Propensity Score Analysis of Conditioning Intensity in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation.

T cell replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) of 148 patients that underwent haplo-HCT with either MAC (n = 61) or RIC (n = 87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (hazard ratio [HR], .47; 95% confidence interval [CI], .31 to .70), but was associated with higher NRM (HR, 1.74; 95% CI, 1.13 to 2.67). OS and DFS were not significantly different between groups (HRs for MAC versus RIC were .87 [95% CI, .64 to 1.18] and .90 [95% CI, .68 to 1.18] for OS and DFS, respectively). Rates of acute and chronic GVHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo-HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study.

Severe Cytokine-Release Syndrome after T Cell-Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti-IL-6 Therapy Is Safe and Well Tolerated.

Use of high-dose post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis has expanded the use of unmanipulated haploidentical hematopoietic cell transplantation. The immediate post-transplantation course in T cell-replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling cytokine-release syndrome (CRS), previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received granulocyte colony-stimulating factor-mobilized T cell-replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T cell therapies, we found 65 of 75 (87%) met criteria for CRS, although most cases were only mild (grades 1 or 2). However, 9 patients (12%) experienced severe (grades 3 or 4) CRS. Median survival was 2.6 months (95% confidence interval [CI], .43 to 5.8) in patients with severe CRS, compared with 13.1 months (95% CI, 8.1 to not reached) in patients with mild CRS. Transplantation-related mortality was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI, 1.43 to 14.67) compared with that in the mild CRS cohort. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in 10 haplo-HCT patients and were elevated in the early post-transplantation setting. Seven patients with CRS were treated with tocilizumab, resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT and is associated with worse outcomes. Anti-IL-6 receptor therapy is associated with rapid resolution of the CRS symptoms.

Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs).

OBJECTIVE: To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs). BACKGROUND: PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor. METHODS: A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival and disease-free survival were calculated using Kaplan-Meier method. Results were expressed as P values and odds ratio estimates, with 95% confidence intervals. RESULTS: One hundred thirty-six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for larger tumors [> 1.5 cm (odds ratio [OR] = 4.7)], tumors of the head as compared with body-tail of the pancreas (OR = 2.8), tumors with Ki-67 greater than 20% (OR = 6.7), and tumors with lymph vascular invasion (OR = 3.6) (P < 0.05). Median disease-free survival was lower for patients with nodal metastases (4.5 vs 14.6 years, P < 0.0001). CONCLUSIONS: Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectomy in patients undergoing pancreatic resections for PNET.

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia.

The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.

Primary care visits for asthma monitoring over time and association with acute asthma visits for urban Medicaid-insured children.

OBJECTIVES: To examine the association between numbers of primary care provider (PCP) visits for asthma monitoring (AM) over time and acute asthma visits in the emergency department (ED) and at the PCP for Medicaid-insured children. METHODS: We prospectively enrolled 2-10 years old children during ED asthma visits. We audited hospital and PCP records for each subject for three consecutive years. We excluded subjects also receiving care from asthma subspecialists. PCP AM visits were those with documentation that suggested discussion of asthma management but no acute asthma symptoms or findings. PCP "Acute Asthma" visits were those with documentation of acute asthma symptoms or findings, regardless of treatment. ED asthma visits were those with documented asthma treatment. Generalized liner models were used to analyze the association between numbers of AM visits and acute asthma visits to the ED and PCP. RESULTS: One hundred three subjects were analyzed. Over the 3 years, the mean number of AM visits/child was 2.5 ± 2.3 (standard deviation), range 0-10. Only 50% of subjects had at least 1 PCP visit with an asthma controller medication documented. The mean number of ED asthma visits/child was 3.2 ± 2.8; range 1-18. The mean number of PCP Acute Asthma visits/child was 0.7 ± 1.6; range 0-11. Increasing AM visits was associated with more ED visits (estimate 0.088; 95% CI 0.001, 0.174), and more PCP Acute Asthma visits (estimate 0.297; 95% CI 0.166, 0.429). Increasing PCP visits for any diagnosis was not associated with ED visits (estimate 0.021; 95% CI -0.018, 0.06). CONCLUSIONS: Asthma monitoring visits and documented controller medication for these urban Medicaid-insured children occurred infrequently over 3 years, and having more asthma monitoring visits was not associated with fewer ED or PCP acute asthma visits.

