In vitro proliferation of primitive hemopoietic stem cells supported by stromal cells: evidence for the presence of a mechanism(s) other than that involving c-kit receptor and its ligand.

The preadipose cell line, PA6, can support long-term hemopoiesis. Frequency of the hemopoietic stem cells capable of sustaining hemopoiesis in cocultures of bone marrow cells and PA6 cells for 6 wk was 1/5.3 x 10(4) bone marrow cells. In the group of dishes into which bone marrow cells had been inoculated at 2.5 x 10(4) cells/dish, 3 of 19 dishes (16%) contained stem cells capable of reconstituting erythropoiesis of WBB6F1-W/Wv mice, indicating that PA6 cells can support the proliferation of primitive hemopoietic stem cells. When the cocultures were treated with an antagonistic anti-c-kit monoclonal antibody, ACK2, only a small number of day 12 spleen colony-forming units survived; and hemopoiesis was severely reduced. However, when the cocultures were continued with antibody-free medium, hemopoiesis dramatically recovered. To examine the proliferative properties of the ACK2-resistant stem cells, we developed a colony assay system by modifying our coculture system. Sequential observations of the development of individual colonies and their disappearance demonstrated that the stem cells having higher proliferative capacity preferentially survive the ACK2 treatment. Furthermore, cells of subclones of the PA6 clone that were incapable of supporting long-term hemopoiesis expressed mRNA for the c-kit ligand. These results suggest that a mechanism(s) other than that involving c-kit receptor and its ligand plays an important role in the survival and proliferation of primitive hemopoietic stem cells.

The mouse Wnt-10B gene isolated from helper T cells is widely expressed and a possible oncogene in BR6 mouse mammary tumorigenesis.

From libraries made from activated mouse T lymphocytes, we have isolated cDNAs encoding Wnt-10B, a new member of the Wnt family of developmental control genes. This protein appears to be the mammalian orthologue of Wnt-10B, first identified in several non-mammalian vertebrates and recently in mouse. The mRNA expression pattern of mouse Wnt-10B indicates that it is induced following activation of helper T cells, but is also expressed in a variety of other tissues and cells of fetal or adult origin. 93 bp at the 5' end of the cDNA clone are identical to sequences previously reported as 3' flanking genomic DNA adjacent to a mouse mammary tumor virus (MMTV) provirus in the MMTV-induced BR6 mammary tumor, W26. Sequence analysis of tumor-derived genomic DNA confirms that the entire Wnt-10B gene is immediately adjacent to the provirus, suggesting that MMTV integration drives transcription of Wnt-10B, possibly contributing to the oncogenic process. Consistent with this idea is the detection of hybrid MMTV-Wnt-10B transcripts in BR6 tumor cells. T cells which produce abundant Wnt-10B mRNA were also found to produce protein.

Second relapse of acute promyelocytic leukemia (ANLL-M3) with t(15;17) and t(1;3)(p36;q21).

We describe herein a patient with acute promyelocytic leukemia (APL)-(ANLL-M3) whose bone marrow cells in the second relapse showed t(1;3)(p36;q21) together with t(15;17) (q22;q11-q12). Although a total of 21 patients with t(1;3) have been reported so far, among which three cases with de novo acute nonlymphocytic leukemia were included, our patient is the first case with APL. The hematologic findings in our case confirmed the previous observations that this anomaly is associated with relatively high platelet count and the multi-myeloid lineage involvement of leukemic cells. Our patient responded well to chemotherapy and achieved first and second remission with 42 months of total survival, contrary to our expectation that patients with this anomaly have a poor prognosis.

Oculomotor nerve invasion of acute myelogenous leukemia demonstrated by magnetic resonance imaging.

A 53-year-old male was diagnosed as having acute myelogenous leukemia (M2, FAB). He complained of double vision and right blepharoptosis after receiving remission induction chemotherapy. Magnetic resonance imaging (MRI) showed enlargement of the bilateral oculomotor nerves. Intrathecal injections of methotrexate and cytosine arabinoside were partially effective and repeated MRI showed shrinkage of the enlarged oculomotor nerves, after therapy. This case shows the importance of MRI in the early diagnosis of CNS leukemia.

