Robert V.B. Emmons

Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival.

The mechanism by which malignant melanoma (MM) cells survive in lymph nodes is poorly understood. One possible mechanism by which MM cells can escape immune surveillance is through upregulation of immunomodulatory enzymes such as indoleamine 2,3-dioxygenase (IDO). In this study, 25 cases of MM lymph node metastases from patients with long and short survival were evaluated for expression of IDO and the number of Forkhead box p3 (FOXP3)-expressing regulatory T cells. Moderate to strong cytoplasmic IDO expression was present in all (15/15) MM lymph node metastases in patients with poor survival. Eight of 10 patients with metastatic MM and long survival were negative or only weakly positive for IDO. Upregulation of IDO in metastatic MM cells was associated with an increased number of regulatory T cells (Tregs). There was a statistically significant association between shorter survival and both a stronger IDO expression (p=0.0019) and a higher number of FOXP3 expressing Tregs (p

Lack of effect of donor-recipient ABO mismatching on outcome following allogeneic hematopoietic stem cell transplantation.

Several recently published studies have suggested that patients who undergo ABO mismatched hematopoietic stem cell transplantation may be at increased risk for relapse, graft-versus-host disease, transplant-related mortality, and/or all-cause mortality. To investigate this issue further, we analyzed potential associations between the donor–recipient ABO mismatch pattern and the above outcome measures among 240 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation at our institution. Our analyses uncovered no significant associations between donor–recipient ABO mismatch pattern and overall survival, event-free survival, transplant-related mortality, incidence of acute graft-versus-host disease (GVHD), or incidence of chronic GVHD. Our data do not support recent assertions that donor–recipient ABO mismatching is a major risk factor for patients undergoing allogeneic transplant, nor do they support recent assertions that ABO matching should be an important consideration in selecting allogeneic hematopoietic stem cell donors.

Increased natural killer cells and decreased regulatory T cells are seen in complex atypical endometrial hyperplasia and well-differentiated carcinoma treated with progestins

Progestins are used to treat complex atypical hyperplasia and well-differentiated endometrial carcinoma in women who desire fertility preservation and those who are poor surgical candidates. Although sensitivity to progestins is thought to be associated with the presence of estrogen and progesterone receptors, it is known that receptor-negative tumors can also respond to the agent, suggesting that there is another direct antitumor action of progestin. Because tumor immune response is an additional predictor of survival in well-differentiated endometrial carcinoma, it is surprising that the role of progestins in tumor immunity has not been investigated. Regulatory T cells modulate the immune response, whereas cytotoxic T cells directly target tumor cells. In this study, we investigated the effect of progestins on regulatory T cells and cytotoxic T cells. The pre- and posttreatment endometrial samples of 15 progestin-treated patients with complex atypical hyperplasia or well-differentiated endometrial carcinoma were evaluated for therapeutic response and the presence of cytotoxic T cells and regulatory T cells. Immunohistochemical analysis was performed for FOXP3 to identify regulatory T cells and for granzyme B to identify activated cytotoxic T cells. To further characterize the cytotoxic T cells subpopulations, we performed CD8 (cytotoxic T-cell marker) and CD56 (natural killer cells marker). Ten of 15 patients had normal morphology on follow-up endometrial samplings, and 4 patients had persistence or progression of the disease. Regulatory T-cell counts pretreatment were significantly higher in complex atypical hyperplasia and well-differentiated endometrial carcinoma than in posttreatment normal endometrium. Residual complex atypical hyperplasia and well-differentiated endometrial carcinoma present in posttreatment samples maintained high regulatory T cells and low number of cytotoxic T cells. Progestin treatment was associated with striking increase in cytotoxic T cells in areas with decidual reaction. Before treatment, most of the granzyme B+ cytotoxic T cells in complex atypical hyperplasia and well-differentiated endometrial carcinoma were CD8(+) T cells, whereas after treatment, up to 80% of cytotoxic T cells were natural killer cells. These results suggest that progestin treatment affects subpopulations of lymphocytes in the endometrium and may induce immune suppression of complex atypical hyperplasia and well-differentiated endometrial carcinoma.

Foxp3-expressing T regulatory cells and mast cells in acute graft-versus-host disease of the skin.

Acute graft-versus-host disease (aGVHD) limits the effectiveness of allogeneic hematopoietic stem cell transplantation. Foxp3 is required for the development and function of CD4+/CD25+ regulatory T cells (T-regs). Foxp3-expressing T-regs are thought to protect against GVHD. Mast cells are thought to be essential in CD4+/CD25+ regulatory T cell-dependent peripheral tolerance. Twenty biopsies of skin with grades I-III aGVHD were stained for Foxp3 and CD117. Inflammation was quantified by a 4 point scale, 0=no inflammation, 1=50%. T-regs and mast cells were quantified by a 4 point scale, 0=no cells per 20x field, 1=10 cells. T-regs were positively correlated with both inflammation and aGVHD grade. Twelve cases with low T-regs had mild inflammation and lower grades of aGVHD and 6 cases with high T-regs had dense inflammatory infiltrate and higher grades of aGVHD. The number of T-regs, mast cells and density of the inflammatory infiltrate were positively correlated only in cases with mild inflammation. In aGVHD of the skin, T-regs increased with the degree of inflammation and GVHD grade. Mast cells were present at the same density whether aGVHD was of lower or higher grade.

