Search

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

Candida auris presents a unique challenge to practitioners and infection control teams worldwide because of its virulence, alarming resistance profile, environmental fitness, and risk of nosocomial transmission. We describe 2 cases of Candida auris infection managed with the CDC recommendations with no evidence of in-hospital transmission.

Background: Central venous catheter (CVC) maintenance bundle elements, including labeling IV tubing and dressings, consistently changing them, intact dressings, and dry healthy insertion sites, together have been shown to reduce risks of developing central-line–associated bloodstream infections (CLABSIs).1,2 CLABSIs are a significant, but preventable, cause of mortality among critically ill patients.3 In the last 12 months, the 16-bed medical intensive care unit (MICU) at a large, urban, academic facility had 2,621 central-line days, presenting many opportunities for CLABSI prevention. During that time, weekly observations assessed compliance with CVC maintenance bundle elements. Interventions: Multidisciplinary rounds were conducted to monitor nursing staff adherence to CVC maintenance bundle elements. The following bundle elements observed during rounds: (1) Is central-line dressing occlusive/intact? (2) Is CVC insertion site healthy with no redness/drainage? (3) Is CVC dressing labeled with insertion date? (4) Date/time of last dressing change adheres to policy? (4) All CVC tubing is labeled with date/time? (5) All CVC tubing dates adhere to policy? (6) If stopcock is present, is cap present over unused port? “Just-in-time” staff coaching was employed when noncompliance was observed. Findings were sent to leadership for manager follow-up. Staff were informed about products available within the hospital, which can improve dressing adherence and mitigate insertion-site bleeding. Education was provided to staff defining exact requirements for CVC dressings. The acronym “IDOL” was used to help remind staff of these fundamentals: (1) Intact dressing borders are well adhered, with Results: In the first 2 months of rounds, overall compliance averaged 85%. Compliance increased to an average of 91% during the subsequent 10 months. Early on, most fallouts were found with dressings not occlusive or intact and excessive drainage from insertion sites. Initially, 71% of sites were without excess drainage, and 57% of dressings were occlusive or intact. These measures increased to 83% and 89%, respectively, after the interventions. A 50% decrease in the number of CLABSIs was observed during the observation period, compared to the previous 12-month period. Conclusions: Consistent use of bundles has been shown to significantly improve patient outcomes with regard to hospital-acquired infections (HAIs).3 Frequent observations, education to define staff expectations, and holding staff accountable have all helped improve compliance with maintenance bundle elements. Preventing CLABSIs is not only important for patient safety and quality of care. Regulatory and accrediting agencies are now increasing their focus on infections and are tying them to reimbursement.Funding: NoneDisclosures: None

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

Background: Nationally, gaps exist in the timely and appropriate care of young women with breast cancer. Few women receive genetic and fertility counseling, while contralateral prophylactic mastectomy rates rise. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer direct breast cancer treatment and symptom management, but care of young newly diagnosed women requires providers to combine elements of several guidelines and consider an appropriate order of assessments and treatments utilizing multidisciplinary consultation. In Nebraska, fewer than 300 women under age 50 are diagnosed with breast cancer annually. One-third of these women live rurally, miles from the NCCN Member Institution. Thus, rural physicians encounter these patients infrequently and may lack local specialists with whom to consult and refer, thus challenging the provision of the highest quality care. Purpose: To improve the efficacy and efficiency with which rural oncology care providers recognize and address physical, psychosocial, and decision-making needs of young women with breast cancer through development and delivery of education, multidisciplinary consultation, and clinical pathways. Methods: Baseline, 2-year electronic medical record data on surgical, medical, and supportive oncology practice patterns for women with breast cancer under age 50 were collected from the University of Nebraska Medical Center and collaborating rural cancer centers. Records were hand searched for fertility and genetic data. The PROMIS Global Health Survey and Sexual Function Profile, the Brief Subjective Decision Quality Measure, and a project-specific care satisfaction survey were mailed to these patients. Data were entered into SPSS and descriptive statistics used to identify the project’s starting point. Results: To date, clinics (rural and urban) identified a 2-year total of 199 women with breast cancer, ages 21 to 49 years. Cancers were stage 0 (n=21), 1 (n=50), 2 (n=40), 3 (n=19), 4 (n=3), and unavailable (n=66). Eight clinical pathways based on ER, PR, and HER2 status were developed to guide treatment, considerations, evidence-based neoadjuvant and adjuvant therapy, and survivorship care. Pathways, with associated educational webinars and links to NCCN Guidelines, are accessible to providers and patients on the project-derived Pathway to Cure website. Website use and webinar views following program implementation will be reported as will comparison of baseline practice patterns with data at the first 3-month analysis.