Adult T cell leukemia lymphoma (ATL) localized in the right tibial bone.

A 56-year-old man was admitted complaining of pain in the right tibia. He was diagnosed as having adult T-cell leukemia/lymphoma (ATL/L) in the right knee joint by roentgenographic and histological examination. Monoclonal integration of HTLV-I proviral DNA was demonstrated in the bone tumor cells, although polyclonal integration was observed in the peripheral blood. These results led us to make a diagnosis of ATL with localized growth in the right knee joint. The osteolytic bone change was progressive despite radiation therapy. Complete remission was achieved after amputation of his right lower leg and two courses of chemotherapy. Resection of the localized lesion might be useful in cases of ATL, but further studies are necessary to confirm this conclusion.

Effects of high dose opioids and sedatives on survival in terminally ill cancer patients.

Concerns that high dose opioids and sedatives might shorten patient survival could contribute to insufficient symptom alleviation for terminally ill cancer patients. To examine the effects of opioids and sedatives prescribed in the final 48 hours on patient survival, a re-analysis of the prospectively collected data was performed on 209 hospice inpatients. Patient characteristics and clinical symptoms were prospectively recorded, and information about the use of opioids and sedatives in the last two days was collected by a chart review. Opioids were prescribed in 82% of the patients, with a median dose of 80 mg oral morphine equivalent (OME)/48 hours. Sixty percent received some sedative medications, mainly haloperidol (43% of total sample, 7.5 mg/48 hours), midazolam (23%, 23mg/48 hours), and hydroxyzine (15%, 50 mg/48 hours). There were no significant differences in survival between the patients who received different doses of opioids (<240, 240--599, and > or =600 mg OME/48 hours) and of benzodiazepines (0, 1--59, and > or =60 mg parental midazolam equivalent/48 hours). Also, the survival of patients with haloperidol, hydroxyzine, and other sedative medications did not differ from those without. Furthermore, an addition of use of opioids and sedatives in the final 48 hours into the multiple regression model for survival prediction achieved no significant increase in predictability. In conclusion, opioids and sedatives used for symptom control in the last days are not associated with patient survival. They are safe and useful medications to palliate severe distress in the terminal stage of cancer when administered with a low initial dosage and adequate titration.

Contributing factors to physical symptoms in terminally-ill cancer patients.

Prediction of future suffering could improve palliative care. To identify the factors contributing to physical symptoms, a prospective study was performed on two series of hospice inpatients with cancer (n = 150 and n = 200, respectively). Physical symptoms, patients' characteristics, and tumor locations were recorded using a structured protocol on admission and throughout the clinical course. Common symptoms on admission and during the patient's course were pain (65%, 88%), general malaise (58%, 77%), anorexia (57%, 94%), constipation (33%, 71%), dyspnea (33%, 66%), nausea/vomiting (29%, 48%), cough/sputum (29%, 48%), edema (27%, 65%), fever (26%, 70%), abdominal swelling (26%, 42%), and dry mouth (25%, 61%), respectively. The mean number of symptoms was 5.7 +/- 3.0 on admission and 9.6 +/- 3.1 during the course. Factors that contributed to the symptoms were young age (pain, abdominal swelling, dry mouth), performance status (anorexia, general malaise, edema, dyspnea), brain tumor (paralysis), neoplasms of lung/pleura (dyspnea, cough/sputum, death rattle), bone metastasis (pain, paralysis), gastric/pancreas cancer (abdominal swelling), peritoneal metastasis (general malaise, edema, nausea/vomiting, abdominal swelling, dry mouth), opioids (constipation, dry mouth, myoclonus), anticholinergics (dry mouth), and antidopaminergics (myoclonus). Opioid requirement was positively correlated with the presence of bone metastasis, and negatively correlated with age and brain involvement. Additional opioids were frequently used in the final 48 hours in cases with lung/pleura neoplasms. These data suggest that terminal symptoms in cancer patients are determined by local and/or general factors. Clinicians can predict the probability of future symptoms from patients' characteristics, general condition, tumor locations, and medications.

Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients.

Delirium is a common complication in terminally ill cancer patients. Identification of underlying pathologies and prediction of clinical features may improve effective symptom alleviation. This study aims to clarify precipitating factors and their associations with clinical features of terminal delirium. Consecutive hospice inpatients who developed delirium were prospectively evaluated following a structured protocol. Among 237 patients followed until death, 245 episodes of delirium were identified in 213 patients. Precipitating factors for delirium were disclosed in 93% of the 153 cases in which investigations were completed. Mean number of etiologies was 1.8 +/- 1.1 per patient, and two or more factors were recognized in 52%. The main pathologies identified were hepatic failure, medications, prerenal azotemia, hyperosmolality, hypoxia, disseminated intravascular coagulation, organic damage to the central nervous system, infection, and hypercalcemia. Occurrence of hyperactive delirium and the requirement for symptomatic sedation significantly correlated with hepatic failure, opioids, and steroids, while dehydration-related pathologies were significantly associated with hypoactive delirium. Complete recovery was frequently achieved in cases with medication- and hypercalcemia-induced delirium, whereas a low remission rate was related to hepatic failure, dehydration, hypoxia, and disseminated intravascular coagulation. In conclusion, standard examinations can confirm factors potentially contributing to delirium and thereby predict the severity of agitation and clinical outcomes.

Terminal sedation for existential distress.

Although sedation for existential distress has been actively discussed in the palliative care literature, empirical reports are limited. A retrospective cohort study was performed to clarify the physical conditions of terminally ill cancer patients who expressed existential distress and received sedation. Of 248 consecutive hospice inpatients, 20 patients expressed a belief that their lives were meaningless and received sedation. The target symptoms for sedation were dyspnea (n = 10), agitated delirium (n = 8), and pain (n = 1). Only one patient received sedation for psychological distress alone, although physical symptoms were acceptably relieved. The Palliative Performance Scale just before sedation was 10 (n = 7), 20 (n = 11), 30(n = 1), and 40(n = 1). All but one patient could take nourishment orally of only mouthfuls or less. Edema, dyspnea at rest, and delirium were observed in 10, 13, and 14 cases, respectively. The Palliative Prognostic Index was greater than 6.0 in all but one case with a mean of 12 +/- 3.3. In conclusion, in our practice, sedation was principally performed for physical symptoms of cancer patients in very late stages. Further research is encouraged to establish standard therapy for existential distress of the terminally ill.

Perceptions and decision-making on rehydration of terminally ill cancer patients and family members.

Although the appropriateness of forced rehydration for terminally ill cancer patients has been actively discussed, few studies have investigated its psychological aspects. To clarify patients' and family members' perceptions about rehydration and identify contributing factors for decision-making, a prospective structured survey was performed on 121 hospice inpatients with insufficient oral intake. Physicians did not recommend rehydration in 78 percent of patients, and 75 percent decided not to receive artificial fluid therapy. Various concerns affected decision-making: 76 percent of patients and 85 percent of family members believed patients could not get appropriate nutrition without artificial rehydration. Some 56 percent of patients and 84 percent of family members said that withholding rehydration would cause premature death, while more than half agreed that forced rehydration might worsen the patients' suffering. Patients' performance status, fluid retention signs, denial, physicians' recommendations, patients' and family members' beliefs about the effect of hydration on patients' distress, and family members' anxiety about withholding rehydration were significantly associated with decision-making. Multiple regression analyses revealed patients' denial, physicians' recommendations determined by patients' performance status and fluid retention symptoms, and family members' belief that rehydration could worsen patients' distress as independent determinants for rehydration. In conclusion, hospice care receivers had various concerns about rehydration, related to patients' nutrition, survival, and distress. The main determinants for rehydration therapy were patients' performance status, fluid retention symptoms, denial, and care receivers' beliefs about the effect of hydration on the patients' distress.

