'I don't want to burden my family': handling communication challenges in geriatric oncology.

Oncologists need excellent communication skills to effectively handle challenging conversations regarding prognosis, transition to palliative care, code status, and other sensitive topics. Foundational skills include: 1) posing open-ended, exploratory questions, 2) allowing for appropriate silence in the conversation, 3) listening actively, 4) recognizing emotions, 5) responding to emotions with empathy rather than biomedical information, and 6) speaking with clarity by avoiding technical jargon and offering small chunks of information. Conversations about sensitive topics can be particularly challenging with geriatric patients, who experience functional and sensory limitations. The risk-benefit ratio of diagnostic and therapeutic interventions tips precariously in older patients as many develop geriatric syndromes. Older cancer patients have the unique perspective of looking back on a long life and looking forward to impending death. Higher order skills can be very powerful in helping geriatric cancer patients find meaning and dignity at the end of life. These skills include exploring spirituality and coping strategies and engaging the patient in conversation and reflection about their legacy.

Promoting new approaches for cancer care in the Middle East.

Cancer is now the fastest growing killing disease in the Middle East. Accordingly, there is an urgent need to train local health professionals: oncologists, palliative care experts, oncology nurses, psychologists, along with social workers, physiotherapists and spiritual counselors on strategies for early detection, curative therapies and palliation. Professionals in the region, along with the public, need to convince medical administrators, regulators and policymakers about investing in education and training of YOUNG professionals, as well as those with already proven experience in cancer care. Training is the basis for any future cancer care program, which aims at the integration of palliative care practices into standard oncology care across the trajectory of the illness.

Patient-centered care: the key to cultural competence.

Much of the early literature on 'cultural competence' focuses on the 'categorical' or 'multicultural' approach, in which providers learn relevant attitudes, values, beliefs, and behaviors of certain cultural groups. In essence, this involves learning key 'dos and don'ts' for each group. Literature and educational materials of this kind focus on broad ethnic, racial, religious, or national groups, such as 'African American', 'Hispanic', or 'Asian'. The problem with this categorical or 'list of traits' approach to clinical cultural competence is that culture is multidimensional and dynamic. Culture comprises multiple variables, affecting all aspects of experience. Cultural processes frequently differ within the same ethnic or social group because of differences in age cohort, gender, political association, class, religion, ethnicity, and even personality. Culture is therefore a very elusive and nebulous concept, like art. The multicultural approach to cultural competence results in stereotypical thinking rather than clinical competence. A newer, cross cultural approach to culturally competent clinical practice focuses on foundational communication skills, awareness of cross-cutting cultural and social issues, and health beliefs that are present in all cultures. We can think of these as universal human beliefs, needs, and traits. This patient centered approach relies on identifying and negotiating different styles of communication, decision-making preferences, roles of family, sexual and gender issues, and issues of mistrust, prejudice, and racism, among other factors. In the current paper, we describe 'cultural' challenges that arise in the care of four patients from disparate cultures, each of whom has advanced colon cancer that is no longer responding to chemotherapy. We then illustrate how to apply principles of patient centered care to these challenges.

Association of glyceraldehyde-3-phosphate dehydrogenase expression with cell motility and metastatic potential of rat prostatic adenocarcinoma.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression is increased in Dunning R-3327 rat prostatic adenocarcinoma cell lines relative to normal rat ventral prostate tissue. GAPDH expression closely correlates with cell motility of Dunning prostate cancer cell lines and accurately distinguishes cell lines with high metastatic potential from those with low metastatic potential. Increased GAPDH expression in the cancer cell lines is not simply related to increased growth rate, since rapidly proliferating normal prostate tissue did not exhibit elevated GAPDH expression.

Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex.

Previous studies have shown that androgen up-regulates expression of the p21 (WAF1, CIP1, SDI1, CAP20) gene, which contains a canonical androgen response element (ARE) in its proximal promoter region. We undertook the current studies to determine whether elements in the p21 promoter other than the ARE mediate androgen action. We found that deletion of the ARE did not completely abolish the promoter responsiveness to androgen, suggesting that additional cis-regulatory elements within the p21 core promoter may also be involved in androgen responsiveness. The p21 core promoter is GC-rich and contains six binding sites for transcription factor Sp1. We determined whether one or more of these Sp1 sites mediate androgen responsiveness of the p21 promoter. To do so, we used a transient transfection assay with p21 promoter-luciferase reporter constructs. The reporter activity of a construct lacking the ARE but containing all six Sp1 sites was induced approximately 3-fold by androgen. Mutation of Sp1-3 nearly eliminated basal promoter activity as well as androgen responsiveness, whereas deletion of Sp1-1 and Sp1-2 sites and mutation of Sp1-4, Sp1-5, and Sp1-6 sites had relatively little effect. We also used the mammalian one-hybrid assay and coimmunoprecipitation assay to show that androgen receptor (AR) and transcription factor Sp1 interact with one another. The current studies suggest a model in which AR and transcription factor Sp1 not only bind to their respective consensus sites within the p21 promoter, but also complex with one another, thereby recruiting coactivators and general transcription factors and inducing p21 transcription.

Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter.

Androgen is essential for the physiological maintenance of the integrity of prostatic epithelial cells, and castration causes the cells to undergo apoptosis. To study the molecular mechanism of androgen-dependent cell growth, we showed that androgen up-regulates the expression of the cyclin-dependent kinase inhibitor p21 (WAF1, CIP1, SDI1, CAP20) gene at both the mRNA and protein levels. Nuclear run-on assays demonstrated that androgen stimulates endogenous p21 gene expression at the transcriptional level. Transient transfection experiments showed that androgen can enhance the activity of a 2.4-kb promoter of the p21 gene linked to a luciferase reporter. These results suggested that a putative androgen response element (ARE), which mediates androgen response to enhance the p21 transcription, is included in the 2.4-kb promoter fragment. Deletion analysis of the promoter revealed a functional ARE (AGCACGCGAGGTTCC) located at -200 bp of the p21 gene proximal to the promoter region. Electrophoretic mobility shift assay further demonstrated that the androgen receptor specifically binds to this element. Wild-type ARE, but not mutant ARE, confers androgen responsiveness to a heterologous promoter. The up-regulation of p21 gene expression by androgen suggests that p21 may have an antiapoptotic function in prostatic epithelial cells. However, this hypothesis will need to be tested in future experiments.

Outcome of mechanical ventilation for adults with hematologic malignancy.

BACKGROUND: Patients with hematologic malignancy who develop respiratory failure generally have a very poor prognosis. A few such patients, however, enjoy long-term survival. The objective of this study was to identify clinical characteristics of patients with hematologic malignancy and respiratory failure that are predictive of outcome. METHODS: We performed a retrospective chart review of all patients who required mechanical ventilation for acute respiratory failure while on the leukemia or bone marrow transplantation units at the Johns Hopkins Oncology Center between January 1985 and October 1991 (n = 157). RESULTS: Overall hospital mortality was 83%. Major organ system dysfunction, as measured by the acute physiology score (APS) of the APACHE III prognostic system, was significantly (P < 0.05) related to hospital mortality. Three disease-specific clinical characteristics were predictive of mortality: 1) stage beyond first complete remission, 2) duration of neutropenia greater than 30 days, and 3) treatment with bone marrow transplantation, especially if HLA-mismatched. None of the 15 (10%) patients with neutropenia greater than 30 days or the four patients who underwent HLA-mismatched transplantation survived to discharge. Age was also a significant predictor of hospital mortality. CONCLUSIONS: Overall outcome of patients with hematologic malignancy and acute respiratory failure is poor. A larger prospective study will be required to confirm the relative value of disease-specific variables identified in this study when combined with established predictive variables. In the future, it may be possible to develop a predictive instrument that is specifically tailored for patients with hematologic malignancy who develop respiratory failure.

Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer?

Most metastatic tumors, such as those originating in the prostate, lung, and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore desperately needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. Numerous in vitro and animal studies demonstrate the effectiveness of dietary methionine restriction in inhibiting growth and eventually causing death of cancer cells. In contrast, normal host tissues are relatively resistant to methionine restriction. These preclinical observations led to a phase I clinical trial of dietary methionine restriction for adults with advanced cancer. Preliminary findings from this trial indicate that dietary methionine restriction is safe and feasible for the treatment of patients with advanced cancer. In addition, the trial has yielded some preliminary evidence of antitumor activity. One patient with hormone-independent prostate cancer experienced a 25% reduction in serum prostate-specific antigen (PSA) after 12 weeks on the diet, and a second patient with renal cell cancer experienced an objective radiographic response. The possibility that methionine restriction may act synergistically with other cancer treatments such as chemotherapy is being explored. Findings to date support further investigation of dietary methionine restriction as a novel treatment strategy for advanced cancer.

Molecular mechanisms of cell cycle block by methionine restriction in human prostate cancer cells.