Systemic therapy for premenopausal women with hormone receptor–positive breast cancer has evolved in the last 5 years, but critical questions remain. Recent randomized trials have demonstrated a benefit for the addition of ovarian suppression to endocrine therapy in patients with breast cancers considered to be at high risk for recurrence, whereas those with lower-risk cancers seem to have a favorable outcome with tamoxifen alone. Two large randomized trials have demonstrated a benefit for extending adjuvant tamoxifen beyond 5years. Currently the choice of systemic therapy is selected empirically but molecular profiling may, in the near future, provide a more conclusive means of selecting an endocrine therapeutic approach for premenopausal patients. Given that a significant subset of hormone receptor–positive cancers are intrinsically resistant to endocrine agents, as well as the finding that inhibiting cyclin-dependent kinases 4 and 6 and mammalian target of rapamycin appears to potentially reverse this resistance in patients with metastatic disease, evaluation of these agents in the early-stage setting is ongoing.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option.

but has yet to be accepted by all investigators. The heterogeneous nature of MDSCs has stimulated studies to iden -tify the MDSC subpopulation(s) responsible for T-cell suppression. This includes a number of different membrane growth factor receptors and markers of activation (CD80, prostaglandin E

Purpose Engagement in advance care planning (ACP) is viewed as a way to prepare for possible death. In patients undergoing hematopoietic stem-cell transplantation (HSCT), an aggressive but possibly curative procedure for cancer, encouraging engagement in ACP is difficult. We conducted this analysis to determine if engagement in ACP among patients who undergo HSCT is associated with adverse outcomes. Patients and Methods Adult patients who were undergoing their first HSCT for hematologic malignancies between 2001 and 2003 were included. ACP was defined as having a living will, a power of attorney for health care, or life-support instructions. Outcomes assessed included the length of hospital stay, in-hospital mortality, and overall survival. Results Of the 343 patients, 172 did not have ACP, whereas 171 did have ACP, and 127 of those were reviewable. Of those with reviewable ACP, 28 patients (22%) completed ACP before cancer diagnosis, 87 (68%) completed ACP after the cancer diagnosis but before HSCT, and 12 (10%) engaged in ACP after HSCT. Patients without ACP before HSCT had a significantly greater risk of death compared with patients with ACP (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P = .001) while adjusting for statistically significant factors. Conclusion Our study demonstrated that lack of engagement in ACP is associated with adverse outcomes after HSCT. Thus, the patients least likely to have planned for poor outcomes are the ones most likely to face them. Additional studies should evaluate the nature of this association and should seek modifiable explanatory factors that could be the target of interventions.

These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

To assess the effect of diabetes mellitus (DM) on the pathogenesis and outcomes from colon cancer.A retrospective chart review was conducted on 1853 patients with colon cancer.A higher percentage of males than females with colon cancer had DM (16.2% vs 11.3%; p0.01). Males had a slightly lower risk of dying from colon cancer (RR - 0.88; p=0.08). There was no difference in the median age of diagnosis of colon cancer in patients with and without DM, but a larger proportion of patients with diabetes mellitus wereor=70 yr at diagnosis (50% vs 43%) (p=0.0004). No significant relationship was noted between stage of colon cancer or survival and presence of DM.DM did not affect either the stage at diagnosis, or outcomes from colon cancer. More males with colon cancer tended to have DM and a larger proportion of patients with DM wereor=70 yr at the time of diagnosis.

In order to reveal patterns of reproductive aging in birds we focus on a short lived species, the Japanese quail and the American kestrel, which has a life span of medium length. Quail have been studied extensively in the laboratory as models for understanding avian endocrinology and behavior, and as a subject for toxicological research and testing. In the lab, Japanese quail show age-related deterioration in endocrine, behavioral, and sensory system responses; the American kestrel is relatively long lived and shows moderate evidence of senescence in the oldest birds. Using data collected from captive kestrels at the Patuxent Wildlife Research Center, a database was designed to document selected parameters over the life cycle of the kestrels. Life table data collated from many species indicate that longer lived species of birds show senescence in survival ability but this pattern has not been established for reproductive function. We suggest that useful comparisons among species can be made by identifying stages in reproductive life history, organized on a relative time scale. Preliminary data from quail and kestrels, admittedly only two species, do not yet indicate a pattern of greater reproductive senescence in longer-lived birds.

Breast cancer cells have been detected in autologous blood stem cell collections of early stage breast cancer patients, but their clinical significance is undefined. From October 1993 to August 1998, 32 consecutive Stage II breast cancer patients with 4-9-positive nodes underwent stem cell apheresis. The patients were treated with cyclophosphamide 1.75 gm/m(2), etoposide 400 mg/m(2) and cisplatin 50 mg/m(2) daily for 3 days, followed by infusion of the autologous cells. Cytospins of cells from each apheresis collections and from an aliquot of three pooled collections were examined for cytokeratin expression using an immunocytochemical assay. The cells were considered positive for tumor if at least one cell with tumor morphology stained positively for cytokeratin. Negative aliquots were confirmed with RT-PCR. Six patients (19%) had positive collections. In total, 24 patients (75%) were disease free a median of 61 (30-86) months after transplant. Eight patients relapsed at a median of 17 (8-27) months after transplant. Four of the disease-free patients and two of the relapsed patients had positive apheresis collections. There was no significant correlation between the presence of detectable tumor cells in the graft product and outcome.