A prospective study on the dying process in terminally ill cancer patients.

To determine the physical and medical change in the dying process, a prospective study was performed on 100 terminally ill cancer patients. The mean (median) time from the onset of death rattle, respiration with mandibular movement (RMM), cyanosis on extremities, and pulselessness on the radial artery to death was 57 (23) hours, 7.6 (2.5) hours, 5.1 (1.0) hours, and 2.6 (1.0) hours respectively. Death rattle preceded the other three conditions in 74 percent of the subjects, while RMM preceded cyanosis and pulselessness in 63 percent. The ratio of awake-drowsy-comatose patients was 56-44-0 percent one week before death, 26-62-12 percent in the last 24 hours, and 8-42-50 percent in the final six hours. The number of opioid users and average dose increased significantly as death approached, from 42 percent and 49 mg/day (parental morphine equivalent) four weeks before death to 87 percent and 139 mg/day in the final 48 hours. The frequency of extra dosage also increased significantly, from 32 percent (opioid) and 40 percent (non-opioid) one week before death to 68 percent and 66 percent in the last 48 hours, respectively. The change of physical signs and medical intervention when death is impending has a common pathway in spite of large individual variations; thus, understanding this nature can help clinicians to offer better palliative care to terminal cancer patients.

[Acute myeloid leukemia with monosomy 7 accompanied by central diabetes insipidus].

A 27-year-old female was diagnosed as having atypical aplastic anemia in 1979 because of hypercellular bone marrow with abnormal erythroblasts and megakaryocytes. Afterward the diagnosis was corrected to myelodysplastic syndrome (RA) due to the reevaluation of the bone marrow smears. In March, 1995, thirst and polyurea occurred. In April, 1995, bone marrow aspiration biopsy showed the proliferation of atypical blasts (28%), and two months later, the number of the blasts increased (30%) and leukemic progression was noticed. Only 0.5 percent of the blasts showed weak peroxidase activity, and most of the blasts had CD13, CD33 and several adhesion molecules as CD11a, CD11b, CD44, CD54 and CD56. Karyotype of the bone marrow cells was 45, XX, -7. Her polyurea was caused by central diabetes insipidus. She was also complicated by pleuritis, colon ulcer, sinusitis and hypothalamic dysfunction. The etiology of these signs was due to the leukemic cell infiltration. She died despite of receiving multi-drug chemotherapy.

[Staphylococcus aureus sepsis in patients with hematological malignancies: increase in MRSA sepsis].

From January 1978 to August 1990, Staphylococcus aureus bacteremia (SAB) were identified in 31 patients with hematological malignancies at Jichi Medical School hospital. Mortality due to SAB was 48.4% (15/31). Of the variables analyzed, four factors were significantly associated with a poor prognosis; elderly age (p = 0.015), high granulocyte count (more than 500/microliters) (p = 0.015), presence of DIC (p = 0.011) and presence of pneumonia (p = 0.023). The incidence of methicillin-resistant SAB was 32.3% (10/31) and the first patient developed in 1985. Although not statistically significant, there was a trend of higher mortality for methicillin-resistant SAB (70%) than for methicillin-sensitive SAB (38.1%). Most strains of methicillin-resistant Staphylococcus aureus were sensitive to minocycline, chloramphenicol and vancomycin.

[Double autologous peripheral blood stem cell transplantation (double APBSCT) for lymphoblastic lymphoma].

