Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib.

Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497.

Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia.

BACKGROUND: We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses. METHODS: Patients from the nilotinib registration trial (CAMN107A2101; registered at http://www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123). RESULTS: More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months. CONCLUSIONS: Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS.

Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML). METHODS: Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (Cmin) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available. RESULTS: Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib Cmin was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels. CONCLUSIONS: When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.

Proinflammatory state, hepcidin, and anemia in older persons.

In patients with overt inflammatory diseases, up-regulated hepcidin impairs iron absorption and macrophage release, causing anemia. Whether the mild proinflammatory state of aging is associated with increased hepcidin is unknown. We characterized the relationships between urinary hepcidin, iron status, anemia, and inflammation in 582 patients 65 years or older participating in the InCHIANTI (Invecchiare in Chianti, "Aging in the Chianti Area") study, a population-based study of aging in Tuscany, Italy. Compared with nonanemic persons, urinary hepcidin (nanograms/milligram of urinary creatinine) was significantly lower in iron deficiency and inflammation anemia compared with no anemia or other anemia types. Urinary hepcidin was positively correlated with log(ferritin) and negatively correlated with the soluble transferrin receptor/log(ferritin) ratio but not correlated with markers of inflammation: interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha, and C-reactive protein (CRP). Lower iron was significantly correlated with higher IL-6 and CRP. Adjusting for confounders, IL-6 and CRP remained significantly associated with serum iron, with no evidence that such a relationship was accounted for by variability in urinary hepcidin. In conclusion, elevated proinflammatory markers were associated with anemia and low iron status, but not with higher urinary hepcidin. Future studies should test whether hepcidin production becomes up-regulated only in situations of overt inflammation.

Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study.

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.

Anaemia and the risk of injurious falls in a community-dwelling elderly population.

BACKGROUND: Anaemia in the elderly is associated with a number of health-related functional declines, such as frailty, disability and muscle weakness. These may contribute to falls which, in the elderly, result in serious injuries in perhaps 10% of cases. OBJECTIVE: To investigate whether anaemia increases the risk of injurious falls in an elderly population. METHOD: Health insurance claims and laboratory test results data from January 1999 to April 2004 for 47 530 individuals >or=65 years of age enrolled in over 30 managed care plans were analysed. An open-cohort design was employed to classify patients' observation periods by anaemia status (based on the WHO definition) and haemoglobin (Hb) level category. Injurious falls outcomes were defined as an injurious event claim, within 30 days after a fall claim, for fractures of the hip/pelvis/femur, vertebrae/ribs, humerus or lower limbs; Colles' fracture; or head injuries/haematomas. Univariate and multivariate (adjusted for age, gender, health plan, history of falls, co-morbidities and concomitant medications) analyses were conducted. Subset analyses based on injurious falls of the hip and head were also conducted. RESULTS: In the univariate analysis, anaemia increased the risk of injurious falls by 1.66 times (95% CI 1.41, 1.95) compared with no anaemia. The incidence of injurious falls increased from 6.5 to 15.8 per 1000 person-years when Hb levels decreased from >or=13 to <10 g/dL (trend test: p < 0.001). Multivariate analysis confirmed that Hb levels were significantly associated with the risk of injurious falls (rate ratio = 1.47, 1.39 and 1.14 for Hb levels of <10, 10-11.9 and 12-12.9 g/dL, respectively, compared with Hb >or=13 g/dL; p < 0.001). Even stronger linear negative trends were observed in the subsets of hip and head injurious falls. CONCLUSION: Anaemia was significantly and independently associated with a risk increase for injurious falls. Furthermore, the risk of injurious falls increased as the degree of anaemia worsened. Correction of anaemia, a modifiable risk factor, warrants further investigation as a means of preventing falls in the elderly.

Anemia and cancer in older persons.

Although the overall prevalence for many cancers is declining, cancer still remains a diagnosis more common in the elderly than in younger individuals. As the population ages, the proportion of patients with cancer who are elderly is expected to increase dramatically. Anemia occurs more often in older individuals for a variety of reasons, and its prevalence in elderly patients with cancer is significantly increasing. Although information on anemia in the elderly is limited, data on cancer patients of all ages have shown that the presence of anemia is associated with poorer prognosis and functional status. The impact of anemia on performance status in patients with cancer is matched by results from a large number of studies indicating negative effects of anemia on a wide variety of performance measures. Despite an apparent reluctance to undertake aggressive therapy in elderly patients with cancer, physicians are using a wider range of treatments with increasing frequency in this older population. Optimizing treatment outcomes in elderly patients with cancer depends on careful determination of performance status as well as the potential of therapies to treat anemia in these patients.