Previous studies have shown that dietary or pharmacological methionine restriction inhibits growth of human prostate cancer cells in vitro or as xenografts in mice. We undertook the present studies to clarify the molecular mechanisms by which methionine restriction inhibits prostate cancer cell growth. We found that PC-3 and DU 145 cells stopped proliferating within six days in growth medium containing homocysteine in place of methionine. In contrast, proliferation of LNCaP cells was only partially inhibited by the absence of methionine. Using flow cytometry, we found that methionine restriction caused PC-3 cells to arrest in all phases of the cell cycle, but predominantly in the G2/M phase, whereas LNCaP cells accumulated exclusively in the G1 phase. Methionine restriction led to accumulation of the cyclin-dependent kinase inhibitors p21 and p27, as determined by Western blot analysis, and inhibited the enzymatic activities of the cyclin-dependent kinases CDK2 and cdc2, as determined by an in vitro kinase assay: However, methionine restriction had little or no effect on CDK2 or cdc2 protein levels. Methionine restriction also induced PC-3 cells to undergo apoptosis, as indicated by the appearance of a typical nucleosomal ladder on gel electrophoresis of genomic DNA. We conclude that methionine restriction has potential as a novel treatment strategy for prostate cancer.

Heavy metals induce expression of the TPA-inducible sequence (TIS) genes.

We previously cloned a set of primary response genes, which we call TIS (TPA-Inducible Sequence) genes, from a cDNA library prepared from Swiss 3T3 cells treated with tetradecanoyl phorbol acetate (TPA) and cycloheximide. TPA, polypeptide growth factors, and serum induce TIS gene expression in 3T3 cells. We now report that cadmium and zinc elevate mRNA levels for the TIS genes, including TIS28 (c-fos), in Swiss 3T3 cells. The time-course of TIS gene mRNA accumulation after metal exposure is delayed in comparison to the accumulation of TIS gene mRNA after treatment with TPA and growth factors. Cadmium induction of the TIS gene message accumulation is blocked by actinomycin D. Moreover, cadmium treatment does not significantly stabilize TIS gene messages. TIS gene induction by metal is a primary response; TIS8, which encodes a zinc-finger transcription factor, and TIS28 (c-fos) can be induced in the presence of cadmium and cycloheximide, an inhibitor of protein synthesis. Down-regulation of protein kinase C does not attenuate TIS gene induction by heavy metals.

There are multiple forms of glyceraldehyde-3-phosphate dehydrogenase in prostate cancer cells and normal prostate tissue.

We analyzed glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in normal and malignant human prostate tissues, normal rat prostate, and Dunning R-3327 rat prostate cancer cell lines. We detected multiple forms of GAPDH in Dunning cell lines by two-dimensional protein electrophoresis and Western analysis. Five forms of GAPDH that differed by isoelectric point were detected for each of the two metastatic Dunning cell lines, while four or fewer forms were detected for Dunning cell lines with low metastatic ability. We also detected multiple forms of GAPDH in normal and malignant human prostate specimens by two dimensional protein electrophoresis and immunohistochemical analysis. GAPDH was undetectable in normal human prostate secretory epithelium by immunohistochemistry, but was abundant in nuclei of normal basal cells and stromal cells. In human prostate cancer specimens, there was a rough correlation between cytoplasmic staining for GAPDH and tumor grade, but GAPDH staining was extremely heterogeneous. GAPDH was abundant in nuclei of some high-grade human prostate tumors. Both of the human prostate cancer bone metastases analyzed with immunohistochemistry had markedly elevated cytoplasmic GAPDH expression. We conclude that multiple forms of GAPDH may play diverse roles in normal prostate tissue and in prostate cancer.

Increased glyceraldehyde-3-phosphate dehydrogenase gene expression in late pathological stage human prostate cancer.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme best known to many investigators as a 'housekeeping' gene used as a loading control on northern blots. Prior studies, however, have shown that GAPDH RNA levels vary greatly among different prostate cancer cell lines. We undertook this study to determine the level of GAPDH gene expression within primary human prostate tumors and to determine the validity of using GAPDH as a loading control for northern analysis of human prostate cancer specimens and normal human organs. We found that GAPDH expression was significantly higher in specimens from patients with pathological stage C and D prostate cancer than those with stage B disease. Within the human prostate cancer cell lines TSUPr1, DU145, LNCaP and PC-3 and a normal neonatal prostate epithelial cell line FNC 267beta1, LNCaP cells expressed the highest level of GAPDH but all cell lines, including the normal neonate prostate cell line had very strong GAPDH gene expression. GAPDH RNA levels were highly variable among 16 normal human adult organs and four human fetal organs examined. We conclude that GAPDH RNA levels in human prostate tumors correlate with pathologic stage and that GAPDH should not be used as a loading control in northern blot experiments. Other controls, such as beta-actin or 28s ribosomal RNA, would be more suitable for such purposes.

