Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress.

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease representing a major source of global disability burden. Disease-modifying therapies are showing promise in chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease with method and timing of initial treatment impacting long-term disease outcomes. Whether disease-modifying therapies, specifically those used as an early interventional approach, impacts disease course and comorbidity development in AD is not well-understood. We reviewed the progress in disease modification strategies, emphasizing early intervention approaches in common (or proto-typical) inflammatory diseases. Although more common in other fields, disease modification approaches are becoming increasingly investigated in dermatology, though studies in AD are lacking. Despite significant limitations in ongoing and completed studies, early data are promising and suggest that both the choice and timing of early intervention approach can affect long-term disease course and comorbidity development. To best improve AD patient outcomes, more research is needed to further explore the impact of early disease-modifying therapies. Future studies should focus on identifying the most effective approaches and extend the early results to a more inclusive set of comorbidities and longer-term outcomes.

Pharmacological effects of D-Pinitol - A comprehensive review.

In recent years, the application of phytochemicals to prevent or treat diseases has received greater attention. These phytochemicals have little or no toxicity against healthy tissues and are thus considered as ideal compounds. An impressive number of modern drugs are obtained from natural sources based on their traditional value. D-Pinitol is a natural compound that is derived from soy and soy products. It is a potentially active molecule that belongs to the class of inositols. D-pinitol has been pharmacologically evaluated for its potent antioxidant, anti-diabetic, anti-inflammatory, anti-cancer, hepatoprotective, cardioprotective, renoprotective, neuroprotective, immunosuppressive, and anti-osteoporotic efficacies. This review is an attempt to validate the plausible pharmacological effects of D-pinitol using various in vivo and in vitro studies. PRACTICAL IMPLICATIONS: The consumption of plant-based products has been significantly increased all over the world. The active phytochemicals that are found in plants are stated to have numerous health promoting functions for the treatment of diabetes, cancer, inflammation, cardiac diseases, liver dysfunction, and many other. D-Pinitol is abundantly present in soybeans that possess notable therapeutic activities. Understanding the effects of D-Pinitol would potentially help in applying this compound in clinical research for the treatment of different disorders.

A pilot randomized study comparing extralevator with conventional abdominoperineal excision for low rectal cancer after neoadjuvant chemoradiation.

AIM: The aims of this study were to assess the feasibility of performing an extralevator abdominoperineal excision (ELAPE) after neoadjuvant chemoradiation (NCRT), to compare the rates of circumferential resection margin (CRM) involvement and intra-operative perforation (IOP) of the specimen, and to assess the amount of tissue removed around the muscularis propria (MP)/internal sphincter (IS) of the lower rectum in patients with low rectal cancer undergoing ELAPE compared with conventional abdominoperineal excision (CAPE) after NCRT. METHOD: This was an open-label, parallel-arm pilot randomized trial conducted in India. Twenty patients were randomized to one of the study arms. The surgical specimens were fixed, serially cross-sectioned and photographed. Using specialized morphometry software, the amount of tissue resected with each operation was measured. RESULTS: There was a nonsignificant trend towards more IOPs (30% vs 0%, P = 0.06) and a higher CRM involvement rate (40% vs 20%, P = 0.32) in the CAPE arm. ELAPE removed a significantly greater amount of tissue around the IS/MP when compared with CAPE (mean ± SD: 1911.39 ± 382 mm2 vs 1132.03 ± 371 mm2 , P < 0.001). The mean distance from the IS/MP to the CRM was significantly greater in the ELAPE arm both in the posterior (mean ± SD: 28.28 ± 3 mm vs 9.63 ± 3 mm, P < 0.001) and lateral (mean ± SD: 13.69 ± 3 mm vs 9.72 ± 3 mm, P = 0.009) parts of the rectum but not in the anterior part (mean ± SD: 6.74 ± 2 mm vs 6.10 ± 4 mm, P = 0.64). The short-term morbidity was not significantly different between the two procedures. CONCLUSION: ELAPE removed more tissue in the lower rectum and resulted in a lower rate of IOP and CRM involvement when compared with CAPE, even after NCRT.

Robotic pancreaticoduodenectomy: comparison of complications and cost to the open approach.

