Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia

The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Identification of bombesin-immunoreactive cells in rat, human, and other mammalian pituitaries, their ontogeny and the effect of endocrine manipulations in the rat.

Bombesin and gastrin-releasing peptide are homologous peptides which have biological activity in mammals. The distribution of bombesin immunoreactivity in rat, guinea pig, cat, dog, pig, cow, monkey, and human pituitaries was investigated using immunocytochemistry with various different antisera. Polyclonal antisera identified bombesin-immunoreactive (IR) cells in the anterior pituitaries of all species except monkey and human, although positive nerves were present in the human posterior lobe. In contrast, a monoclonal antibody demonstrated bombesin-IR cells in anterior and intermediate lobe (or equivalent) of all species. Both types of antibodies identified the anterior pituitary cells as somatotrophs, which may be significant because bombesin and related peptides influence pituitary growth hormone secretion. Differences in bombesin immunoreactivity were seen in male and female rats, with males having more positive cells, and females showing more intense immunoreactivity in those cells which were positive. Ontogenetic studies in rats revealed that bombesin-IR cells were first seen at birth. The effect of estrogen on bombesin-IR cells was studied using ovariectomized and estrogen-treated female rats. Estrogen treatment decreased very significantly the number of bombesin-IR cells, compared with controls, whereas ovariectomy increased significantly the frequency of bombesin-IR cells, so that the staining pattern began to resemble that seen in normal male rats. No bombesin-IR cells were detected in pituitaries from thyroidectomized rats. These results suggest that immunoreactive bombesin/gastrin-releasing peptide in the pituitary is modulated by endocrine status and this peptide may be involved in paracrine interactions in this tissue.     

Platelet-melanoma cell interaction is mediated by the glycoprotein IIb- IIIa complex

A human malignant melanoma cell line (M3Dau) was observed by electron microscopy to interact directly with human platelets and induced platelet aggregation. Fab fragments of a monoclonal antibody MoAb (LYP18), directed against the platelet glycoprotein (GP) IIb-IIIa complex, inhibited platelet-melanoma interactions and platelet-platelet aggregation. M3Dau melanoma cells bind LYP 18 and synthesize IIb-IIIa- like GPs. When the melanoma cells were preincubated with LYP 18, tumor- platelet interaction did not occur, suggesting that the interaction may be mediated by the IIb-IIIa-like GPs present on the melanoma cell surface. Glanzmann's thrombasthenic platelets, lacking GPIIb and IIIa, did not interact with melanoma cells, indicating that the platelet GPIIb-IIIa complex is also necessary for the platelet-melanoma cell interaction. This work demonstrates the importance of the IIb-IIIa-like GPs, present on M3Dau melanoma cells, in mediating tumor-platelet interactions.     

Additive effect of erythropoietin and heme on murine hematopoietic recovery after azidothymidine treatment [see comments]

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT- treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.     

Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry

To evaluate the clinical relevance of multidrug resistance (MDR) phenotype, the intracellular daunorubicin accumulation (IDA) and P- glycoprotein (P-gp) expression were investigated in 87 adult patients with acute leukemia: 69 patients with de novo acute myeloid leukemia (AML), 10 with AML at relapse, and eight with secondary leukemia to myelodysplastic syndromes (MDS-AML). IDA and P-gp expression were determined by double-labeling flow cytometry analysis. Of 87 patients, 36 expressed P-gp (41%). P-gp expression was more frequently observed in AML at relapse and MDS-AML as compared with de novo AML (P = .0001). P-gp expression was significantly associated with CD34 expression (P = .0003) and chromosome 7 abnormalities (P = .027). A significantly reduced IDA was observed in P-gp+ as compared with P-gp- patients (P = .0007). Of the 87 patients, 51 achieved complete remission (CR). A reduced IDA was observed in patients in failure as compared with patients in CR (22% +/- 17% v 42% +/- 21%; P = 10(-4). Twelve of 36 P- gp+ patients as compared with 40 of 51 P-gp- patients achieved CR (33% v 78%; P = 10(-4). The prognostic value of IDA and P-gp expression was confirmed in multivariate analysis. These data suggest that the determination of IDA and P-gp expression may be useful in designing therapy for patients with AML.     