Anemia in the elderly: current understanding and emerging concepts.

Anemia is currently defined by the World Health Organization (WHO) as a hemoglobin (Hb) level <13 g/dL in men and <12 g/dL in women. While estimates vary widely, nearly one quarter of community-based octagenerians and one half of the chronically ill elderly have Hb levels that satisfy a diagnosis of anemia according to these criteria. A growing body of evidence has linked adverse events with even "mild" anemia or low-normal Hb in the elderly. Recent studies suggest strongly that aging is associated with dysregulation of pro-inflammatory cytokines, most notably interleukin-6 (IL-6), which may negatively impact hematopoiesis, either by inhibition of erythropoietin (EPO) production or interaction with EPO receptors. Anemia in older individuals is associated with a very wide range of complications, including increased risk for mortality, cardiovascular disease, cognitive dysfunction, longer hospitalization for elective procedures and comorbid conditions, reduced bone density, and falls and fractures. Not surprisingly, anemia also has a significant effect on quality of life (QOL) in the elderly. Most anemia in older individuals results from iron deficiency, chronic inflammation, or chronic kidney disease, or it may be unexplained. Future research on anemia in the elderly should focus on the age-related physiologic changes underlying this condition and whether anemia correction can reduce anemia-associated risks, and improve QOL.

Anemia, physical disability, and survival in older patients with heart failure.

BACKGROUND: Anemia is common in congestive heart failure, and it has been associated with poor prognosis. The effect of anemia on functional ability in heart failure has not been described. We evaluated the relationship of anemia, physical disability, and survival in patients with heart failure. METHODS AND RESULTS: One-year longitudinal study of 567 non-disabled, hospitalized heart failure patients, age > or = 65 years, enrolled in the Italian Group of Pharmacoepidemiology in the Elderly Study. Anemia was defined according to the World Health Organization criteria. Physical disability was defined as dependence in performing at least 2 basic activities of daily living. After adjustment for disease severity and health-related variables, anemia was associated with higher risk of disability (odds ratio = 2.17; 95% confidence interval [CI] = 1.12-4.24). After stratification according to gender, a strong relationship of anemia and risk of disability persisted in women, but it was reduced in men. Anemic women were significantly more likely to die during the follow-up, even after adjustment for potential confounders (hazard ratio = 2.33; CI = 1.02-5.30). CONCLUSION: Anemia is a predictor of physical disability in older heart failure patients, and in women anemia is associated with increased mortality.

Meaningful change and responsiveness in common physical performance measures in older adults.

OBJECTIVES: To estimate the magnitude of small meaningful and substantial individual change in physical performance measures and evaluate their responsiveness. DESIGN: Secondary data analyses using distribution- and anchor-based methods to determine meaningful change. SETTING: Secondary analysis of data from an observational study and clinical trials of community-dwelling older people and subacute stroke survivors. PARTICIPANTS: Older adults with mobility disabilities in a strength training trial (n=100), subacute stroke survivors in an intervention trial (n=100), and a prospective cohort of community-dwelling older people (n=492). MEASUREMENTS: Gait speed, Short Physical Performance Battery (SPPB), 6-minute-walk distance (6MWD), and self-reported mobility. RESULTS: Most small meaningful change estimates ranged from 0.04 to 0.06 m/s for gait speed, 0.27 to 0.55 points for SPPB, and 19 to 22 m for 6MWD. Most substantial change estimates ranged from 0.08 to 0.14 m/s for gait speed, 0.99 to 1.34 points for SPPB, and 47 to 49 m for 6MWD. Based on responsiveness indices, per-group sample sizes for clinical trials ranged from 13 to 42 for substantial change and 71 to 161 for small meaningful change. CONCLUSION: Best initial estimates of small meaningful change are near 0.05 m/s for gait speed, 0.5 points for SPPB, and 20 m for 6MWD and of substantial change are near 0.10 m/s for gait speed, 1.0 point for SPPB, and 50 m for 6MWD. For clinical use, substantial change in these measures and small change in gait speed and 6MWD, but not SPPB, are detectable. For research use, these measures yield feasible sample sizes for detecting meaningful change.

Anemia and recovery from disability in activities of daily living in hospitalized older persons.