BACKGROUND: Robotic pancreaticoduodenectomy (RP) has shown some advantages over open pancreaticoduodenectomy (OP) but no data has been published providing a cost comparison. METHODS: Retrospective analysis of all pancreaticoduodenectomies at a single quaternary cancer referral center was performed. Patient demographics, comorbidities, operative characteristics, complications, and charge data were recorded, and then compared using standard statistical methods. RESULTS: 71 pancreaticoduodenectomies were performed: 22 RP and 49 OP. Patients undergoing OP had similar demographics, comorbidities, pathology, and oncologic characteristics as patients undergoing RP. While operative charges were higher for RP, once inpatient stay associated costs and follow-up costs were included, there was no difference in total costs between RP and OP. CONCLUSIONS: Patients undergoing RP have equivalent rates of R0 resection as OP, and benefit from decreased number of complications, surgical site infections, and length of stay in the intensive care unit. Once cost of complications and follow-up are incorporated, no significant difference between procedures exists. Copyright © 2015 John Wiley & Sons, Ltd.

Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort.

PTLD is an important complication following heart transplantation. To better define the risk factors of PTLD in children, we performed a case-control study. All pediatric cardiac transplant recipients who developed their first episode of PTLD were matched by age (+/-1 yr) and time since transplant (+/-1 yr) with those who did not. PTLD occurred in nine of 95 cardiac transplant recipients (9%), 0.3-7.8 yr following cardiac transplantation (median = 2.5 yr). Patients were 0.1-16.4 yr (median = 3.7) at transplantation. Biopsies revealed polymorphic B cell hyperplasia (three), polymorphic B cell lymphoma (one), monomorphic diffuse large cell B cell lymphoma (three) and monomorphic Burkitt's-like lymphoma (two). Patients who developed PTLD were at no greater risk of death (p = 0.31). Recipient EBV seronegativity at time of transplant (p = 0.08), EBV seroconversion (p = 0.013) and recipient CMV seronegativity (p = 0.015) were associated with the development of PTLD by conditional logistic regression; sex, race, donor age, recipient diagnosis, donor CMV seropositivity, recipient treatment for CMV infection, EBV seropositivity at the time of PTLD diagnosis, and number of rejection episodes, treated rejection episodes, and lympholytics used were not. There was no significant association between PTLD and death in our recipients. EBV seroconversion and recipient CMV seronegativity were associated with the development of PTLD.

Weight loss and reduced body mass index: a critical issue in children with multiorgan chronic graft-versus-host disease.

Weight loss and malnutrition are major problems in patients with chronic graft-versus-host disease (GVHD). In adults, low body mass index (BMI) is a predictor for mortality; however, weight loss and BMI have not been studied in pediatric chronic GVHD. A retrospective study on 18 children with extensive chronic GVHD was completed. Median age at SCT was 12.3 (range 0.6-23) years; age at chronic GVHD diagnosis was 12.5 (1-23) years. Patients with multiorgan involvement had a mean maximal decrease in BMI of 20.9% and most dropped below 10th percentile in expected weight-for-age. This change in BMI not only indicates a significant decrease in weight but often a plateau in stature. In contrast, patients with one organ system involved had a mean maximal decrease in BMI of 5% and did not fall below 10th percentile. All patients with multiorgan involvement required salvage therapy beyond steroids and CSA. Three patients died due to complications of chronic GVHD. Weight loss and malnutrition (as reflected by a decrease in BMI) are clinically significant issues in children with multisystem chronic GVHD. Weight loss is likely another systemic manifestation of the disease and may contribute, along with other factors such as increased immunosuppression and infection, to increased mortality in this group.

Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia.

Acute lymphocytic leukemia (ALL) is a common indication for hematopoietic stem cell transplantation (HSCT) in children. Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased GVHD potential. Publications describing outcomes of children with leukemia who underwent UCB transplants have compared them to those having received unrelated donor marrow transplants. Results are similar. We compared our outcomes using UCB vs allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n=21) or in CR2 (n=28) with initial remission less than 36 months. Patients received myeloablation with fractionated total body irradiation, cyclophosphamide, and etoposide and GVHD prophylaxis with cyclosporine and methotrexate. Antithymocyte globulin was added for UCB recipients to address the HLA differences. In all, 23 patients underwent allogeneic -related HSCT and 26 underwent UCB transplantation. Other than increased time to engraftment for UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. UCB is a reasonable option for children with ALL who are referred for HSCT.

Frequency and genetic basis of MHC, beta-2-microglobulin and MEMO-1 loss of heterozygosity in sporadic breast cancer.

