Janet L. Abrahm

Elevated Methylmalonic Acid and Total Homocysteine Levels Show High Prevalence of Vitamin B12 Deficiency after Gastric Surgery

Elderly persons [1, 2] and persons who have had gastric surgery [3-11] are at increased risk for developing vitamin B12 (cobalamin) deficiency. The hematologic and neurologic manifestations of vitamin B12 deficiency have been well described; however, this deficiency often remains undetected, and some patients receive a misdiagnosis of Alzheimer disease, spinal cord compression, amyotrophic lateral sclerosis, or diabetic or alcoholic peripheral neuropathy [12]. Although megaloblastic anemia is usually reversible with vitamin B12 treatment, the neurologic injuries are reversible only if they are treated soon after their onset [12, 13]. In addition, as do patients with folate deficiency [14], patients with untreated vitamin B12 deficiency have elevated total homocysteine levels. Substantial biochemical and epidemiologic evidence now suggests that an elevated serum total homocysteine level contributes to the development of carotid artery stenosis, coronary artery disease, and peripheral vascular disease [15-18]. Thus, in theory at least, patients with untreated vitamin B12 deficiency may be at increased risk for developing atherosclerotic vascular disease. In the future, the prevalence of vitamin B12 deficiency in the aging population may be expected to increase. Among persons at major risk are those who had subtotal gastrectomy for ulcer disease between the 1930s [19] and 1974 [5, 7] (in 1974, the first histamine-2 blocker, cimetidine, was released [20]). It is not possible to determine how many Americans had gastric surgery during this period, but representative data from the University of Minnesota Hospital suggest that the number is large. At that hospital alone, 1550 patients had subtotal gastrectomy between 1938 and 1950 [4]. Throughout the United States, therefore, hundreds of thousands of patients probably had this surgery. A new operation, gastric bypass for obesity, is currently creating another cohort at risk for developing vitamin B12 deficiency [11]. As these cohorts age, an unknown number of persons will develop vitamin B12 deficiency, and clinicians caring for such persons currently have no accurate guidelines on which to base screening decisions. Previous prevalence estimates are unreliable because clinical manifestations are insensitive and radiodilution vitamin B12 assays were nonspecific [21, 22]. The Schilling test is unreliable after gastrectomy [8, 9], anemia is often absent in vitamin B12-deficient patients [2, 12, 23], and macrocytosis may be masked by coexisting iron deficiency [7, 24]. See editorial comment on pp 509-511. Recently, however, measurements of the metabolites from two vitamin B12-dependent pathways (Figure 1)serum methylmalonic acid [25] and total homocysteine [14]were shown to be highly sensitive detectors of vitamin B12 deficiency [26]. Two enzymes have a known requirement for vitamin B12: L-methylmalonyl-CoA mutase and methionine synthase [22]. Methionine synthase requires folate in addition to vitamin B12 for normal functioning. If the conversion of L-methylmalonyl-CoA to succinyl-CoA is impaired by a deficiency of the vitamin B12 cofactor adenosylcobalamin, the excess methylmalonyl-CoA is cleaved to methylmalonic acid and methylmalonic acid levels in the serum and urine are elevated [25]. Similarly, if the methylation of homocysteine to methionine is impaired by a deficiency of methylcobalamin or methyltetrahydrofolate, serum total homocysteine levels are elevated [14]. The metabolic pathways in which these two enzymes function are not always equally affected by vitamin B12 deficiency. At the time vitamin B12 deficiency is diagnosed, therefore, levels of methylmalonic acid, total homocysteine, or both may be elevated [22]. Figure 1. The two vitamin B12-dependent enzymes, L-methylmalonyl-CoA mutase (left) and methionine synthase (right). In vitamin B12-deficient patients, elevated levels of both serum methylmalonic acid and total homocysteine decrease promptly with adequate vitamin B12 therapy [22, 26]. However, in folate-deficient patients, total homocysteine levels return to normal only after folate replacement [22]. Therefore, in addition to serum vitamin B12 levels, we used methylmalonic acid, total homocysteine, and folate levels to determine whether the prevalence of vitamin B12 deficiency differed between persons who had had gastric surgery and those who had not. Methods Between September 1991 and March 1993, 65 patients who had had gastric surgery were identified at the Philadelphia Veterans Affairs Medical Center. These patients were identified either by review of gastrointestinal radiographs, surveys of the house-staff assigned to the medicine and surgery inpatient services, or referral of outpatients from physicians in the medical clinic. Four of the 65 patients were excluded: Three were receiving vitamin B12 therapy, and one had a hepatoma. Hepatoma can produce increased levels of