OBJECTIVES: To evaluate the predictive value of hemoglobin levels upon hospital admission on recovery from activity of daily living (ADL) disability during hospital stay in older patients. DESIGN: Longitudinal observational study. SETTING: Geriatric and internal medicine acute care units. PARTICIPANTS: Data are from 5,675 patients aged 65 and older enrolled in the Italian Group of Pharmacoepidemiology in the Elderly Study with ADL disability upon hospital admission. MEASUREMENTS: ADL disability was defined as inability to perform or need for assistance in performing one or more ADLs. Recovery from ADL disability was defined as independence in ADLs upon hospital discharge. Anemia was defined according to the World Health Organization criteria. Sociodemographic and clinical characteristics were considered as potential confounders. RESULTS: Mean age was 80.5 years; 57.7% of subjects were female. Prevalence of anemia was 46.8%. A total of 536 (9.4%) participants regained independence in all six ADLs at hospital discharge. Patients with anemia had a lower rate of recovery from ADL disability than those with normal hemoglobin levels (7.0% vs 11.6%; P<.001). Adjusted analyses confirmed that anemia was inversely associated with the likelihood of ADL recovery (odds ratio=0.71, 95% confidence interval=0.57-0.88). The probability of ADL recovery in anemic patients was higher at higher hemoglobin concentrations. CONCLUSION: In older hospitalized patients, anemia is inversely associated with the likelihood of regaining ADL independence during a hospital stay.

Anemia in old age is associated with increased mortality and hospitalization.

BACKGROUND: Anemia is common in old age and has been shown to affect older persons' physical function. To more fully understand the detrimental health effects of anemia, we examined the relationship of anemia with death and hospitalization outcomes in a large community-based sample of older persons. METHODS: Data are from 3607 persons, aged 71 years or older, participating in the National Institute on Aging (NIA)-sponsored Established Populations for Epidemiologic Studies of the Elderly (EPESE) study. Anemia was defined according to World Health Organization (WHO) criteria as a hemoglobin concentration below 12 g/dL in women and below 13 g/dL in men. Data on subsequent mortality and hospital admissions over 4 years were obtained from death records and the Medicare database. RESULTS: Anemia was present in 451 of the 3607 (12.5%) participants. During the follow-up period, anemic persons were more likely to die than were nonanemic persons (37.0% vs 22.1%, p<.001). Also, anemic persons were more often hospitalized (65.9% vs 54.6%, p<.001) and spent more days in hospital (25.0 vs 13.7, p<.001). After adjustment for demographics and baseline comorbidities, anemia significantly predicted subsequent mortality and hospitalization (relative risk=1.61, 95% confidence interval, 1.34-1.93; and relative risk=1.27, 95% confidence interval, 1.12-1.45, respectively). After excluding persons with prevalent diseases at baseline, anemia remained significantly associated with increased risks of mortality and hospitalization. A higher hemoglobin level was significantly associated with lower risks of mortality and hospitalization (p for trend<.001 for both). CONCLUSIONS: These findings indicate that late-life anemia characterizes persons at risk for important clinical health outcomes, and demonstrate the importance of clinical awareness of anemia even if the person is without apparent clinical disease.

Randomized, open-label comparison of epoetin alfa extended dosing (80 000 U Q2W) vs weekly dosing (40 000 U QW) in patients with chemotherapy-induced anemia.

OBJECTIVE: This randomized, open-label, multicenter study compared the efficacy and safety of epoetin alfa (EPO) 80 000 U every 2 weeks (Q2W) to the FDA-approved regimen of 40 000 U weekly (QW) in patients with chemotherapy-induced anemia. RESEARCH DESIGN AND METHODS: A total of 310 patients with nonmyeloid malignancy and baseline hemoglobin (Hb)

Renal function, erythropoietin, and anemia of older persons: the InCHIANTI study.

BACKGROUND: In the older population, anemia has been associated with poor outcomes including disability and mortality. Understanding the mechanisms leading to anemia is essential to plan better treatment and prevention strategies. We tested the hypothesis that the age-related decline in kidney function is associated with an increased prevalence of anemia and that such an increase is accompanied by a concomitant decrement in erythropoietin levels. METHODS: Data were from the InCHIANTI study, a population-based study performed in a sample of community-dwelling older (> or = 65 years) persons living in Italy. This analysis included 1005 participants with complete data on hemoglobin and erythropoietin levels and markers of renal function. RESULTS: The prevalence of anemia according to the World Health Organization criteria (hemoglobin level < 12 g/dL for women and < 13 g/dL for men) was 12.0% and increased with age in both sexes. After adjusting for age, diseases, and other confounders, only participants with a creatinine clearance (CrCl) of 30 mL/min or lower (< or = 0.50 mL/s) had a higher prevalence of anemia compared with those with a CrCl higher than 90 mL/min (> 1.50 mL/s) (P<.01). Consistently, participants with a CrCl of 30 mL/min or lower (< or = 0.50 mL/s) had significantly lower age- and hemoglobin-adjusted erythropoietin endogenous levels. After excluding men and women with CrCl of 30 mL/min or lower (< or = 0.50 mL/s) and adjusting for confounders, we found a trend toward an increase in prevalence of anemia with decreasing renal function; however, it was not statistically significant. CONCLUSIONS: Severe age-related decline in renal function is associated with a reduced erythropoietin secretion and anemia. Whether moderate kidney impairment in older persons is associated with a progressively increasing risk of anemia remains to be determined.

Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II.

BACKGROUND: The physiological basis of the geriatric syndrome of frailty, a clinical state of increased vulnerability to adverse outcomes such as disability and mortality, remains to be better characterized. We examined the cross-sectional relationship between hemoglobin (Hb) and a recently-validated measure of frailty in community-dwelling older women, and whether this relationship was modified by cardiovascular disease (CVD) status. METHODS: Data were pooled from women 70-80 years old participating in the Women's Health and Aging Studies I and II (Baltimore, MD, 1992-1996) with known frailty status and Hb > or = 10 g/dL (n = 670). Logistic regression was used to model the relationship between frailty and Hb, adjusting for demographics, major chronic diseases, and physiologic and functional impairments. RESULTS: Prevalence of frailty was 14%. Frailty risk was highest at the lowest Hb levels, and lowest at mid-normal Hb levels (e.g., 13-14 g/dL). Mildly low and low-normal Hb concentrations were independently associated with frailty. Compared to an Hb concentration equal to 13.5 g/dL, the adjusted odds of being frail were 1.9 (95% confidence interval: 1.1-3.4) and 1.5 (95% confidence interval: 1.0-2.1) times higher for Hb concentrations equal to 11.5 g/dL and 12 g/dL, respectively. A statistically significant (p <.05) multiplicative interaction between Hb level and CVD status with respect to frailty risk was observed. CONCLUSION: In community-dwelling older women, mildly low and low-normal Hb levels were independently associated with increased frailty risk. This risk was synergistically modified by the presence of CVD. These results suggest that mild anemia, and even low-normal Hb levels are independent, potentially modifiable risk factors for frailty in community-dwelling older adults.

The GOLD ReGISTry: a Global, Prospective, Observational Registry Collecting Longitudinal Data on Patients with Advanced and Localised Gastrointestinal Stromal Tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007-2011). METHODS: Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analysed using descriptive statistics. RESULTS: The registry included 1663 patients (advanced GIST, n=1095; localised GIST, n=537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (≈40% and ≈70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively. CONCLUSIONS: In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations.

Modulation of neutrophil function by the tripeptide feG.

BACKGROUND: Neutrophils are critical in the defense against potentially harmful microorganisms, but their excessive and inappropriate activation can contribute significantly to tissue damage and a worsening pathology. Through the release of endocrine factors submandibular glands contribute to achieving a balance in neutrophil function by modulating the state of activation and migratory potential of circulating neutrophils. A putative hormonal candidate for these effects on neutrophils was identified as a heptapeptide named submandibular gland peptide T (SGP-T; sequence = TDIFEGG). Since the tripeptide FEG, derived from SGP-T, and its D-amino acid analogue feG had similar inhibitory effects on inflammatory reactions, we investigated the effects of feG on human and rat neutrophil function. RESULTS: With human neutrophils feG had no discernible effect on oxidative burst or phagocytosis, but in picomolar amounts it reduced PAF-induced neutrophil movement and adhesion, and the binding of CD11b by 34% and that of CD16b close to control values. In the rat feG (10-11M) reduced the binding of CD11b and CD16 antibodies to PAF-stimulated circulating neutrophils by 35% and 43%, respectively, and at 100 micrograms/kilograms intraperitoneally feG reduced neutrophil in vivo migration by 40%. With ovalbumin-sensitized rats that were challenged with antigen, feG inhibited binding of antibodies against CD16b but not CD11b, on peritoneal leukocytes. CONCLUSIONS: The inhibitory effect of feG on neutrophil movement may be mediated by alterations in the co-stimulatory molecules CD11b and CD16.

Anemia is associated with disability and decreased physical performance and muscle strength in the elderly.