This study was designed to examine the relationship of prior therapy, bone marrow metastases, mobilization, and blood progenitor/stem cell (BSC) collection in breast cancer patients. Cells were collected from 19 breast cancer patients during steady state (nonmobilized group) and from 69 breast cancer patients after cytokine administration (mobilized group). Characteristics of the patients were compared with the cells obtained. A significant inverse association was found between the number of chemotherapy regimens the patients had received prior to BSC collection and the mononuclear cell (MNC) count of the product per liter of blood processed (LBP) with apheresis (P = .0006) and the granulocyte monocyte/macrophage colony-forming cell (GM-CFC) numbers per LBP (P = .0002). This association was evident in both mobilized and nonmobilized patients. Similar results were seen in those 25 patients who had received prior radiation therapy (MNC/LBP, P = .0003; GM-CFC/LBP, P = .0004). Patients in both the mobilized and nonmobilized groups with marrow metastases at the time of collection also had significantly lower levels of MNC/LBP (P = .0039) and GM-CFC/LBP (P = .0001) than did those without marrow metastases. The findings suggest that prior administration of radiation therapy and/or chemotherapy and the presence of marrow metastases all negatively impacted the collection of mobilized and nonmobilized progenitor cells from breast cancer patients. The mechanisms of this impact are not understood.Biol Blood Marrow Transplant 2002;8(5):268-72.

Bone marrow (BM) is one of the most common sites and often the first clinical indication of metastatic progression of breast cancer. Multivariate analyses have shown that the presence of cytokeratin positive tumor cells in the marrow of women with newly diagnosed stage I, II or III breast cancer is an independent predictor of survival. The objective of this study was to develop an orthotopic model of spontaneous BM metastasis to facilitate studies of this process. A murine mammary adenocarcinoma cell line, Clone 66, was transduced with the neomycin resistance gene (Cl66neo) and injected orthotopically into female Balb/c mice. Polymerase chain reaction (PCR) for the neo gene performed on BM cells harvested from tumor bearing mice demonstrated as few as 10(2) injected tumor cells produced BM micrometastases at 4 weeks postinjection. Small foci of tumor cells were identified in the mammary fatpad (mfp) without gross evidence of primary tumors. Higher doses of tumor cells produced BM micrometastases, detectable by PCR, at one week post-injection. Constructs containing green fluorescent protein (GFP) and the neomycin resistance gene (neo) were also transduced into Clone 66 cells (Cl66-GFPneo) and injected into the mfp. GFP transduced tumor cells were identified in multiple tissues in addition to BM by flow cytometric analysis (FACS) but less 13% of the animals developed gross metastases. This model is a clinically relevant tool for the analysis of organ specificity of metastasis.

A series of para-substituted N-methyl-N-phenylnitrenium ions (N-(4-biphenylyl)-N-methylnitrenium ion, N-(4-chlorophenyl)-N-methylnitrenium ion, N-(4-methoxyphenyl)-N-methylnitrenium ion, and N-(4-methylphenyl)-N-methylnitrenium ion) were generated through photolysis of the appropriately substituted 1-aminopyridinium salt. Laser flash photolysis using UV−vis detection as well as photoproduct analysis verified that the expected nitrenium ions were formed cleanly and rapidly following photolysis. Laser flash photolysis with time-resolved infrared detection allowed for structural characterization of the nitrenium ions through observation of a symmetrical aromatic CC stretch in the region 1580−1628 cm-1. The specific frequencies reflect the degree of quinoidal character present in each phenylnitrenium ion (i.e., the degree to which the nitrenium ion resembles a 4-iminocyclohexa-2,5-dienyl cation). The 4-methoxy derivative shows the highest frequency CC stretch, indicating that this strongly π-electron-donating...

Development of CNS dysfunction in the setting of hematopoietic stem cell transplant (HSCT) has been previously shown to predict for subsequent second organ dysfunction and death. In this paper, we describe the characteristics of this isolated CNS dysfunction, and its relationship to multiple organ dysfunction syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days after the start of the preparative regimen. Compared with 137 patients who developed no organ dysfunction, patients presenting with CNS dysfunction were more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a total body irradiation-based regimen (P = 0.001), and were less likely to have been transplanted for lymphoma (P = 0.008). Patients who developed CNS dysfunction were more likely to die than those with no organ dysfunction (P0. 001). Of the 21 patients who developed CNS dysfunction, 48% resolved their dysfunction by a mean of 4.6 days later without progression to second organ dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of patients with CNS dysfunction progressed to second organ dysfunction (pulmonary or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P = 0.02). The patients who progressed to second organ dysfunction and those who did not were not different in terms of type of HSCT (allogeneic vs autologous), stem cell source (blood vs bone marrow), age, diagnosis or preparative regimen. Development of CNS dysfunction in the setting of HSCT, as with other organ dysfunctions (such as hepatic veno-occlusive disease), probably represents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of transplant-related mortality. Early systemic therapies directed at modulating this systemic disorder are probably indicated. Bone Marrow Transplantation (2000) 25, 79-83.