The Human Leukocyte Antigen (HLA) class I molecules are critical factors in T cell recognition of abnormal, including neoplastic, cells. Loss of HLA class I expression phenotypes, as defined by immunohistochemistry-based tests, have been previously described in many types of cancer. Here we describe a microsatellite marker DNA-based loss of heterozygosity (LOH) analysis of three distinct chromosomal regions which have been implicated in HLA class I expression on a cohort of 99 unselected sporadic breast cancer samples. These regions comprise the 4Mb major histocompatibility complex (MHC) region on chromosome 6p, which contains the HLA class I heavy chain loci and other genes responsible for antigen processing, the HLA class I light chain (beta-2-microglobulin, beta2m) gene on chromosome 15q, and the putative HLA class I modifier of methylation gene (MEMO-1) on chromosome 1p. Additional chromosome 6 markers were also employed to determine the likely genetic mechanism for MHC loss. We show that 25/99 (25%) of samples show allelic loss within the MHC, 28/95 informative samples (29%) show allelic loss of beta2m and 21/76 informative samples (28%) show allelic loss of MEMO-1. Approximately half of the samples are predicted to have compromised HLA class I gene expression due to LOH at one and/or other of these three loci. Sequencing of the remaining beta2m allele in samples displaying beta2m LOH failed to detect any additional intragenic mutations. Analysis of the frequency of samples showing LOH at either 0, 1, 2 or 3 of the genomic regions analyzed suggested clustering of tumors into either 'no loci loss' or '3 loci loss' categories. These results reveal major underlying genetic causes for the high level of HLA class I expression loss seen in breast cancer.

Differential transduction efficiency of SCID-repopulating cells derived from umbilical cord blood and granulocyte colony-stimulating factor-mobilized peripheral blood.

The gene transfer efficiency into nonobese diabetic/severe combined immunodeficient (NOD/SCID)-repopulating cells (SRCs) derived from umbilical cord blood (UCB) (n = 11 NOD/SCID mice) and granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (MPB) (n = 64 NOD/SCID mice) was compared using a clinically relevant protocol and a retrovirus vector expressing the enhanced green fluorescent protein (EGFP). At 6-9 weeks after transplantation, the frequency of transduced human cells in the bone marrow (BM) (40.5% +/- 2.4% [mean +/- SE]) and spleen (SPL) (36.4% +/- 3.2%) in recipients of UCB cells was significantly higher (p < 0.001) than that observed in the BM (2.2% +/- 1.8%) and SPL (2.0% +/- 2.6%) in recipients of MPB. In subsequent studies, MPB was cultured for 2-8 days in cytokines prior to transduction to determine if longer prestimulation was required for optimal gene transfer. A significant increase in gene transfer into CD45(+) human cells and clonogenic cells derived from MPB SRCs was observed when cells were prestimulated for 6 days compared to 2 days prior to transduction (p = 0.019). However, even after 6 days of prestimulation, transduction was still significantly less than UCB. A substantial discrepancy exists in the ability to introduce genes effectively via retrovirus vectors into SRCs derived from MPB as compared to UCB.

Recent trends in central venous catheter placement: a comparison of interventional radiology with other specialties.

The authors determined changing trends and growth in tunneled and nontunneled central venous catheter placement procedures. With use of Medicare billing data for tunneled and nontunneled catheter placement, a comparison was made among interventional radiology (IR), surgery, anesthesia, and internal medicine. There has been substantial growth in the placement of central venous catheters. Currently, a minority of these procedures are performed in IR departments. However, there has been significant growth in the radiologic placement of both types of catheters.

Swallowing problems in post irradiated NPC patients.

We present three patients with Nasopharyngeal Carcinoma (NPC) developing swallowing problems after radiotherapy as the primary modality of treatment. All patients had advanced stage NPC presenting with enlarged neck nodes and underwent radical external beam radiotherapy. All three patients had both CN X and CN XII palsies and had difficulty in both the oral and pharyngeal phases of swallowing. None of them has any clinical or radiological evidence of local recurrence in the post nasal space and neck or metastasis to the skull base. One patient underwent cricopharyngeal myotomy with epiglottopexy and hyoid suspension which failed and subsequently underwent laryngectomy. Another patient had medialisation thyroplasty and the third underwent a percutaneous endoscopic gastrostomy (PEG).

Accuracy of bedside clinical methods compared with fiberoptic endoscopic examination of swallowing (FEES) in determining the risk of aspiration in acute stroke patients.