OBJECTIVES: To examine the association between anemia and disability, physical performance, and muscle strength in older persons. DESIGN: Cross-sectional. SETTING: Community-dwelling older persons in the Chianti area in Italy. PARTICIPANTS: A total of 1,156 persons aged 65 and older participating in the InChianti Study ("Invecchiare in Chianti," i.e., Aging in the Chianti Area). MEASUREMENTS: Anemia was defined according to World Health Organization criteria as a hemoglobin concentration below 12 g/dL in women and below 13 g/dL in men. Disability in six basic and eight instrumental activities of daily living was assessed. Physical performance was assessed using the short physical performance battery (4-m walk, balance, and chair stands), which yields a summary performance score ranging from 0 to 12 (high). Muscle strength was determined using knee extensor and handgrip strength assessments. RESULTS: Overall, 11.1% of the men and 11.5% of the women had anemia. After adjustment for age, sex, body mass index, Mini-Mental State Examination score, creatinine level, and presence of various comorbid conditions, anemic persons had more disabilities (1.71 vs 1.04, P=.002) and poorer performance (8.8 vs 9.6, P=.003) than persons without anemia. Anemic persons also had significantly lower knee extensor strength (14.1 vs 15.2 kg, P=.02) and lower handgrip strength (25.3 vs 27.1 kg, P=.04) than persons without anemia. Further adjustment for inflammatory markers (interleukin-6, C-reactive protein, tumor necrosis factor-alpha) did not change these associations. CONCLUSION: Anemia is associated with disability, poorer physical performance, and lower muscle strength. Further research should explore whether treating anemia has a beneficial effect on the functional status of older persons.

Successful treatment of posttransplant lymphoproliferative disorder in a renal transplant patient by autologous peripheral blood stem cell transplantation.

Posttransplant lymphoproliferative disorder (PTLD), a well recognized complication of organ transplantation, comprises a wide spectrum of heterogeneous lymphoid proliferations ranging from self-limiting mononucleosis through aggressive monoclonal non-Hodgkin's lymphoma (NHL). There has been marginal success in treating PTLD using a number of treatment modalities, including combination chemotherapy. There have been few reports of the use of high dose chemotherapy with stem cell rescue as a treatment for PTLD. We report a renal allograft recipient who developed PTLD of the diffuse large cleaved B cell, NHL type. Reduction of immunosuppression was initially effective, however the patient relapsed, and was treated successfully with CHOP chemotherapy. Two years later he again relapsed and was treated with high dose melphalan followed by autologous peripheral blood stem cell transplantation (PSCT). The patient has remained in complete remission for 4 years with no major organ toxicities and a functioning renal allograft on minimal immunosuppression. This case illustrates a potential role for high dose chemotherapy with stem cell transplantation for the treatment of PTLD.

Primary amyloidosis presenting as small bowel encapsulation.

Amyloidosis is a pathological process which encompasses a spectrum of diseases that result from extracellular deposition of pathological fibrillar proteins. Clinical presentations vary depending on the organs involved. There is no documented case of amyloidosis presenting as small bowel encapsulation. A previously healthy 62-year-old man developed a small bowel obstruction in 1997. At surgery, a peculiar membrane encasing his entire small bowel was discovered. This appeared to have no vascularity and was removed without difficulty, exposing a grossly normal bowel. Histopathology revealed thick bands of collagen overlying the peritoneal surface, which was congo red positive and showed apple green birefringence. The findings were consistent with encapsulating peritonitis due to amyloidosis. There was no history or symptoms of any chronic inflammatory condition and he became symptom-free postoperatively. An abdominal fat pad biopsy failed to demonstrate amyloidosis. Endoscopic duodenal biopsies revealed classical primary amyloidosis. Quantitative immunoglobulins, lactate dehydrogenase, C3, C4 and beta-2 microglobulin were normal. Protein electrophoresis identified monoclonal paraprotein, immunoglobulin G lambda 3.7 g/L. Bone marrow biopsy and aspirate revealed only a mild plasmacytosis (5% to 10%). Echocardiogram and skeletal survey were normal. He had mild proteinuria. Complete blood count, C-reactive protein, calcium, albumin and total protein were normal. No specific therapy was instituted. In January of 1998 the patient remained asymptomatic with no gastrointestinal, cardiovascular or constitutional symptoms. He had developed nephrotic range proteinuria (3.95 g/24 h), microalbuminuria, hypoalbuminemia and a renal biopsy consistent with renal amyloidosis. In 1999 there was an increase in the monoclonal paraprotein (6.2 g/L). The remaining investigations were normal except for an echocardiogram which showed left ventricular hypertrophy but a normal ejection fraction and no diastolic dysfunction. He went on to have high-dose chemotherapy and an autologous stem cell transplant in September, 2000. He has subsequently developed renal insufficiency. To our knowledge this is the first reported case of primary amyloidosis presenting as small bowel obstruction from encapsulating peritonitis.