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Purpose: To determine whether there was a difference in the sensitivity to change of the subscales of the Functional Independence Measure and the Assessment of Motor and Process Skills within three different post-acute inpatient rehabilitation populations., Material and Methods: We conducted retrospective chart review of patients consecutively admitted to inpatient rehabilitation units, with both admission and discharge Functional Independence Measure and Assessment of Motor and Process Skills scores. A total of 276 participants were included and categorized into diagnostic groups (orthopedic, oncology, and geriatric). Within group, sensitivity to change was evaluated for the subscales of each measure by calculating the difference in standardized response means (SRM) and 95% confidence intervals (CI)., Results: The Functional Independence Measure motor subscale was more sensitive to change than the Assessment of Motor and Process Skills in the orthopedic and geriatric groups (SRM difference  = 1.53 [95% CI 0.93, 2.3] and 0.65 [95% CI 0.3, 1.02], respectively) but not in the oncology group (SRM difference  = 0.42 [95% CI -0.2, 1.04]). For the cognitive subscales, the Assessment of Motor and Process Skills was more sensitive to change than the Functional Independence Measure in all three groups (SRM difference  = 0.38 [95% CI 004, 0.74], 0.65 [95% CI 0.45, 0.90], and 1.15 [95% CI 0.77, 1.69] for orthopedic, geriatric, and oncology, respectively)., Conclusions: The Functional Independence Measure is a mandated measure for all rehabilitation units in Canada. As the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change than the Functional Independence Measure, we recommend also administering the Assessment of Motor and Process Skills to better detect changes in the cognitive aspect of function. Implications for rehabilitation When deciding between the Functional Independence Measure or the Assessment of Motor and Process Skills, it is important to consider whether patients' functional status is expected to change similarly or differently. The difference in sensitivity to change between the subscales of the two outcome measures varies with the characteristics of change (similar or different) in patients' functional status. We recommend using the Assessment of Motor and Process Skills, along with the Functional Independence Measure, for patients who are expected to make similar amounts of change in functional status, as the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change and can better detect changes in the cognitive aspect of functioning. For patients whose functional status are expected to change differently (diverse diagnoses), the Functional Independence Measure may be more useful as the motor subscale was more sensitive to change when comparing between rehabilitation populations.

Many solid cancers respond to chemo or radiotherapy with a type 2 form of programmed cell death. This requires direct participation of mitochondria with release of cytochrome c and other factors that activate the 'execution' phase of the process. It is believed that as solid cancers progress, less differentiated clones containing fewer mitochondria evolve. Consequently, the mitochondrial 'switch' that activates the type 2 process will become less effective, as the number of elements available and their mass-effect declines. The opportunity for successful therapy, considered to depend upon the ability to activate programmed cell death, therefore becomes progressively less probable., (Copyright 2001 Harcourt Publishers Ltd.)

Generally it has been believed that a maximum therapeutic induction of programmed cell death in cancer cells is universally desirable. As a corollary, the presence of Bcl-2, a major anti-programmed cell death protein, is considered an unfavorable prognostic sign. The latter is not and the former may not be universally true.

With a combination of inhibitors at less than their individual 'therapeutic' concentrations directed against dissimilar cellular hierarchical developmental controls and 'downstream' metabolic pathways, it may be possible to modulate the biologic behavior of malignantly transformed cells synergistically. Ideally the cumulative systemic toxicity of such a 'polytherapy' would be reduced.

Recent information about apoptosis or programmed cell death, the anti-apoptotic gene, BCL2, its interaction with reactive oxygen species and the role of these agents in senescence and apoptosis, suggests a discussion of their relationships could be of interest. Such information may eventually provide alternative approaches to modifying the biological behavior of therapeutically resistant cancers. Some of these comments probably are self-evident, others may be less so and provide ideas for further studies.

The capacity of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) to elicit monocyte cytotoxicity in vitro in the peripheral blood monocytes of patients with solid tumors was investigated. The cytotoxicity elicited by IFN gamma was significantly reduced in cancer patient monocytes compared to normal monocytes. The cytotoxicity elicited by GM-CSF, however, was comparable between cancer patient monocytes and normal monocytes, but was lower than that induced by IFN gamma. Indomethacin, a cyclooxygenase inhibitor, significantly augmented IFN gamma-elicited cytotoxicity in cancer patient monocytes, but not in normal monocytes. In contrast, indomethacin augmented GM-CSF-elicited cytotoxicity in both cancer patient monocytes and normal monocytes. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was found to suppress cytotoxicity in response to IFN gamma and GM-CSF in both cancer patient monocytes and normal monocytes. The addition of leukotrienes to NDGA-treated cultures restored the development of cytotoxicity. Thus there are differences in the in vitro response of cancer patient monocytes and normal monocytes to distinct biological activators. Furthermore, these responses can be manipulated by agents that modulate arachidonic acid metabolism.