This prospective study was undertaken to determine the accuracy of bedside clinical methods compared with fiberoptic endoscopic examination of swallowing (FEES) for detecting aspiration in acute stroke patients. Fifty patients underwent an examination of their ability to swallow 50 ml of water in 10-ml aliquots. Later their oxygen saturation levels before and after swallowing 10 ml of water were measured using a pulse oximeter. Oxygen desaturation of more than 2%, was considered to be clinically significant. All patients then underwent a FEES assessment by a speech therapist and were followed up during their inpatient stay for evidence of aspiration pneumonia. The oxygen desaturation test had a sensitivity of 76.9% and specificity of 83.3% (chi2 = 18.154, p = 0.00002), while the 50-ml water swallow test had a sensitivity of 84.6% and specificity of 75.0% (chi2 = 18.001, p = 0.00002). However, when these two tests were combined into one test called "bedside aspiration," the sensitivity rose to 100% with a specificity of 70.8% (chi2 = 27.9, p = 0.000001). Five (10%) patients developed pneumonia during their inpatient stay. The relative risk (RR) of developing pneumonia, if there was evidence of aspiration on FEES, was 1.24 (1.03 < RR < 1.49). We conclude that the oxygen desaturation test combined with the 50-ml water swallow test is suitable as a screening test to identify all acute stroke patients at risk of aspiration for further evaluation and management.

Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions.

Loss of heterozygosity (LOH) at the long arm of chromosome 16 occurs in at least half of all breast tumors and is considered to target one or more tumor suppressor genes. Despite extensive studies by us and by others, a clear consensus of the boundaries of the smallest region of overlap (SRO) could not be identified. To find more solid evidence for SROs, we tested a large series of 712 breast tumors for LOH at 16q using a dense map of polymorphic markers. Strict criteria for LOH and retention were applied, and results that did not meet these criteria were excluded from the analysis. We compared LOH results obtained from samples with different DNA isolation methods, ie., from microdissected tissue versus total tissue blocks. In the latter group, 16% of the cases were excluded because of noninterpretable LOH results. The selection of polymorphic markers is clearly influencing the LOH pattern because a chromosomal region seems more frequently involved in LOH when many markers from this region are used. The LOH detection method, i.e., radioactive versus fluorescence detection, has no marked effect on the results. Increasing the threshold window for retention of heterozygosity resulted in significantly more cases with complex LOH, i.e., several alternating regions of loss and retention, than seen in tumors with a small window for retention. Tumors with complex LOH do not provide evidence for clear-cut SROs that are repeatedly found in other samples. On disregarding these complex cases, we could identify three different SROs, two at band 16q24.3 and one at 16q22.1. In all three tumor series, we found cases with single LOH regions that designated the distal region at 16q24.3 and the region at 16q22.1. Comparing histological data on these tumors did not result in the identification of a particular subtype with LOH at 16q or a specific region involved in LOH. Only the rare mucinous tumors had no 16q LOH at all. Furthermore, a positive estrogen content is prevalent in tumors with 16q LOH, but not in tumors with LOH at 16q24.3 only.

Prognostic value of TP53 gene mutation in adjuvant treated breast cancer patients.

We investigated the prognostic significance of mutation to the TP53 tumor suppressor gene in a series of 908 breast cancer patients treated with or without adjuvant therapies. The frequency of TP53 mutation detected by single strand conformation polymorphism (SSCP) was 19.4% (176/908) in the overall tumor series. In multivariate analysis, TP53 mutation was independently associated with worse survival in the overall (HR = 2.1, 95% CI [1.5-3.1], P<0.0001), non-adjuvant treated (HR=2.2, 95% CI [1.2-4.2], P=0.017) and adjuvant treated (HR= 2.0, 95% CI [1.3-3.1], P = 0.0009) patients.

Hairy cell leukemia: treatment prospects.

The recent advances in the management of hairy cell leukemia, a chronic and indolent B-cell lymphoproliferative disorder are reviewed. The introduction of alpha-interferon, purine analogs and recombinant monoclonal antibodies/immunotoxins has dramatically improved the outcome in a disease that once had a dismal prognosis. The underlying genetic defect remains unknown.

Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry.