Poor spellers in 2nd grade (n = 128) participated in 24 20-min sessions that included (a) direct instruction in the alphabet principle (most frequent phoneme-spelling connections); (b) modeling of different approaches, singly and in combination, for developing connections between spoken and written words for 48 words ordered by sound-spelling predictability; and (c) practice in composing. Results of this multilayered intervention showed that (a) more than 1 way of developing sound-spelling connections is effective in teaching spelling but that after training in the alphabet principle, combining whole word and onset-rime training is most effective in achieving transfer of the alphabet principle across word contexts; (b) functional spelling units of not only a single letter but also 2 or more letters are important in beginning spelling; and (c) training in spelling transfers to composition and word recognition.

Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of 4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of

Children with only spelling ( n=24) or handwriting and spelling disabilities ( n=24) were randomly assigned to a pencil or computer response mode. They were taught 48 words of varying orders of sound-spelling predictability using a method that emphasized hearing the word in the mind's ear and seeing the word in the mind's eye and making connections between the phonological and orthographic representations at the whole word and subword levels. Although no main effects were found for response mode, at posttest the pencil was superior to the computer for easy orders (single-letter spelling units with high sound-spelling predictability), but the computer was superior to the pencil for moderate and difficult orders (multiletter spelling units with intermediate or low sound-spelling predictability). Prior to and in response to treatment, children with handwriting and spelling problems spelled less well than children with only spelling problems. Multiletter spelling units of moderate or difficult orders of sound-spelling predictability explained unique increments of variance in spelling achievement, whereas single-letter spelling units of easy order of sound-spelling predictability did not. Based on these findings, instructional recommendations are to provide explicit instruction in the correspondence between sound and multiletter spelling units.

Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) >500/microl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.

Almost 700 children were screened to identify 144 1st graders at risk for handwriting problems who were randomly assigned to 1 of 6 treatment conditions. Treatment was delivered to groups of 3 that met twice a week in 20-min sessions until they completed 24 lessons. Five groups received 10 min of different kinds of handwriting instruction. The contact control group received 10 min of phonological awareness training. All 6 groups composed and shared their writing for 10 min. Converging evidence across multiple measures showed that combining numbered arrows and memory retrieval was the most effective treatment for improving both handwriting and compositional fluency (composing with time limits). Thus instruction aimed at improving transcription transfers to improved text generation in beginning writers.

Sixteen children referred for severe reading problems in first grade participated in a year-long individual tutorial. The tutorial, which was designed to bring children up to expected level based on ability and grade in reading and writing, lasted from the end of first grade to the end of second grade. Growth curve analyses for the group on measures of orthographic and phonological coding, word identification of real words, word attack of pseudowords, reading comprehension, letter automaticity, and spelling showed that gains were significantly greater than chance. Growth curves for the group were marginally significant for written composition. Individual subject analysis revealed that most children were treatment responders (i.e., growth significantly greater than chance) on most of the measures and all reached expected levels, based on ability or grade, on some of the measures. Results have implications for analysis of response to intervention in reading and writing as a form of dynamic assessment.

In an effort to determine whether subcutaneous or continuous intravenous infusion administration of rhGM-CSF results in better hematopoietic progenitor mobilization, the findings of two sequential clinical trials were reviewed. Patients who had received prior chemotherapy for leukemia, lymphoma, multiple myeloma, breast cancer, or other solid tumors and were candidates for high-dose therapy received rhGM-CSF, 250 micrograms/m2/day, either as a continuous intravenous infusion (trial 1) or subcutaneously (trial 2) for stem cell mobilization. At least five apheresis collection procedures were performed to collect a target number of 6.5 x 10(8) mononuclear cells (MNC)/kg. For the 37 patients in trial 1, the collections contained a median of 7.99 x 10(8) MNC/L (range 6.42-21.36) and a median of 5.27 x 10(4) CFU-GM/kg (range 0.28-19.35). In trial 1, 25 patients were autografted with their cells and recovered 0.5 x 10(9) granulocytes/L at a median of 12 days (range 6-16). For the 33 patients in trial 2, the autograft product contained a median of 7.63 x 10(8) MNC/kg (range 6.51-22.66) and 6.31 x 10(4) CFU-GM/kg (range 0.06-60.4). In trial 2, 25 patients were autografted. The median time to reach 0.5 x 10(9) granulocytes/L was 11 days (range 9-26). All patients received rhGM-CSF after peripheral stem cell transplant. No significant differences in the collected products or the time to hematopoietic recovery was found between the two trials (p0.05). The mobilization effects of subcutaneous rhGM-CSF in these pretreated patients were similar to those of intravenous rhGM-CSF.

Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effect on hematopoietic recovery and (2) the effect on the underlying malignancy. The dynamics of hematopoietic recovery after autologous bone marrow transplantation and after autologous peripheral blood stem cell transplantation in a clinical setting are similar if no exogenous cytokines are administered and the peripheral stem cells are collected while their numbers are not deliberately increased (mobilised). If mobilized peripheral stem cells are transplanted, hematopoietic recovery is accelerated. In some circumstances, patients who receive peripheral stem cell transplantation may experience an improved progression-free survival after high-dose therapy when compared with similar patients who receive autologous bone marrow transplantation. Explanations for such a survival advantage might include (1) a lower likelihood of occult tumor cells capable of restoring disease in peripheral stem cell autograft products than in bone marrow harvests, (2) a greater number of cytotoxic effector cells capable of destroying occult tumor cells in the peripheral stem cell collections than in bone marrow harvests, and (3) a different and advantageous pattern of immunologic recovery following autologous peripheral stem cell transplant compared to autologous bone marrow transplant.

Objectives:Evaluate aerobiological monitoring for fungal spores during hospital construction and correlate results with an outbreak of invasive aspergillosis (IA).Design:Prospective air sampling for molds was done using the gravity air-settling plate (GASP) method.Setting:A university medical center special care unit consisting of single-patient rooms with high-efficiency particulate air filtration under positive pressure.Patients:Five neutropenic patients who subsequently developed IA.Result:Four of the five patients with IA were housed in rooms adjacent to a construction staging area. Aerobiological monitoring detected an increase in the number of airborne fungal spores including Aspergillus species in these rooms; however, increased counts preceded IA diagnosis by 1 to 7 days in only three of the five patients. Swab cultures of the exhaust vents within each room confirmed results from air-settling plates. Follow-up monitoring, using the GASP method, demonstrated that control procedures were effective in reducing air mold contamination.Conclusion:The GASP method, although able to demonstrate that infection control measures reduced mold contamination of the air, was insensitive to detect levels of mold contaminates in time to prevent IA.

background: Diffuse alveolar hemorrhage is a frequent complication of treating malignancies with high-dose chemotherapy and bone marrow transplantation and is associated with very high mortality. This disorder's association with pulmonary inflammation, its coincidence with marrow recovery, and the usefulness of corticosteroids for treating other pulmonary hemorrhage syndromes provided the rationale for this study. methods: We retrospectively studied 65 episodes of diffuse alveolar hemorrhage that had occurred in 63 of 603 consecutively treated patients who had undergone high-dose chemotherapy with bone marrow transplantation. Patients were divided into three groups according to the therapy they had received for diffuse alveolar hemorrhage: supportive therapy alone (n = 12); low-dose corticosteroids (30 mg or less of methylprednisolone or its equivalent; n=10); and high-dose corticosteroids (more than 30 mg methylprednisolone or its equivalent; n=43). The primary outcome measures were overall survival and survival to hospital discharge, occurrence of respiratory failure requiring intubation, and development of infections subsequent to the diagnosis of diffuse alveolar hemorrhage. results: Overall survival at the end of the follow-up period was significantly higher for the high-dose corticosteroid group compared with the supportive therapy group ( P = 0.005); however; treatment with low-dose steroids did not increase survival over supportive therapy alone ( P = 0.198). In addition, survival to discharge was significantly increased for the high-dose group compared with the other two groups combined (33% versus 9.1%, P = 0.038). Respiratory failure after the diagnosis of diffuse alveolar hemorrhage developed in only 12 of the 22 unintubated patients in the high-dose group compared with 9 of the 10 initially unintubated patients in the other two groups ( P = 0.056). Although the incidence of infections was high (40%) subsequent to diffuse alveolar hemorrhage, neither high-dose nor low-dose corticosteroid treatment significantly increased the risk of infections ( P >0.4, all comparisons). conclusions: In this study, high-dose corticosteroid therapy for diffuse alveolar hemorrhage related to bone marrow transplantation was associated with improved total survival and survival to hospital discharge, and decreased development of respiratory failure in these patients. These results suggest the therapy is beneficial, and further prospective studies are warranted to verify the effectiveness of the treatment.

