenetic changes that give rise to tumor-associated antigens capable of eliciting a host antitumor immune response. Although host immune surveillance may prevent tumor outgrowth during the earliest stages of tumor growth, locally invasive or metastatic tumors must evade host immunity. 1 Immune escape is not merely a passive process of immune evasion but an active one by which both tumor cells and stromal cells present within the tumor microenvironment actively suppress the antitumor immune response. This distinction between immune evasion and suppression is an important one and may explain the paradoxical observation that many tumor immunotherapy clinical trials, despite eliciting an antitumor immune response, are not associated with a meaningful clinical response. 2 Improved mechanistic understanding of tumor-associated immune suppression is needed if the next generation of immunotherapeutic strategies is to be rationally designed.Malignant cells may suppress host immunity directly, by producing immunoregulatory cytokines or expressing inhibitory ligands on their cell surface. In addition, malignant cells may influence the tumor microenvironment leading to the induction or recruitment of immunoregulatory cells capable of suppressing host immunity. 3 Both myeloid-derived cells (including tumor-associated macrophages, dendritic cells [DCs], and myeloid-derived suppressor cells) and lymphocyte subsets, most notably regulatory T (Treg) cells, present within the tumor microenvironment, collaborate with their malignant counterparts to suppress host immunity. 3,4 The microenvironment's role in promoting tumor growth in nonHodgkin lymphoma (NHL) was recently highlighted by both gene expression profiling and immunohistochemistry-based approaches. [5][6][7] Therapeutic approaches capable of targeting the tumor microenvironment are currently being translated into clinical practice in hematologic malignancies and may be associated with improved outcomes. 8,9 Fundamentally, 2 distinct approaches capable of targeting the tumor microenvironment may be imagined. The first seeks to eliminate immunosuppressive cells present within the tumor microenvironment and is highlighted by recent attempts to eliminate Treg. As different stromal cells may use common immunosuppressive mediators, the alternative approach seeks to identify and neutralize these shared molecular mediators of host immune suppression.Members of the B7 family have emerged as important mediators of host immune suppression. In contrast to B7-1 (CD80) and B7-2 (CD86), which play an important role in T-cell activation and costimulation, the B7 homologs (B7-H, including B7-H1, B7-H2, B7-H3, and B7-H4), which have been described more recently may function as important "coinhibitors" of host T-cell immunity and have been associated with poor clinical outcomes in a variety of human tumors. 10,11 B7-H1, for example, may be inducibly expressed on tumor cells and confer resistance to killing media...

A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell-derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxo-rubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Mono-cytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously unde-scribed role for monocytes in T-cell lym-phoproliferative disorders. (Blood. 2009;

Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. Nine of forty-five (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, fluorescence in situ hybridization for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99% and 90%, respectively (p=0.00002, Fisher’s exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98% and 90%, respectively (p=0.005). Fluorescence in situ hybridization abnormalities other than translocations and IRF4 protein expression were seen in 13% and 65% of cases, respectively, but were non-specific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of fluorescence in situ hybridization for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all fluorescence in situ hybridization studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.

Background:  Wegener’s granulomatosis (WG), a systemic vasculitis, can be associated with cutaneous signs and symptoms before, during or after the diagnosis of systemic disease. Methods:  We reviewed clinical and histologic features of cutaneous lesions from 17 patients with WG. The temporal relationship between development of cutaneous symptoms and onset of systemic disease was determined, and antineutrophil cytoplasmic antibody (ANCA) status of the patients was also established. Results:  In six patients, systemic and cutaneous disease developed concurrently. In eight patients, cutaneous disease developed after patients received the diagnosis of systemic disease. In three patients, cutaneous disease preceded systemic disease. Cytoplasmic ANCA or proteinase‐3‐ANCA [c‐ANCA/proteinase 3 (PR3)‐ANCA] serologic test results were negative for one patient when cutaneous disease developed, and one patient had c‐ANCA/PR3‐ANCA seroconversion a year before systemic disease developed. Histopathologic features of cutaneous WG were not limited to leukocytoclastic vasculitis; they also included acneiform perifollicular and dermal granulomatous inflammation and palisaded neutrophilic and granulomatous inflammation. Conclusions:  Patients with WG can present initially with cutaneous symptoms. Histopathologic patterns vary, but leukocytoclastic vasculitis is most commonly noted. Patients with WG and skin lesions are likely to have positive c‐ANCA/PR3‐ANCA serologic test results.