PURPOSE: To compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in detecting the HER-2/neu alteration in human breast cancer. PATIENTS AND METHODS: Unselected stage I, II, and III breast cancer patients (N = 900) were tested for HER-2/neu gene amplification by FISH in paraffin-embedded, formalin-fixed archival material. Of these samples, 856 were tested for HER-2/neu overexpression by non-antigen-retrieval IHC with the polyclonal antibody R60, the sensitivity and specificity of which was preliminarily compared with the United States Food and Drug Administration-approved HercepTest (Dako Corp, Carpinteria, CA). Patient survival was analyzed in relation to the presence of the HER-2/neu alteration as determined by these two methodologies. RESULTS: A total of 189 (21%) of 900 patients were positive by FISH and 147 (17.2%) of 856 were positive by IHC. This discrepancy is consistent with expected loss of IHC sensitivity associated with tissue fixation/embedding. The HercepTest did not improve sensitivity and introduced false positives. Comparison of R60-based IHC with FISH demonstrates that patient survival is associated progressively to gene amplification level as determined by FISH, whereas for IHC an association is found only in the highest (3+) immunostaining group. Among FISH-negative tumors, 45 (6.6%) of 678 were IHC-positive, with a survival probability similar to that of FISH-negative/IHC-negative cases; FISH-positive/IHC-negative patients have a survival probability similar to that of FISH-positive/IHC-positive cases. CONCLUSION: IHC does not consistently discriminate patients likely to have a poor prognosis, whereas FISH provides superior prognostic information in segregating high-risk from lower-risk beast cancers. HER-2/neu protein overexpression in the absence of gene amplification occurs infrequently in breast cancer, in which case, patient outcome is similar to that of patients without the alteration.

Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells.

Direct reversal of O6 adducts caused by chemotherapy agents is accomplished in mammalian cells by the protein O6-methylguanine DNA methyltransferase (MGMT). Some tumors overexpress MGMT and are resistant to alkylator therapy. One future approach to treatment of these tumors may rely on concurrent pharmacological depletion of tumor MGMT with O6-benzylguanine (6-BG) and protection of sensitive tissues, such as hematopoietic stem and progenitor cells, using genetic modification with 6-BG-resistant MGMT mutants. We have used retroviral-mediated gene transfer to transduce murine hematopoietic bone marrow cells with MGMT point mutants showing resistance to 6-BG depletion in vitro. These mutants include proline to alanine and proline to lysine substitutions at the 140 position (P140A and P140K, respectively), which show 40- and 1000-fold resistance to 6-BG compared with wild-type (WT) MGMT. Lethally irradiated mice were reconstituted with murine stem cells transduced with murine stem cell virus retrovirus expressing each mutant, WT MGMT, or mock-infected cells and then treated with a combination of 30 mg/kg 6-BG and 10 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or with 40 mg/kg BCNU alone. Compared with mice treated with BCNU alone, significant myeloid toxicity and death occurred in mice reconstituted with mock-infected or WT MGMT (<0.1 probability of survival) or the P140A mutant (0.13 probability of survival) MGMT cDNAs. In contrast, after an initial period of mild cytopenia, mice reconstituted with the P140K mutant (0.83 probability of survival) recovered nearly normal blood counts, even during continued treatment. Comparison of peripheral blood neutrophils after completion of 5 weekly treatments in these animals showed a direct correlation between the treatment and in vivo selection for progeny of transduced cells (pretreatment, approximately 8-12% transduced cells; no treatment, approximately 6% transduced cells; BCNU only, 51% transduced cells; 6-BG/BCNU, 93% transduced cells). To determine whether this selection occurred at the stem cell level, bone marrow from each treatment group was infused into secondary recipients. Whereas animals that received bone marrow from untreated animals reconstituted with 2% transduced cells, animals receiving marrow from 6-BG/BCNU-treated animals reconstituted with 94% transduced cells, demonstrating nearly complete selection for stem cells in the primary animals. Mice reconstituted with marrow from animals treated with BCNU only demonstrated 23% transduced cells, consistent with partial selection of stem cells in the primary mice. The levels of transduced cells also correlated with survival during a second round of intensive combination chemotherapy (probability of survival: 6-BG/BCNU, 1.0; BCNU alone, >0.70; no treatment, <0.1). These data demonstrate that mutant MGMT expressed in the bone marrow can protect mice from time- and dose-intensive chemotherapy and that the combination of 6-BG and BCNU leads to uniform selection of transduced stem cells in vivo in mice.

High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.

PURPOSE: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. PATIENTS AND METHODS: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months). RESULTS: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality. CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.