Colorectal Cancer Screening Among American Indians in a Pacific Northwest Tribe: Cowlitz Tribal BRFSS Project, 2009–2010

Objectives

Colorectal cancer (CRC) screening is low among American Indians (AIs). We describe the demographics, health status, prevalence of modifiable CRC risk factors, and use of CRC screening modalities in a Pacific Northwest AI tribe.

Methods

We conducted a survey among Cowlitz tribal members using a Behavioral Risk Factor Surveillance System (BRFSS) questionnaire. We analyzed demographic, health status, behavioral risk factor, and CRC screening variables. Using the Washington State 2010 BRFSS, we compared tribal members with non-Hispanic white (NHW) people. We used logistic regression to examine factors associated with CRC screening for tribal members.

Results

A greater proportion of tribal members than NHW people reported living below the federal poverty level (12% vs. 7%, p=0.013). A greater proportion of tribal members than NHW people aged ≥50 years had poor self-reported health (27% vs. 16%, p=0.006) and were without health insurance (12% vs. 6%, p=0.004). A greater proportion of tribal members than NHW people had a fecal occult blood test within the past year (20% vs. 13%, p=0.006). Being 60–69 years of age (odds ratio [OR] = 2.6, 95% confidence interval [CI] 1.4, 4.9), ≥70 years of age (OR=2.2, 95% CI 1.1, 4.5), and having a personal health-care provider (OR=3.7, 95% CI 1.4, 9.6) were associated with increased screening adherence in tribal members.

Conclusion

Data from the Cowlitz Tribal BRFSS demonstrate that members are receiving CRC screening in the same proportions as NHW people despite lower sociodemographic and health status indicators among members. Unique characteristics of the tribe likely contribute to this finding.Cancer is the second leading cause of death among American Indian/Alaska Native (AI/AN) people; cardiovascular disease is the leading cause of death.¹ Overall, colorectal cancer (CRC) is the third most common cancer among AI/ANs behind prostate and lung cancer for men and breast and lung cancer for women.^2,3 In the most recent “Annual Report to the Nation on the Status of Cancer,” the incidence of CRC decreased among men and women in all racial/ethnic groups except AI/ANs.⁴Based on the Surveillance, Epidemiology, and End Results (SEER) program, the incidence of CRC is lower for AI/AN people than for those in other racial/ethnic groups.⁵ However, regional diversity in CRC incidence and racial misclassification can bias these nationwide estimates.^3,6,7 One strategy to overcome these biases is to link Indian Health Service (IHS) records with state cancer registries. Using the linkage strategy, researchers in the Pacific Northwest have found that the incidence of CRC is greater, and “one- and five-year CRC-related survival is lower among Pacific Northwest AI/ANs than among non-Hispanic white (NHW) people”⁷ (Unpublished thesis. Peterson PS. Colorectal cancer survival among American Indian and Alaska Native people in the Pacific Northwest. Oregon Health and Science University, 2011). Thus, investigations are needed to understand CRC screening patterns in this region, as well as barriers to screening that are unique to these tribal communities.Self-reported history of CRC screening is lower among AI/ANs than among NHW people.⁸ IHS Government Performance and Results Act (GPRA) data indicate improvement in CRC screening adherence among AI/ANs nationwide; however, these numbers are significantly lower than the Healthy People 2020 target of 70.5%.^9,10 According to GPRA 2010 data, the percentage of CRC screening adherence among IHS tribal users in the Pacific Northwest aged ≥50 years was 38%.¹⁰CRC screening behaviors vary regionally and are influenced by a complex set of sociodemographic, health-care-access, and cultural factors.^11–13 Among Northern Plain and Southwest AIs, Perdue et al. found an inverse association between cultural identity measures and screening by endoscopy or colonoscopy, but no trend with fecal occult blood tests (FOBTs).¹¹ In a study conducted in Alaska and the Southwest, researchers demonstrated that age >60 years, state of residence, urban residence, higher education, family history of CRC, former smoking, multiple medical conditions, English language spoken at home, and higher income were factors associated with an increase in age-appropriate CRC screening.¹² In another study conducted among AIs in North Carolina, self-rated health status, nonsmoking, and physical activity were associated with CRC screening.¹³While progress has been made, disparities persist in CRC screening, incidence of CRC cases, and CRC-related mortality in AI/ANs nationwide, including in the Pacific Northwest.^2–10 To date, no published research has addressed factors associated with CRC screening in Pacific Northwest tribes. The Cowlitz Tribal Behavioral Risk Factor Surveillance System (BRFSS) Project 2009–2010 provided a unique opportunity to investigate the health information of a tribe that has not been previously studied and to gain a better understanding of factors associated with cancer screening behaviors in this at-risk population.     