vitamin B12-binding protein, which may complicate interpretation of serum vitamin B12 levels. Patients who had not had gastric surgery (controls) were drawn from 127 consecutive patients attending one authors Philadelphia Veterans Affairs Medical Center clinic between November 1992 and March 1993. One hundred seven controls participated, and 20 either declined to participate or did not complete the required blood tests. We determined the type of gastric surgery that had been done either from patient reporting or by reviewing radiologic, endoscopic, or surgical records. In most patients (51 of 61), we determined the year surgery had been done from patient report or chart review. For patients who could not provide the year of surgery but could specify the decade, we used the mid-decade year. For example, if the patient said that the surgery had been done in the 1950s, we recorded the year as 1955. Serum vitamin B12 and folate levels were determined at the Philadelphia Veterans Affairs Medical Center using a commercially available radioligand kit (Bio-Rad, Diagnostics Group, Hercules, California). In the hospitals laboratory, normal values for vitamin B12 and folate levels were 171 to 840 pmol/L and 5 to 39 nmol/L, respectively. The remaining serum samples were frozen at 20 C and were shipped to Denver so that serum methylmalonic acid and total homocysteine levels could be analyzed by the stable isotope dilution gas chromatography-mass spectrometry method [27-30]. The normal range for serum methylmalonic acid levels (determined in 50 normal blood donors 18 to 65 years of age) is 73 to 271 nmol/L, and the normal range for serum total homocysteine levels is 5.4 to 16.2 mol/L [22]. Vitamin B12 deficiency was defined as one of the following: 1) a serum vitamin B12 level less than 221 pmol/L and an elevated methylmalonic acid level; 2) a serum vitamin B12 level less than 221 pmol/L and a total homocysteine level that decreased after vitamin B12 therapy; or 3) in patients unavailable for treatment, a serum vitamin B12 level less than 221 pmol/L, a folate level greater than 9 nmol/L, and an elevated total homocysteine level. Hemoglobin level, hematocrit, and mean corpuscular volume were measured by automatic devices. Macrocytosis was defined as a mean corpuscular volume of 95 fL or less. The peripheral smears of 71% of patients (43 of 61) and 88% of controls (94 of 107) were reviewed by one hematologist who was blinded to each participants vitamin B12 level, hemoglobin level, hematocrit, and gastric surgery status. Hypersegmentation was defined as five neutrophils with five or more lobes or one neutrophil with six lobes per 100 cells counted. Treatment Vitamin B12 treatment generally consisted of daily intramuscular injections of 1000 g of vitamin B12 for 5 days, followed by monthly injections. Folic acid was given orally, 1 mg/d. Serum vitamin B12, folate, methylmalonic acid, and total homocysteine levels were measured 1 to 6 weeks after treatment. Statistical Analysis Data were examined to determine whether the variables were suitable for parametric analyses. Although relatively modest, the skew for the numeric variables necessitated that several variables be transformed to logs for entry into two-way analysis of variance or be subjected to nonparametric analyses. The comparison between patients and controls for levels of vitamin B12, folate, methylmalonic acid, and total homocysteine was done by two-factor analysis of variance on log-transformed variables. In each analysis of variance, race was included as a factor (along with study group) to control for possible race-by-group interactions. We used unpaired t-tests or Mann-Whitney U tests to do comparisons of other numeric variables, such as hemoglobin and mean corpuscular volume; comparisons between other groups, such as patients with a positive and patients with a negative peripheral blood smear; and comparisons between deficient and nondeficient patients. We used chi-square tests to compare groups on dichotomous variables (such as white patients compared with black patients). Spearman correlations were used to assess the association between the time since surgery and other variables. The Human Studies Subcommittee and the Research and Development Committee of the Philadelphia Veterans Affairs Medical Center approved the study. Results Clinical Characteristics The 61 patients (who had had gastric surgery) and 107 controls (who had not) were similar in the ratio of men to women (60:1 compared with 104:3), age, and race (Table 1). The indications for surgery included peptic ulcer disease (56 patients), obesity (3 patients), gastric cancer (3 patients [2 of whom had previously had surgery for peptic ulcer disease]), and gastric lymphoma (1 patient). The type of gastric surgery could be determined in 36 of 61 patients (59%). The types of surgery were Billroth II (23 patients), repair of perforated ulcer (6 patients), vagotomy and pyloroplasty (2 patients), gastric bypass or gastric banding for obesity (3 patients), Billroth I (1 patient),