Between June 1989 and June 1992, 144 patients participated in sequential clinical trials using peripheral blood progenitor cells (PBC) as their sole source of hematopoietic rescue following high-dose chemotherapy. All patients had received prior extensive combination chemotherapy and had marrow defects that precluded autologous bone marrow transplantation (ABMT). PBC were collected according to a single apheresis protocol. The initial 86 patients (group 1) had PBC collected without mobilization. Beginning in April 1991, PBC were mobilized solely with recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). Thirty-four patients (group 2) received rHuGM-CSF at a dose of 125 micrograms/m2/d by continuous intravenous infusion, and 24 patients (group 3) received rHuGM-CSF at a dose of 250 micrograms/m2/d by continuous intravenous infusion. Patients underwent at least six aphereses and had a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg collected. Cytokines were not routinely administered immediately after transplantation. A median of nine aphereses were required to collect PBC in group 1 and seven aphereses for groups 2 and 3 (P = .03). The time required to recover 0.5 x 10(9)/L granulocytes after transplant was significantly shorter (P = .0004) for the mobilized groups; the median time to recovery was 26 days for group 1, 23 days for group 2, and 18 days for group 3. Transplantation of PBC mobilized with rHuGM-CSF resulted in a shorter time to platelet (P = .04) and red blood cell (P = .01) transfusion independence. Mobilization with rHuGM-CSF alone resulted in efficient collection of PBC, that provided rapid and sustained restoration of hematopoietic function following high-dose chemotherapy. Mobilization of PBC with rHuGM-CSF alone is an effective method for patients who have received prior chemotherapy and have bone marrow abnormalities.

purpose: A prospective study to determine the usefulness of quantitative bacterial cultures of fluid obtained via fiberoptic bronchoscopy and bronchoalveolar lavage as an aid in the diagnosis of bacterial pneumonia. patients and methods: All patients undergoing fiberoptic bronchoscopy with bronchoalveolar lavage during a 612-month period. Presence of pneumonia was determined using clinical, radiographic, laboratory, and histologic data. Quantitative bacterial cultures of bronchoalveolar lavage fluid were determined using a 1-μL culture loop. results: Quantitative bacterial cultures of bronchoalveolar lavage (BAL) fluid were sensitive and specific predictors of bacterial pneumonia. Using 10 3 colony-forming units (cfu)/mL as the threshold value for a positive culture, we determined the sensitivity and specificity to be 90% and 97%, respectively. The data were also analyzed for the subgroups of patients who were intubated or were receiving antibiotics. The sensitivity and specificity were 78% and 96% for the group of patients receiving antibiotics and 100% and 82% for the group of patients intubated for more than 24 hours at the time of BAL. Values for the area under the receiver operating characteristic curve for the 3 groups were 0.94, 0.88, and 0.96, respectively. conclusions: Quantitative bacterial cultures of BAL fluid are sensitive and specific in the diagnosis of bacterial pneumonia. The use of antibiotics at the time of BAL reduces the sensitivity of the test, and prolonged intubation reduces the specificity of the test.

PURPOSE To compare the use of intravenous (IV) hydration plus either continuous bladder irrigation or mesna for the prevention of hemorrhagic cystitis in the bone marrow transplant setting. PATIENTS AND METHODS Two hundred patients were prospectively randomized to receive either continuous bladder irrigation with 200 mL/h of normal saline, or continuous infusion mesna at 100% of the cyclophosphamide dose. RESULTS The overall incidence of hematuria of any grade was significantly higher in the bladder-irrigation group (76%) compared with the mesna group (53%) (P = .007). However, the incidence of grade III and IV hematuria was the same in both groups (18%; P = NS). Moderate or severe discomfort or bladder spasms were reported in 84% of the patients who received bladder irrigation, compared with 2% of the patients who received mesna prophylaxis (P < .0001). Urinary tract infections (UTIs) were documented in 27% of the patients in the bladder-irrigation group, compared with 14% of the patients in the mesna group (P = .03). CONCLUSION Both continuous bladder irrigation and mesna were equally effective in preventing severe hemorrhagic cystitis associated with high-dose cyclophosphamide and bone marrow transplantation. However, the use of mesna was associated with significantly less discomfort and a lower incidence of UTIs.

Infections occurring after autologous bone marrow transplantation are similar to infections reported in the early and mid posttransplant periods after allogeneic transplant. The viral and bacterial complications linked with acute and chronic graft-versus-host disease that occur in the mid to late post-transplant periods are uncommon after autologous transplant. The most common bacterial, fungal, and viral infections that occur after autologous transplant as well as management strategies for controlling them are discussed.