Appraisal of emerging symptoms of colorectal cancer: associations with dispositional, demographic, and tumor characteristics.

The time it takes for individuals to realize that their emerging colorectal cancer (CRC) symptoms are serious is often an impediment to expeditious help-seeking. Tailored educational efforts to hasten symptom appraisal time would benefit from knowledge of the characteristics of individuals who tend to neglect their symptoms as well as the nature of symptoms that are most often neglected. In a sample of 112 CRC patients, we investigated associations between duration of symptom appraisal and: (1) trait anxiety, and (2) tumor location, which affects symptomatology. Symptom appraisal duration was associated with a sex-by-anxiety interaction (p = 0.007). The longest times (in weeks) were among high anxiety females (Mdn = 26.0) and low anxiety males (Mdn = 17.0), with shorter times among low anxiety females (Mdn = 9.0) and high anxiety males (Mdn = 2.0). Symptom appraisal times were also longer for patients with distal (vs. proximal) tumors (p = 0.036).

Glycogen synthase kinase 3ß inhibition as a therapeutic approach in the treatment of endometrial cancer.

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3ß (GSK3ß), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3ß inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3ß by either lithium chloride (LiCl) or specific GSK3ß inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3ß activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.

A gene expression signature that predicts the therapeutic response of the basal-like breast cancer to neoadjuvant chemotherapy.

Several gene expression profiles have been reported to predict breast cancer response to neoadjuvant chemotherapy. These studies often consider breast cancer as a homogeneous entity, although higher rates of pathologic complete response (pCR) are known to occur within the basal-like subclass. We postulated that profiles with higher predictive accuracy could be derived from a subset analysis of basal-like tumors in isolation. Using a previously described "intrinsic" signature to differentiate breast tumor subclasses, we identified 50 basal-like tumors from two independent clinical trials associated with gene expression profile data. 24 tumor data sets were derived from a 119-patient neoadjuvant trial at our institution and an additional 26 tumor data sets were identified from a published data set (Hess et al. J Clin Oncol 24:4236-4244, 2006). The combined 50 basal-like tumors were partitioned to form a 37 sample training set with 13 sequestered for validation. Clinical surveillance occurred for a mean of 26 months. We identified a 23-gene profile which predicted pCR in basal-like breast cancers with 92% predictive accuracy in the sequestered validation data set. Furthermore, distinct cluster of patients with high rates of cancer recurrence was observed based on cluster analysis with the 23-gene signature. Disease-free survival analysis of these three clusters revealed significantly reduced survival in the patients of this high recurrence cluster. We identified a 23-gene signature which predicts response of basal-like breast cancer to neoadjuvant chemotherapy as well as disease-free survival. This signature is independent of tissue collection method and chemotherapeutic regimen.

The Cancer Pain Inventory: preliminary development and validation.

OBJECTIVE: The purpose of this study was to develop a Cancer Pain Inventory (CPI) that measures cancer patients' beliefs and concerns about pain. This paper describes development and pilot testing of a preliminary version of the CPI and describes its psychometric properties including its reliability and validity relative to established pain measures. METHODS: Subjects were recruited from inpatient and outpatient oncology services of an NCI-designated comprehensive cancer center. Participants completed the 50 potential CPI items and these standard measures-Orientation-Memory-Concentration Test, Survey of Pain Attitudes, Brief Pain Inventory, Pain Disability Index, and Center for Epidemiological Studies-Depression Scale. The magnitude and significance of associations between the CPI and the other measures were examined. RESULTS: Of 366 patients who were eligible and agreed to participate in the study, 262 completed the questionnaires. Principal components analyses were used to select items most appropriate for retention in the preliminary version of the CPI and to describe its factor structure. Based on the content of items that loaded on each factor, the five factors were labeled as Catastrophizing, Interference with Functioning, Stoicism, Social Aspects, and Concerns about Pain Medication. Correlations between the CPI and other measures supported construct validity of the five CPI factors. CONCLUSIONS: The results supported the validity of the CPI as a measure of five constructs relevant to the experience of pain in the cancer setting. The results also underscored the presence of unique features of cancer-related pain that clearly differ from commonly recognized dimensions of chronic, non-cancer-related pain.