Spinal Cord Compression in Patients With Advanced Metastatic Cancer: “All I Care About Is Walking and Living My Life”

As 1 of the 12,700 US cancer patients who, each year, develops metastatic spinal cord compression, Ms H wishes to walk and live her life. Sadly, this wish may be difficult to fulfill. Before diagnosis, 83% to 95% of patients experience back pain, which often is referred, obscuring the site(s) of the compression(s). Prediction of ambulation depends on a patients ambulatory status before therapy and time between developing motor defects and starting therapy. Ambulatory patients with no visceral metastases and more than 15 days between developing motor symptoms and receiving therapy have the best rate of survival. To preserve ambulation and optimize survival, magnetic resonance imaging should be performed for cancer patients with new back pain despite normal neurological findings. At diagnosis, counseling, pain management, and corticosteroids are begun. Most patients are offered radiation therapy. Surgery followed by radiation is considered for selected patients with a single high-grade epidural lesion caused by a radioresistant tumor who also have an estimated survival of more than 3 months. Team discussions with the patient and support network help determine therapy options and include patient goals; assessment of risks, benefits, and burdens of each treatment; and discussion of the odds of preserving prognosis of ambulation and of the effect of therapy on the patients overall prognosis. Rehabilitation improves impaired function and its associated depression. Clinicians can help patients cope with transitions in self-image, independence, family and community roles, and living arrangements and can help patients with limited prognoses identify their end-of-life goals and preferences about resuscitation and entering hospice.

Treatment with 13-cis-Retinoic Acid in Transfusion- Dependent Patients with Myelodysplastic Syndrome and Decreased Toxicity with Addition of Alpha-Tocopherol

PURPOSE The purpose of this study was to determine the response and tolerance to long-term treatment using 13-cis-retinoic acid (13-CRA) in transfusion-dependent patients with the myelodysplastic syndrome (MDS) and to determine the effects of therapy on the natural history of the disease. PATIENTS AND METHODS Sixty-six consecutive patients with transfusion-dependent MDS seen in a medical school hospital and outpatient clinic from 1981 to 1988 were studied. The first 21 patients were treated with 13-CRA alone and the next 45 patients with 13-CRA plus alpha-tocopherol (AT). We compared responses to and toxicities of therapy, rates of transformation, and survival from onset of therapy in 20 evaluable patients treated with 13-CRA alone and 43 patients treated with 13-CRA plus AT. RESULTS Four patients responded (20%) at 4 to 8 months to 13-CRA alone, but this response was associated with considerable toxicity and resulted in cessation of therapy. Among the responders, only one continued therapy and is currently in remission, whereas three discontinued therapy because of toxicity and have had a relapse and died. In the 13-CRA plus AT group, we observed one prolonged complete remission and 10 partial remissions (26%), with a decrease in skin and constitutional toxicities by the addition of AT, which enabled the continuation of 13-CRA indefinitely. Although the response rates were similar in both groups, fewer patients (28% versus 60%) experienced progression to acute leukemia in the 13-CRA plus AT group than in the group receiving 13-CRA alone, who terminated treatment (p = 0.018). A twofold increase in median survival of the RA/RARS and RAEB/CMML patient groups was observed with 13-CRA plus AT but was not significant (p greater than 0.5). CONCLUSION This study shows a 20% to 26% response rate to 13-CRA and suggests that 13-CRA, if given continuously, decreases the rate of progression or transformation to acute leukemia in patients with MDS. The addition of AT ameliorates the toxicity of 13-CRA and allows for long-term treatment with 13-CRA. Since the standard treatment for MDS is currently unsatisfactory, these findings indicate that longer treatment with a non-marrow-suppressive agent such as 13-CRA is important, and further trials to determine the role of 13-CRA plus AT in combination with new recombinant growth factors in the therapy for transfusion-dependent MDS should offer a new approach to a disease common in the elderly population.