Glyceraldehyde-3-phosphate dehydrogenase expression during apoptosis and proliferation of rat ventral prostate.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme known to play a critical role in neuronal apoptosis. We undertook the current studies to determine whether GAPDH also plays a role in prostate epithelial cell apoptosis in response to androgen deprivation. To do so, we analyzed GAPDH staining by immunohistochemistry during castration-induced involution and androgen-induced regeneration of rat ventral prostate. We found that GAPDH was undetectable in secretory epithelial cells at baseline and that staining did not increase in the epithelium during the period of peak apoptosis from 1 to 3 days after castration. However, GAPDH levels did increase within nuclei of some basal epithelial cells 5 days after castration and within the cytoplasm of all secretory epithelial cells 7 days after castration. GAPDH was also abundant within the cytoplasm of secretory epithelial cells during the period of maximal cell proliferation from 2 to 3 days after androgen replacement and was clearly apparent within nuclei of some epithelial cells 4 days after androgen replacement. Our studies suggest that GAPDH plays multiple roles during prostate epithelial cell apoptosis and proliferation.

Bioenergetics of rat prostate cancer cell migration.

BACKGROUND: Increased cell motility and increased glycolysis are two well-known hallmarks of cancer. We undertook these studies to determine whether increased glycolysis is required for prostate cancer cell locomotion. METHODS: We studied the highly metastatic MatLu cell line, which is a variant of the Dunning R-3327 rat prostate adenocarcinoma model. Using videomicroscopy and computer image analysis, we compared the speed of migration of cells grown in serum-free medium in either the presence or absence of glucose. RESULTS: We found that cells grown in glucose-free, conditioned medium maintained speeds of migration and intracellular ATP levels for 24 hr which were equivalent to those of cells grown in conditioned medium containing glucose. In contrast, migration was significantly inhibited by growth in glucose-free, unconditioned medium. We also tested the effect of antimycin A and rotenone, two inhibitors of mitochondrial electron transport, on cell migration and ATP levels. Antimycin A had no significant effect on either feature, while rotenone slightly inhibited cell migration without affecting ATP levels. CONCLUSIONS: 1) Glycolysis is not necessary for rat prostate cancer cell locomotion in the presence of conditioned medium. 2) MatLu cells grown in the absence of both serum and conditioned medium require glucose to maintain cellular ATP levels and cell migration. 3) MatLu cells in conditioned medium adapt to inhibition of glycolysis or mitochondrial respiration by increasing the activity of the uninhibited pathway.

Regulation of prostate cancer cell division by glucose.

Previous studies have shown that rapid cell proliferation is associated with elevated glucose consumption. However, those studies did not establish whether glucose is required for prostate cancer cell proliferation or define the molecular mechanisms by which glucose regulates cell division. We addressed these issues by studying two metastatic human prostate cancer cell lines: DU145, which is androgen independent and highly proliferative; and LNCaP, which is androgen dependent and relatively slow growing. We found that proliferation of DU145 cells was significantly inhibited by reduction of glucose in the medium to 0.5 g/L, which is half the physiologic concentration, whereas LNCaP cells grew at control rates even in the presence of only 0.05 g/L glucose. Glucose deprivation of DU145 cells caused a 90% reduction in DNA synthesis; a 10-20-fold reduction in cyclins D and E and CDK4 levels; and cell cycle arrest in G0-G1. However, glucose deprivation did not cause global inhibition of protein synthesis, since mutant p53 levels increased in glucose-deprived DU145 cells. This observed increase in mutant p53 levels was not associated with a rise in p21 levels. Glucose deprivation of DU145 cells also led to apparent dephosphorylation of mutant retinoblastoma (RB) protein. We conclude that: 1) high levels of glucose consumption are required for rapid proliferation of androgen-independent prostate cancer cells, 2) glucose may not be required for slow growth of androgen-dependent prostate cancer cells, and 3) glucose promotes passage of cells through early G1 by increasing the expression of several key cell cycle regulatory proteins that normally inhibit RB function.