Spontaneous graft versus host disease occurring in a patient with multiple myeloma after autologous stem cell transplant

Graft versus host disease (GVHD) is a common complication of allogeneic transplant. Acute GVHD primarily affects the skin, liver, and GI tract generally within the first 100 days after transplant. GVHD following an allogeneic transplant occurs as a result of donor T-cell recognition of host alloantigens. In contrast, patients undergoing ASCT are not subjected to the genetic disparity that occurs with allogeneic transplant, and in principal, should not develop this proinflammatory response. A clinical syndrome, however, has been described in patients following autologous transplant that shares the same features as GVHD occurring in recipients post-allogeneic transplant [1-3]. Previously reported cases have described skin, liver, and GI tract manifestations consistent with what is seen in allogeneic GVHD. Biopsies of the skin and GI tract mucosa have demonstrated similar histological features as well. Interestingly, the majority of reported cases seem to occur in patients with multiple myeloma undergoing consolidative ASCT. Historically, however, these patients have been described as having a relatively benign course with mild skin rash, nausea, vomiting, and/or diarrhea that is responsive to immunosuppression. In this article, we present a case of fatal, spontaneous GVHD in a patient with multiple myeloma following ASCT.

Lack of effect of donor‐recipient Rh mismatch on outcomes after allogeneic hematopoietic stem cell transplantation

BACKGROUND: A recently published study has reported that donor‐recipient Rhesus (Rh)‐mismatched allogeneic hematopoietic stem cell transplantation independently led to significantly poorer survival. This suggests that donor‐recipient Rh mismatching is a risk factor in allogeneic hematopoietic stem cell transplantation and should be a criterion for donor selection.

Stem cell transplantation for reinduction of self-tolerance in autoimmune disease

The diverse manifestations and variable response to immune suppression of autoimmune disorders have made them one of the most challenging areas of medicine. The ability of hematopoietic stem cell transplantation to alter the immune system is currently being tested both experimentally and clinically

Monoclonal Gammopathy of Undetermined Significance Versus Smoldering Myeloma: Is Active Surveillance Enough?

614. 22. www.leukemia-lymphoma.org. 23. Landgren O, Devesa S, Mink P, et al. African-American multiple myeloma patients have a better survival than Caucasian patients: a populationbased study including 28,636 patients [abstract 1832]. Proc Am Soc

Tackling mantle cell lymphoma (MCL): Potential benefit of allogeneic stem cell transplantation

Mantle cell lymphoma (MCL) is a type of non-Hodgkins lymphoma (NHL) associated with poor progression-free and overall survival. There is a high relapse rate with conventional cytotoxic chemotherapy. Intensive combination chemotherapy including rituximab, dose intense CHOP- (cyclophosphamide-doxorubicin-vincristine-prednisone) like regimens, high dose cytarabine, and/or consolidation with autologous stem cell transplant (autoSCT) have shown promise in significantly prolonging remissions. Data from phase II studies show that even in patients with chemotherapy refractory MCL, allogeneic stem cell transplant (alloSCT) can lead to long term disease control. Most patients with MCL are not candidates for myeloablative alloSCT due to their age, comorbidities, and performance status. The advent of less toxic reduced intensity conditioning (RIC) regimens, which rely more on the graft-versus-lymphoma (GVL) effect, have expanded the population of patients who would be eligible for alloSCT. RIC regimens alter the balance of toxicity and efficacy favoring its use. Treatment decisions are complicated by introduction of novel agents which are attractive options for older, frail patients. Further studies are needed to determine the role and timing of alloSCT in MCL. Currently, for selected fit patients with chemotherapy resistant MCL or those who progress after autoSCT, alloSCT may provide long term survival.

Readers' Responses to "Cancer of Unknown Primary Site: Advances in Diagnostics"

agnostic tools used to attempt to identify the primary site of carcinomas, including immunohistochemistry, and acknowledge the limitations of these techniques. 1 They also highlight the recent development of molecular diagnostic tools such as genomic microarray-based Pathwork Tissue of Origin test by Pathwork Diagnostics, using reverse transcription–polymerase chain reaction (RT-PCR)–based assays on paraffin-embedded tissue, which may hopefully enhance diagnostic capabilities, in order to impact on therapeutic decision making. 2 We wish to also highlight the development of microRNA analysis, recently reported at the American Society of Clinical Oncology annual meeting, as an additional tool to aid in molecular diagnosis of cancers of unknown primary site, and propose its availability to the oncologic community at large. Also using RT-PCR, the authors used 22-oligonucleotide RNA molecules (microRNA) involved in gene expression regulation to evaluate RNA extracted from tumors from patients with cancer of unknown primary, and demonstrated concordance (full and plausible) with the actual clinical presentation in 82% of cases. 3 These small RNA molecules have been shown to be highly effective biomarkers, with high tissue specificity, and are more stable for use on formalin-fixed paraffin-embedded block tissue, as well as fine-needle aspiration