Chemiluminescence, indomethacin-sensitive suppression, and adherent cell cytotoxicity were measured in peripheral blood mononuclear cells (PBMC) from normal subjects and solid tumor cancer patients. These functions were found to be differentially affected by malignant disease. In cancer patients with disseminated disease, indomethacin-sensitive suppression and chemiluminescence emission were increased to a level significantly higher than normal without a concurrent increase in adherent cell cytotoxic function. In cancer patients with at most minimum residual diseases, the levels of chemiluminescence, indomethacin-sensitive suppression, and adherent cell cytotoxicity found were comparable to those of the normal study population. In vitro stimulation of cells from patients with disseminated disease by phorbol myristic acetate (PMA) increased chemiluminescence overcame the suppressive effects of indomethacin-sensitive suppressor cells, and increased adherent cell cytotoxicity; in cells from patients with at most minimum residual disease, PMA increased chemiluminescence and cytotoxicity without influencing the activity of indomethacin-sensitive suppressor cells. Vaccination of lung cancer patients with Freund's complete adjuvant or Freund's complete adjuvant plus tumor antigen extracts led to increased levels of chemiluminescence and increased levels of adherent cell cytotoxicity without altering indomethacin-sensitive regulatory cell function.

The relationship between the conversion of arachidonic acid (AA) to E series prostaglandins (PGE), indomethacin-sensitive immunoregulation and lymphocyte PGE sensitivity was investigated in the peripheral blood mononuclear cells (PBMC) of normal subjects and disseminated solid tumor patients. Production of PGE was assessed by thin layer chromatography of ether-extracted glass adherent cells following a 24-hour pulse with 3H-AA. Immunoregulatory cell function was assessed in PHA-stimulated PBMC cultured in the presence of the prostaglandin synthetase inhibitor, indomethacin. Lymphocyte PGE sensitivity was assessed in PHA stimulated glass nonadherent cells cultured in the presence of 10(-8) M PGE. The cells from cancer patients demonstrated greater AA conversion to PGE and greater indomethacin sensitive immunoregulatory cell function than the cells of normal subjects. However, lymphocyte PGE sensitivity was comparable for both groups. When levels of arachidonic acid conversion to PGE were correlated to levels of indomethacin-sensitive immunoregulatory cell function by linear regression analysis, a significant correlation was found. These data suggest that the increased indomethacin-sensitive immunoregulatory cell function seen in PBMC from cancer patients can be directly correlated with increased production of E series prostaglandins by cancer patient peripheral blood monocytes.

This paper will focus on three aspects of work which we have conducted in our laboratory over the past several years. Firstly, it will present results of studies in which we have found a selective inhibition of suppressor cell function in solid tumor cancer patients treated with cytotoxic drugs. Secondly, it will show that this selective inhibition results in an augmentation of other forms of immune reactivity and, in particular, an enhanced interleukin-2 production and response to this. Finally, it will demonstrate how we have made use of that information to intervene pharmacologically to modulate the immunosuppression which usually follows the use of cytotoxic drugs in solid tumor cancer patients.

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.

The effect of cytotoxic chemotherapy on phytohemagglutinin (PHA)-induced lymphocyte DNA synthesis was monitored in the peripheral blood mononuclear cells (PBMC) of drug-treated solid tumor cancer patients. The results obtained were correlated with changes in indomethacin-sensitive immunoregulatory function, prostaglandin E (PGE) levels, and PBMC PGE sensitivity. Those patients who demonstrated "rebound-overshoot" recovery of PHA responsiveness following their drug treatment did so in association with a significant reduction in levels of indomethacin-sensitive immunoregulation. This was associated with a significant decline in PGE-levels in PBMC. This was not consistently associated with a reduction in the sensitivity of PBMC to suppression by PGE. These data show that immune function recovery in drug-treated cancer patients is dependent in part on the effects of chemotherapy on PGE synthesis by PBMC.

Human peripheral blood T-cells were divided into subsets on the basis of their ability to bind to the Fc receptor portion of IgG (TG cells) or IgM (TM cells). These subsets were studied in 25 patients with newly diagnosed disseminated malignant solid tumors. When compared to a group of healthy, age-matched controls, cancer patients as a group exhibited signifcantly increased percentages of TG cells and significantly decreased percentages and numbers of TM cells. Comparison of the values determined for individual patients to those determined for groups of 10 healthy individuals in the same decade of life revealed that most cancer patients had normal levels of lymphocytes and T-cells, but many had aberrant values for T-cell subsets.