The role of radiotherapy for metastatic epidural spinal cord compression

Radiotherapy alone is the most common treatment for metastatic epidural spinal cord compression (MESCC). Decompressive surgery followed by radiotherapy is generally indicated only in 10–15% of MESCC cases. Chemotherapy has an unclear role and may be considered for selected patients with hematological or germ-cell malignancies. If radiotherapy alone is given, it is important to select the appropriate regimen. Similar functional outcomes can be achieved with short-course radiotherapy regimens and longer-course radiotherapy regimens. Longer-course radiotherapy is associated with better local control of MESCC than short-course radiotherapy. Patients with a more favorable survival prognosis (expected survival of ≥6 months) should receive longer-course radiotherapy, as they may live long enough to develop a recurrence of MESCC. Patients with an expected survival of <6 months should be considered for short-course radiotherapy. A recurrence of MESCC in the previously irradiated region after short-course radiotherapy may be treated with another short-course of radiotherapy. After primary administration of longer-course radiotherapy, decompressive surgery should be performed if indicated. Alternatively, re-irradiation can be performed using high-precision techniques to reduce the cumulative dose received by the spinal cord. Larger prospective trials are required to better define the appropriate treatment for the individual patient.

Incidence and Treatment Patterns in Hospitalizations for Malignant Spinal Cord Compression in the United States, 1998-2006

PURPOSE To characterize patterns in incidence, management, and costs of malignant spinal cord compression (MSCC) hospitalizations in the United States, using population-based data. METHODS AND MATERIALS Using the Nationwide Inpatient Sample, an all-payer healthcare database representative of all U.S. hospitalizations, MSCC-related hospitalizations were identified for the period 1998-2006. Cases were combined with age-adjusted Surveillance, Epidemiology and End Results cancer death data to estimate annual incidence. Linear regression characterized trends in patient, treatment, and hospital characteristics, costs, and outcomes. Logistic regression was used to examine inpatient treatment (radiotherapy [RT], surgery, or neither) by hospital characteristics and year, adjusting for confounding. RESULTS We identified 15,367 MSCC-related cases, representing 75,876 hospitalizations. Lung cancer (24.9%), prostate cancer (16.2%), and multiple myeloma (11.1%) were the most prevalent underlying cancer diagnoses. The annual incidence of MSCC hospitalization among patients dying of cancer was 3.4%; multiple myeloma (15.0%), Hodgkin and non-Hodgkin lymphomas (13.9%), and prostate cancer (5.5%) exhibited the highest cancer-specific incidence. Over the study period, inpatient RT for MSCC decreased (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.61-0.81), whereas surgery increased (OR 1.48, 95% CI 1.17-1.84). Hospitalization costs for MSCC increased (5.3% per year, p < 0.001). Odds of inpatient RT were greater at teaching hospitals (OR 1.41, 95% CI 1.19-1.67), whereas odds of surgery were greater at urban institutions (OR 1.82, 95% CI 1.29-2.58). CONCLUSIONS In the United States, patients dying of cancer have an estimated 3.4% annual incidence of MSCC requiring hospitalization. Inpatient management of MSCC varied over time and by hospital characteristics, with hospitalization costs increasing. Future studies are required to determine the impact of treatment patterns on MSCC outcomes and strategies for reducing MSCC-related costs.

Pain assessment and management

Assessment and management of pain is crucial to the success of any program of care for dying patients and their families. With appropriate assessment and management, often using home health or hospice teams, pain can be controlled in more than 90% of patients. This article focuses on the symptomatic care of patients who are dying. The legal and regulatory issues that may inhibit delivery of adequate opioid therapy are also reviewed.

The effect of tumor-promoting phorbol diesters on terminal differentiation of cells in culture.