Control of hypertension with medication: a comparative analysis of national surveys in 20 countries

Objective

To examine hypertension management across countries and over time using consistent and comparable methods.

Methods

A systematic search identified nationally representative health examination surveys from 20 countries containing data from 1980 to 2011 on blood pressure measurements, the diagnosis and treatment of hypertension and its control with antihypertensive drugs. For each country, the prevalence of hypertension (i.e. systolic blood pressure ≥ 140 mmHg or antihypertensive use) and the proportion of hypertensive individuals whose condition was diagnosed, treated or controlled with medications (i.e. systolic pressure < 140 mmHg) were estimated.

Findings

The age-standardized prevalence of hypertension varied between countries: for individuals aged 35 to 49 years, it ranged from around 12% in Bangladesh, Egypt and Thailand to around 30% in Armenia, Lesotho and Ukraine; for those aged 35 to 84 years, it ranged from 20% in Bangladesh to more than 40% in Germany, the Russian Federation and Turkey. The age-standardized percentage of hypertensive individuals whose condition was diagnosed, treated or controlled was highest in the United States of America: for those aged 35 to 49 years, it was 84%, 77% and 56%, respectively. Percentages were especially low in Albania, Armenia, the Islamic Republic of Iran and Turkey. Although recent trends in prevalence differed in England, Japan and the United States, treatment coverage and hypertension control improved over time, particularly in England.

Conclusion

Globally the proportion of hypertensive individuals whose condition is treated or controlled with medication remains low. Greater efforts are needed to improve hypertension control, which would reduce the burden of noncommunicable diseases.     

Psychometric properties of a brief,clinically relevant measure of pain in patients with hepatocellular carcinoma

Purpose

Due to diagnosis at advanced stages, comorbidities, and the impact of treatment, patients with hepatocellular carcinoma (HCC) may experience pain. The purpose of this study was to evaluate the psychometric properties of a brief, clinically relevant measure of pain in HCC.

Methods

We conducted a secondary data analysis from four longitudinal studies of patients with HCC (total n = 304). All patients completed the FACT-Hepatobiliary (FACT-Hep) questionnaire, and 49 patients completed the Brief Pain Inventory (BPI) Interference scale. We conducted confirmatory factor analysis (CFA), Rasch modeling, and correlational analysis to assess the psychometrics of the three items on the FACT-Hep that assess HCC-relevant pain scale.

Results

Patients had an average age of 63.5 (±12.2) and were mostly male (76 %). The mean three-item pain subscale score was 8.5 ± 3.0. Seventy-four (24.3 %) patients reported no pain (score = 12). Results of a one-factor CFA supported unidimensionality of the items, and all items fit the Rasch model. An item-person map demonstrated that the three items covered all patients with non-extreme scores. Pain scores were significantly associated with baseline general health-related quality of life (FACT-General, r = 0.60, p < 0.001) and pain interference (BPI, r = ?0.63, p < 0.001).

Conclusions

The three FACT-Hep pain items are unidimensional, cover the range of pain experienced by most patients with HCC, and demonstrate convergent validity. This pain subscale is, if future research demonstrates its sensitivity to change, potentially useful for HCC clinical trials.