The effects of cytotoxic chemotherapy on NK cell function and on glass adherent cell regulation of NK cell function was evaluated in the peripheral blood mononuclear cells of 20 previously untreated solid tumor patients. Most of the patients studied had lung cancer and received one of four combination chemotherapy treatment regimens. In addition, one patient with colon carcinoma and one patient with melanoma were studied, each of whom received treatment with a single agent. The results demonstrated that chemotherapy exerted a differential influence on NK activity which correlated with the pretreatment NK level of function in the individual patient. In patients with depressed NK levels prior to treatment, chemotherapy augmented NK function; in patients with normal levels prior to treatment, chemotherapy depressed NK function. The effects observed appeared to be associated with the capacity of chemotherapy to influence glass adherent cell regulation of NK activity. There was no apparent correlation between the effects of chemotherapy on numbers of NK effector cells, Leu11+ cells, or latex-ingesting cells. Also, there was no correlation between the effects seen and the type of drug treatment that was administered; rather, this was dependent on the pretreatment NK level of function which in turn was associated with glass adherent cell regulation of NK function.

Leukocytes were quantitated in peripheral blood from 35 solid-tumor cancer patients and related to levels of phytohemagglutinin (PHA)-induced DNA synthesis. Levels of glass-adherent, indomethacin-sensitive, or 24-hour preculture-sensitive immunoregulatory activity were evaluated in PHA-stimulated peripheral blood mononuclear cells (PBMC). Cancer patients and patients with depressed PHA responses had significantly greater monocyte percentages in their PBMC than did healthy subjects; patients with normal PHA responses did not. Patients with disseminated disease had significantly greater monocyte percentages and depressed T-cell percentages than did controls; patients with at most minimum residual disease did not. When monocyte and lymphocyte percentages were correlated by linear regression analysis to PHA responsiveness, no significant correlation was found. A highly significant negative correlation was noted between PHA responsiveness and levels of immunoregulatory cell function. Abnormal immunoregulatory function, apart from alterations in peripheral blood leukocyte percentages and numbers contributes to impaired T-cell function in cancer patients.

Monocyte and lymphocyte subsets were quantitated in the peripheral blood of normal subjects and patients with solid tumors using the monoclonal antibody reagents OKM1, BRL63D3, OKT3, OKT4, and OKT8. Percentages and numbers of cells reacting with monoclonal reagents were analyzed by indirect immunofluorescence. Correlations between leukocyte subset values and stage of disease or immunocompetence were sought. No differences from normal were seen in the percentage of OKT3, OKT4, and OKT8 cells or in the ratios of OKT4/OKT8 cells in peripheral blood mononuclear cells (PBMC) from all cancer patients, patients with localized disease, or patients with advanced disease. A significant decrease in absolute numbers of lymphocytes, OKT3 cells, OKT4 cells, and OKT8 cells was seen in the peripheral blood of patients with advanced disease reflecting the absolute lymphopenia of these patients. A significant increase was seen in the percentages of PBMC reacting with OKM1 and BRL63D3 from patients with advanced disease compared with normal donors or localized disease patients. A positive correlation was found between PHA responsiveness and absolute numbers of OKT3 and OKT4 cells. A negative correlation was found between PHA responsiveness and percentages of OKM1 cells. These data indicate that malignant disease does not alter T cell subset percentages in patient peripheral blood but may decrease their absolute numbers in association with absolute lymphopenia. On the other hand, percentages of OKM1 and BRL63D3 cells are increased in patients with advanced solid tumors in association with impaired PHA responsiveness.

The capacity of the immunomodulators interleukin-2 (IL-2) and indomethacin to augment phytohemagglutinin (PHA)-induced lymphoproliferation in the peripheral blood mononuclear cells (PBMC) of cancer patients was evaluated. Ficoll-Hypaque-isolated PBMC from 20 patients with disseminated non-lymphoreticular solid tumors were stimulated with PHA in the presence of IL-2, indomethacin, or IL-2 plus indomethacin. Augmentation of PHA responsiveness by each immunomodulator was additive. There was a significant negative correlation between PHA reactivity and immunomodulation by indomethacin. There was no correlation between PHA reactivity and immunomodulation by IL-2. A significant negative correlation was also found between indomethacin-induced augmentation and IL-2-induced augmentation in patients with significantly impaired reactivity to PHA. Still, the combined effects of IL-2 and indomethacin could not prevent the suppressive effects of prostaglandin E2 added to PHA-stimulated cultures containing both immunomodulators. These results suggest that the presence of abnormal indomethacin-sensitive immunoregulation in PBMC from cancer patients limits lymphocyte responsiveness to IL-2 and suggests that these two immunomodulators might be combined in certain cancer patient therapies.