SummaryPhorbol diesters with tumor-promoting activity, in particular, 12-0-tetradecanoyl-phorbol-13-acetate (TPA), can induce or inhibit terminal differentiation in a variety of cell systems, with specificity for particular cell lineages. The phorbols are excellent tools to investigate the expression and control of differentiation in some cells and the mechanism by which oncogenic agents interfere with the process of terminal differentiation. The mechanism of action of the phorbols on different target cells is not understood at the present time. It is felt that the status of the cell is of major importance as, in some cases, opposite effects can be achieved by the same concentration of the phorbol diester used. Changes in membranes, receptors, in secretion of prostaglandins and in the level of cyclic AMP have all been reported. However, the relationship of these changes with the alterations in the genetic program involved in the differentiation process is not clear, and the recent report of a possible cell receptor for phorbol diesters should elucidate their mechanism of action. The findings on the effect of phorbol diesters on differentiation have suggested the testable hypothesis that promotion could be mediated through inhibition of cellular differentiation. It has also been suggested that changes in differentiating systems could be of future use in screening for unknown tumor promoters, however, this possibility seems quite remote. Finally, phorbol diesters with tumor-promoting activity appear to exert a specific effect on differentiation of leukemic cells of both mouse and human origin, and therefore, the application of this particular phenomenon in experimental therapy should be the subject of future investigations.

Danazol treatment of myelodysplastic syndromes

Summary. Peripheral cytopenias are common in patients with myelodysplastic syndromes. We previously successfully treated three such patients with improvement of some cytopenias with the impeded androgen danazol. To confirm this finding and elucidate the mechanism of response, we treated an additional 22 patients with myelodysplasia with oral danazol (600–800 mg daily) for 3–12 months. Eleven of 22 evaluable patients taking danazol met our criteria for improvement of peripheral counts, mainly thrombocytopenia. Chromosome analysis, marrow culture studies and serial bone marrow biopsies revealed no alteration of the abnormal clone or normal haematopoiesis in patients on danazol therapy. This suggested that improvement in blood counts was not related to modulation of ineffective haematopoiesis. Investigation of the thrombocytopenia in these patients revealed that most patients presented with markedly elevated platelet associated IgG (PAIgG), elevated plasma platelet‐bindable IgG (PBIgG), and an elevated number of monocyte Fcγ receptors. Treatment with danazol was associated with a decline in monocyte Fcγ receptor number without significantly altering the elevated PAIgG or PBIgG levels. These results are similar to our observations in patients treated with danazol for chronic idiopathic thrombocytopenia purpura (ITP). Our data suggest that a component of the thrombocytopenia occurring in patients with myelodysplasia may be due to enhanced peripheral blood cell destruction by abnormal macrophages. Danazol may modulate cytopenia by decreasing the number of monocyte Fcγ receptors. Danazol treatment was associated with minimal toxicity, but clinically meaningful responses were rare.

Treatment of painful bone metastases

Bone metastases are the most common cause of cancer-related pain. Radiotherapy is a safe and effective therapy and is well established for such a situation. A fractionation regimen with a short overall treatment time (≤1 week) would be preferred if it was as effective as longer courses (2–4 weeks). Randomized clinical trials and meta-analyses have demonstrated that single-fraction radiotherapy with 1 × 8 Gy is as effective for pain relief as multi-fraction regimens such as 5 × 4 Gy in 1 week or 10 × 3 Gy in 2 weeks. Re-irradiation for recurrent pain in the irradiated region is required more often after single-fraction radiotherapy than multi-fraction radiotherapy; however, re-irradiation following single-fraction radiotherapy is safe and effective. Thus, 1 × 8 Gy is considered the standard regimen for uncomplicated painful bone metastases without pathological fractures or spinal cord compression. Multi-fraction radiotherapy results in significantly better remineralization of the osteolytic bone than single-fraction radiotherapy. Remineralization is important for preventing or treating pathological fractures. Multi-fraction long-course radiotherapy results in fewer recurrences of spinal-cord compression within the irradiated spinal region. Thus, long-course multi-fraction radiotherapy should be reserved for patients with a relatively favorable survival prognosis.

ADVANCES IN PAIN MANAGEMENT FOR OLDER ADULT PATIENTS

Management of pain is crucial to the success of any program of care and support for dying patients and their families. Pain can be controlled in more than 90% of older adults. Components of an effective program include comprehensive, repeated pain assessment; detection and treatment of complicating medical and psychological disorders (e.g., delirium); spiritual concerns; and the judicious use of nonpharmacologic and pharmacologic therapies, radiation, and radiopharmaceuticals. Strategies that enable clinicians to prevent and treat the expected complications of nonsteroidal anti-inflammatory and opioid therapies are reviewed. Strategies to change opioid agents or routes to minimize opioid-induced side effects and to provide effective pain relief as death nears are presented.