Objectives:To determine the prevalence of aspergillosis in lymphoma patients housed in a protective environment while undergoing a bone marrow transplant or peripheral stem cell transplant and its relation to lymphoma type, type of transplant, period of neutropenia, method of diagnosis, species of Aspergillus, and the use of empiric amphotericin B.Design:Clinical, autopsy, and microbiology records were reviewed retrospectively to determine the presence or absence of invasive aspergillosis. All positive specimens underwent further review to determine parameters outlined above.Setting:The review took place at the University of Nebraska Medical Center with lymphoma patients housed in the oncology/hematology special care unit, which consists of 30 single-patient rooms under positive pressure with high-efficiency particulate air filtration.Patients:4 17 lymphoma patients admitted to the oncology/hematology special care unit who underwent 427 courses of high-dose chemotherapy with or without total body irradiation followed by a stem cell rescue.Results:Twenty-two cases (5.2%) of nosocomial invasive aspergillosis (14 caused by Aspergillus flavus, 2 by Aspergillus terreus, 2 by Aspergillus fumigatus, and 4 by characteristic histology) were diagnosed. The prevalence of disease according to transplant was 8.7% for allogeneic bone marrow transplant (2/23 treatments), 5.6% for autologous peripheral stem cell transplant (9/161), and 4.5% for autologous bone marrow transplant (11/243). Fifteen patients were presumptively diagnosed prior to death (68.2%) most commonly by histologic examination of skin biopsies. All 22 patients received amphotericin B therapy, 17 prior to aspergillosis diagnosis, and 7 (31.8%) survived. No patient with disseminated disease survived.Conclusions:Even when housing lymphoma patients undergoing myeloablative therapy in a protective environment containing high-efficiency particulate air filtration, there was a risk of developing aspergillosis. These data also showed that antemortem diagnosis with aggressive amphotericin B therapy was most effective in the management of infected lymphoma patients when engraftment occurred and the disease did not become disseminated.

Overview The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer: Noninvasive and Special Situations presented here are the work of the NCCN Breast Cancer panel members. Categories of evidence and consensus were assessed and are noted in the algorithms and text. Although not explicitly stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer. These NCCN Guidelines foNCCN

Of 1506 marrow transplant patients from 1980 through 1986 reviewed for risk factors for invasive candidal infection defined by positive blood cultures, biopsy, or histologic evidence of tissue invasion, 171 (11.4%) had invasive infection, with a significantly higher incidence in the more recent years of review; 40% (69 patients) had evidence of tissue-invasive disease without fungemia. Of 102 patients with fungemia, 45% had candidemia alone with a mortality of 39%. Mortality in patients with tissue involvement was 90% with or without fungemia. Factors that increased infection were age, acute graft-versus-host disease, and donor mismatch. Factors that decreased infection included conditioning with 12 Gy of fractionated irradiation and cyclophosphamide, transplantation for aplastic anemia, and more rapid engraftment. Among fungemic patients, the number of days of fungemia was a risk factor for tissue invasion while more rapid engraftment was protective.

Diffuse alveolar hemorrhage is a life-threatening complication after bone marrow transplantation. We investigated the radiographic abnormalities that occurred in 39 transplantation patients with a diagnosis of diffuse alveolar hemorrhage and correlated the findings with the patients' clinical course. The initial radiographic abnormalities after diffuse alveolar hemorrhage developed an average of 11 days after bone marrow transplantation, and the radiographic abnormalities preceded the clinical diagnosis by an average of 3 days. Twenty-seven patients initially had bilateral radiographic abnormalities; 10 initially had unilateral abnormalities (seven in the right lung, three in the left lung). Two patients had normal chest radiographs throughout their clinical course. All 37 patients with radiographic abnormalities had abnormalities involving the central portion of the lung, primarily the middle and lower lung zones. The initial radiographic pattern was interstitial in 27 and alveolar in 10. In 24 patients, radiographic abnormalities were initially judged to be mild; three were severe from the onset. Radiographic abnormalities rapidly worsened in most patients over 6 days. In 30 patients, diffuse bilateral radiographic abnormalities involving all lung zones developed. Eleven patients persisted in having only interstitial radiographic abnormalities; 26 had a confluent alveolar pattern. At the height of radiographic abnormalities, 27 cases were judged to be severe, and only one case was judged to be mild. The mortality rate in patients with diffuse alveolar hemorrhage was 77%. The radiographic abnormalities of diffuse alveolar hemorrhage are nonspecific and usually precede the clinical diagnosis. The clinical course after hemorrhage is short, often resulting in death.