To evaluate the prevalence of autoantibodies against 2 hemidesmosomal proteins typically found in patients with bullous pemphigoid (BP), BP antigen II (BP180) and BP antigen I (BP230), in persons without BP.

OBJECTIVE: Valid teamwork assessment is imperative to determine physician competency and optimize patient outcomes. We systematically reviewed published instruments assessing teamwork in undergraduate, graduate, and continuing medical education in general internal medicine and all medical subspecialties. DATA SOURCES: We searched MEDLINE, MEDLINE In-process, CINAHL and PsycINFO from January 1979 through October 2012, references of included articles, and abstracts from four professional meetings. Two content experts were queried for additional studies. STUDY ELIGIBILITY: Included studies described quantitative tools measuring teamwork among medical students, residents, fellows, and practicing physicians on single or multi-professional (interprofessional) teams. STUDY APPRAISAL AND SYNTHESIS METHODS:Instrument validity and study quality were extracted using established frameworks with existing validity evidence. Two authors independently abstracted 30 % of articles and agreement was calculated. RESULTS: Of 12,922 citations, 178 articles describing 73 unique teamwork assessment tools met inclusion criteria. Interrater agreement was intraclass correlation coefficient 0.73 (95 % CI 0.63-0.81). Studies involved practicing physicians (142, 80 %), residents/fellows (70, 39 %), and medical students (11, 6 %). The majority (152, 85 %) assessed interprofessional teams. Studies were conducted in inpatient (77, 43 %), outpatient (42, 24 %), simulation (37, 21 %), and classroom (13, 7 %) settings. Validity evidence for the 73 tools included content (54, 74 %), internal structure (51, 70 %), relationships to other variables (25, 34 %), and response process (12, 16 %). Attitudes and opinions were the most frequently assessed outcomes. Relationships between teamwork scores and patient outcomes were directly examined for 13 (18 %) of tools. Scores from the Safety Attitudes Questionnaire and Team Climate Inventory have substantial validity evidence and have been associated with improved patient outcomes. LIMITATIONS: Review is limited to quantitative assessments of teamwork in internal medicine. CONCLUSIONS:There is strong validity evidence for several published tools assessing teamwork in internal medicine. However, few teamwork assessments have been directly linked to patient outcomes. 3,4 Recognizing this, the Institute of Medicine, the Joint Commission, the Agency for Healthcare Research and Quality (AHRQ), and others have made teamwork a top priority in their recommendations for improving healthcare. [5][6][7][8][9] Teamwork is also prominently positioned within the American Board of Internal Medicine (ABIM) requirements for maintenance of certification for internists, 10 as well as the Accreditation Council for Graduate Medical Education's core competencies, 11 milestones, 12 and medical student competencies. 13 As such, every physician at the undergraduate, graduate, and continuing professional level must demonstrate competency in teamwork.While there is broad agreement on the imperative to improve teamwork, there is littl...

Background: Observations highlighting the "unmasking" of cutaneous T-cell lymphoma after treatment with dupilumab for atopic dermatitis (AD) have been recently reported. However, there remains a paucity of literature describing the evolution of clinical and histopathological features that characterizes this phenomenon.Objective: To define the clinical and histopathologic evolution of atypical lymphoid infiltrates after the administration of dupilumab for AD. Methods:A cross-sectional study of clinical and histopathologic features in 7 consecutive patients with a diagnosis of "atypical lymphoid infiltrate" or mycosis fungoides (MF) on dupilumab for AD was performed.Results: Seven patients with atypical lymphoid infiltrates or MF in evolution after dupilumab therapy (age range 27-74 years) were reviewed. Average duration of AD before MF diagnosis was 5.7 years, and the average duration on dupilumab treatment was 9.8 months. Notable histopathologic features across predupilumab and postdupilumab biopsies included progressive increase in the densities of the atypical lymphoid infiltrates (7/7), presence of atypical epidermotropic lymphocytes (6/7), and papillary dermal fibrosis (6/7).

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