Trait anxiety as an independent predictor of poor health-related quality of life and post-traumatic stress symptoms in rectal cancer.

OBJECTIVES: To determine the influence of trait anxiety on patient reports of health-related quality of life (HRQoL) and post-traumatic stress symptoms (PTSS) in a sample of rectal cancer survivors. DESIGN: Eighty patients who had been diagnosed with rectal cancer were assessed at two points in time in a longitudinal study. METHODS: At Time 1, soon after initial treatment, participants completed the State-Trait Anxiety Inventory and the Temperament and Character Inventory Harm Avoidance scale, which were combined into a composite measure of trait anxiety. At Time 2, 2-5 years following Time 1, participants were assessed for HRQoL using the Functional Assessment of Cancer Therapy-Colorectal scale (FACT-C) and for PTSS using the Impact of Event Scale-Revised (IES-R). RESULTS: HRQoL and PTSS were generally favourable on average, although many of the patients reported faring poorly. Higher levels of trait anxiety were predictive of poorer scores on all of the FACT-C and the IES-R total and subscale measures. More severe faecal incontinence was associated with poorer scores on the FACT Emotional well-being subscale, the FACT-Colorectal Cancer Scale, and all of the IES-R scales. Males were more likely than females to have poorer scores on the FACT Social well-being subscale, and those patients who were further out from active treatment had more favourable scores on the FACT-Colorectal Cancer Scale. The presence of a colostomy did not impact HRQoL or PTSS. CONCLUSION: Trait anxiety had a significant influence on HRQoL and PTSS several years following diagnosis and treatment of rectal cancer.

Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients.

PURPOSE: Micrometastatic cells detected in the bone marrow have prognostic significance in breast cancer. These cells are heterogeneous and likely do not exhibit uniform biological behavior. To understand the molecular diversity of disseminated cancer cells that reside in bone marrow, we enriched this cell population and did global gene expression profiling in the context of a prospective clinical trial involving women with clinical stage II/III breast cancer undergoing neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: Enrichment of TACSTD1 (EpCAM)-expressing cells from bone marrow of breast cancer patients was achieved using immunomagnetic beads. Gene expression profiles were compared between enriched cell populations and whole bone marrow from 5 normal volunteers and 23 breast cancer patients after neoadjuvant chemotherapy treatment. Enriched cells from bone marrow samples of breast cancer patients before treatment or at 1 year follow-up were also analyzed (total of 87 data sets). The expression of transcripts specifically detected in enriched cell populations from breast cancer patients was correlated with 1-year clinical outcome using quantitative reverse transcription-PCR in an independent cohort of bone marrow samples. RESULTS: Analysis of EpCAM-enriched bone marrow cells revealed specific expression of a subgroup of transcripts, including the metastasis regulator, TWIST1. Most transcripts identified, including TWIST1, were not expressed in enriched populations of bone marrow from normal volunteers, suggesting that this expression profile reflects a signature of breast cancer bone marrow micrometastases that persist after chemotherapy. In an independent set of bone marrow samples obtained before any treatment, TWIST1 expression correlated with early disease relapse. CONCLUSIONS: Disseminated breast cancer cells present in bone marrow after chemotherapy possess unique transcriptional signatures. Genes whose expression is overrepresented in these cell populations, such as TWIST1, may prove to be excellent markers of early distant relapse in breast cancer patients.

Relation of age, severity of illness, and hemodynamics with brain natriuretic peptide levels in patients <20 years of age with heart disease.

Brain natriuretic peptide (BNP) levels were obtained before cardiac catheterization in 193 pediatric patients with a variety of cardiac lesions. Age and functional status had strong relations to BNP values, with elevations of BNP levels associated with increasing functional disability and decreasing age. Mild but statistically significant correlations were found between BNP levels and right-sided cardiac pressures. In patients with volume-overloaded ventricles, BNP correlated with the degree of overcirculation.

Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.

The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide.

Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 patients with dual refractory/intolerant myeloma diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p = 0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.

IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity.

BACKGROUND: Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs. METHODS: 7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST. RESULTS: 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients. CONCLUSION: These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8+ T cell immunity in humans with cancer.

Sex differences in responding to rectal cancer symptoms.

Many people who develop cancer symptoms wait inordinate amounts of time before seeking medical attention. Studies have found that symptom appraisal time--the time that passes before the individual concludes that their symptoms could be serious--accounts for most of the total delay time across subjects. It is thus important to understand the individual characteristics associated with slow recognition of dangerous symptoms. In this study, 62 patients (38 males) recently diagnosed with rectal cancer answered questions regarding the development of symptoms as well as their decisions and behaviors prior to seeking help. One subgroup of patients--males with the lowest scores on a measure of trait anxiety--took significantly longer to recognize the seriousness of their symptoms as compared to all other patients. This finding is discussed in the context of recent studies where the interaction of sex and negative affect is related to symptom reporting and other health-related behaviors.

Porous implant exposure: Incidence, management, and morbidity.

PURPOSE: To identify what factors may predispose patients to exposure of porous anophthalmic implants and to determine the outcome of exposed porous implants. METHODS: Examination of pooled data obtained through a PubMed literature search of English-language publications from 1989 through 2004 using the key words enucleation, evisceration, and socket reconstruction. RESULTS: Porous implants were inserted in 80% (3012 of 3777) of the cases identified from 49 publications. The difference in exposure rate between coralline hydroxyapatite (4.9%) and porous polyethylene (8.1%) implants is primarily related to a higher reported complication rate of uncovered porous polyethylene implants, particularly in retinoblastoma patients. Other techniques associated with increased exposures include wrapping implants with bovine pericardium or polyglactin mesh. Evisceration and secondary procedures did not have statistically different complication rates compared with enucleation. There are more late exposures of porous polyethylene than coralline hydroxyapatite implants. Spontaneous healing of exposures occurred in 13% (19 of 145) of cases. Covering exposures with patch grafts underneath vascularized conjunctival flaps was the most successful method of surgical repair. Implant removal was necessary after 29% (42 of 145) of exposures. CONCLUSIONS: Although the published literature between 1989 and 2004 reports higher complication rates for uncovered porous implants and implants wrapped with bovine pericardium or polyglactin mesh, pooling data from different studies may mask very good or poor results obtained by individual surgeons. Spontaneous healing of exposed porous implants is relatively uncommon. However, many exposed porous implants can be salvaged with secondary repair.

Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100.

Circulating endothelial progenitor cells (EPCs) are thought to contribute to angiogenesis following vascular injury, stimulating interest in their ability to mediate therapeutic angiogenesis. However, the number of EPCs in the blood is low, limiting endogenous repair, and a method to rapidly mobilize EPCs has not been reported. In this study, healthy donors were mobilized sequentially with the CXCR4 antagonist, AMD3100, and G-CSF. The number of EPCs and circulating angiogenic cells (CACs) in the blood and pheresis product was determined and the angiogenic capacity of each cell population assessed. Compared with baseline, treatment with AMD3100 or G-CSF increased the number of blood CACs 10.0-fold +/- 4.4-fold and 8.8-fold +/- 3.7-fold, respectively. The number of EPCs in the blood increased 10.2-fold +/- 3.3-fold and 21.8-fold +/- 5.4-fold, respectively. On a percell basis, CACs harvested from G-CSF-mobilized blood displayed increased in vivo angiogenic potential compared with AMD3100-mobilized CACs. Mobilized EPCs displayed a greater proliferative capacity than EPCs isolated from baseline blood. Both CACs and EPCs were efficiently harvested by leukapheresis. Cryopreserved CACs but not EPCs retained functional activity after thawing. These data show that AMD3100 is a potent and rapid mobilizer of angiogenic cells and demonstrate the feasibility of obtaining and storing large numbers of angiogenic cells by leukapheresis.