UNLABELLED During a 38-month period, we studied 320 liver transplants in 283 recipients (202 adults, 81 children). CMV disease was documented in 85 patients (30.0%) The major risk factor for CMV disease was primary CMV exposure (transplanting a seropositive allograft into a seronegative recipient). A total of 42 patients (14.8%) had primary CMV exposure. Twenty-one patients were historical controls, while the next 21 received prophylaxis for CMV infection in a nonrandomized trial of consecutive study groups. The regimen of prophylaxis consisted of intravenous immune globulin (IgG; 0.5 g/kg) at weekly intervals for 6 weeks and acyclovir for 3 months. CMV prophylaxis resulted in a dramatic reduction in the incidence of CMV disease (71.4% vs. 23.8%, (P less than 0.01). All cases of CMV were treated with intravenous ganciclovir (5 mg/kg b.i.d. for 14 days), with 5 patients in the control group developing recurrent CMV disease (33.3% relapse). In the 16 patients receiving prophylaxis who did not develop CMV disease, all developed positive CMV-IgG titers with the passive administration of IgG. However, none developed any evidence of CMV infection or viral shedding as assessed by IgM titers and surveillance viral cultures. Four deaths occurred (all control patients), but none were related to CMV disease. Overall patient and graft survivals after primary CMV exposure were 90.5% and 82.2%, respectively, after a mean follow-up of 14 months. CONCLUSION Primary CMV exposure is a major risk factor for CMV disease in liver transplant recipients. Intravenous IgG plus acyclovir is safe and effective in preventing CMV infection and disease in this setting. Because of the scarcity of donor organs, we do not advocate protective matching to avoid primary CMV exposure but rather recommend prophylaxis to prevent CMV disease in this high-risk group.

Objective.To characterize infection control experience during a 6.5-year period in a cooperative care center for transplant patients.Design.Descriptive analysis.Setting.A cooperative care center for transplanted patients, in which patients and care partners are housed in a homelike environment, and care partners assume responsibility for patient care duties.Patients.Nine hundred ninety one transplant patients.Methods.Infection control definitions from the Centers for Disease Control and Prevention were used to ascertain infection rates. Environmental cultures were used to detect methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-resistantEnterococcus(VRE),Clostridium difficile,and fungi during the first 18 months. Surveillance cultures were performed for a subset of patients and care partners.Results.From June 1999 through December 2005, there were 19,365 patient-days observed. The most common healthcare-associated infection encountered was intravascular catheter-related bloodstream infection, with infection rates of 5.74 and 4.94 cases per 1,000 patient-days for hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) patients, respectively. G difficile-associated diarrhea was observed more frequentiy in HSCT patients than in SOT patients (3.97 vs 0.57 cases per 1000 patient-days;P<.0001 ). There was no evidence of environmental contamination with MRSA, VRE, or C.difficile.Acquisition of MRSA was not observed. Acquisition of VRE was documented.Conclusion.This study documented that cooperative care was associated with some risk of healthcare-associated infection, most notably intravascular catheter-associated bloodstream infection and C. difficile-associated diarrhea, it appears the incidences of these infections were roughly commensurate with those in other care settings.

Anticancer immunotherapy using dendritic cell (DC) based vaccines provides an adjuvant therapeutic strategy that is not cross reactive with conventional therapeutics. However, manufacturing of DC vaccines requires stringent adherence to Good Manufacturing Practice (GMP) methods and rigorous standardization. Optimally this includes a closed system for monocyte isolation, in combination with closed culture and washing systems and an effective vector transduction strategy. In this study, we used the Gambro Elutra to enrich monocytes from non-mobilized leukapheresis products collected from healthy donors. This approach enriched monocytes from an average frequency of 13.6 + 3.2% (mean + SEM), to an average frequency of 79.5 + 4.3% following enrichment with a yield of 79 to 100%. The monocytes were then cultured in a closed system using gas permeable Vuelife fluoroethylene propylene (FEP) bags and X-vivo-15 media containing 10 ng/ml granulocyte-macrophage colony-stimulation factor (GM-CSF) and 5 ng/ml Interleukin (IL) 4. The cultures were re-fed on days two and four, with a 25% media volume and cytokines. Following culture for seven days, the cells were harvested using a Cobe-2991 and concentrated using a bench centrifuge retrofitted with blocks to allow centrifugation of 72 ml bags and supernatant removed using a plasma extractor. This approach reduced the media volume to an average of 17.4 ml and an average DC concentration of 6.3 + 1.0 × 107 cells/ml, a viability of 93.8 + 2.2%, a purity of 88.9 + 3.3% and a total yield of 8.5 + 1.4 × 108 DCs. Based on the identification of DR+ cells as DCs we had an average yield of 46 + 8% using a calculation based on the number of monocytes in the apheresis product and the resulting DCs differentiated from monocytes. The use of DCs as a vaccine, required transduction with an adenovirus (Adv) vector with the tumor suppressor, p53 transgene (Adv5CMV-p53) as the antigen at a DC concentration of 9 × 106 DCs/ml at an Ad5CMV-p53: DC ratio of 20,000:1, and a 2 or 3 hour co-culture, followed by a 1:10 dilution with media and an additional 16–22 hour incubation. Following incubation, the DCs were washed twice and the supernatants removed using a plasma extractor. The average viability after infection with Ad5CMV-p53 was 87.9 ± 2.6% with an average of 20.3 + 5.4% of the DCs expressing p53. The calculated yield of DCs following Ad5CMV-p53 transduction, based on the number of monocytes in the apheresis products, averaged 12.4 + 3.8%. We conclude that it is possible to efficiently manufacture Adv transduced DCs using a functionally closed system.