A 24-year-old male was admitted to our hospital, complaining of right back pain, in May 1995. Chest X-ray films showed an abnormal mass in the mediastinum. Computed tomography revealed massive effusion in the pleural and pericardial space. A biopsy specimen of the pleural lesion demonstrated lymphoblastic lymphoma of T cell type. After the completion of intensive chemotherapy by our original protocol, he entered into partial remission. Peripheral blood stem cells (PBSC) were harvested using a high-dose cytarabine (Ara-C) followed by granulocyte-colony stimulating factor (G-CSF) mobilization regimen. The total number of collected PBSC was enough to perform two courses of PBSCT. In January 1996, following the conditioning regimen of nimustine hydrochloride, etoposide (VP-16), Ara-C, thiotepa, he received PBSCT. Complete remission was achieved after the 1st PBSCT. In March 1996, he received the 2nd PBSCT following the conditioning regimen of carboplatin, VP-16, ifosfamide. No regimen-related toxity or delayed engrafment was observed. Subsequently, he received irradiation to his neck and mediastinum, the primary site of the disease. As of February 1997, he has no evidence of the disease.

[Retrospective analysis on 21 patients with follicular lymphoma].

We retrospectively analyzed the clinical data of the 21 patients with follicular lymphoma admitted to our institution from 1977 to 1994. The frequency of follicular lymphoma was 9.1% in the 231 patients with non-Hodgkin's lymphoma. Overall survival rates at 1 year, 3 years, and 5 years were 90.2%, 78.2%, and 52.1%, respectively. The median follow-up of surviving patients and time to treatment failure (TTF) was 43 months and 30 months, respectively. The median time from disease progression to death was 171 days. In univariate analysis, factors associated with poor survival were stage IV (Ann Arbor staging system), anemia (hemoglobin level less than 10g/dl), bone marrow involvement, two or more extranodal sites, and failure in induction of complete remission (CR) in the entire course. Factors associated with short TTF were anemia, bone marrow involvement, and failure in induction of CR. In multivariate analysis, induction of CR affected survival and TTF independently.

[Retrospective analysis of elderly patients > or = 60 years of age with acute leukemia].

A retrospective analysis was performed on 76 consecutive elderly patients with acute leukemia aged 60 years or more (48 men, 28 women). Forty patients were 60-69 years old, 28 were 70-79 years old and 8 were > or = 80 years old. There were 55 patients with acute myelogenous leukemia (AML), 13 acute lymphoblastic leukemia (ALL) and 8 AML from myelodysplastic syndrome (MDS/AML). Patients were treated with the JALSG protocol, CAG regimen, or low-dose Ara-C regimen for AML, and DVP/M-CHOP protocol for ALL. The complete remission (CR) rates were 52.7% (29 of 55) in AML, 61.5% (8 of 13) in ALL, and 0% in MDS/AML. The median CR durations were 226, 85, 0 days, and the median survivals were 204, 177, 99 days, respectively. CR rates were 65.3% for the JALSG protocol, 62.5% for the CAG regimen and 25.0% for low-dose Ara-C regimen. According to age, CR was obtained 62.5% in patients aged 60-69 years and 33.3% in patients over 70 years old. Our results indicated that patients aged 60-69 years should be treated with intensive chemotherapy.

[Prediction of survival of terminally ill cancer patients--a prospective study].

Planning effective palliative care requires accurate estimation of survival. A prospective study was performed on 150 hospice inpatients to identify prognostic factors in terminally ill cancer patients. By univariate analysis, eleven factors were found to be significantly associated with shortened survival: poor performance status, dyspnea at rest, death rattle, appetite loss, dysphagia, dry mouth, general malaise, edema, stomatitis, fever, and delirium. Multiple regression analysis showed that five factors were independent predictors of survival: performance status, dyspnea at rest, appetite loss, edema, and delirium. We discussed current problems and future directions of survival prediction for terminally ill cancer patients.

[Accuracy of clinical prediction of survival for terminally ill cancer patients].

Accurate estimation of survival is vital for effective palliative care. To verify the value of clinical prediction of survival (CPS), a prospective study was performed on 150 terminally ill cancer patients. The CPS was highly correlated with actual survival (AS), but the accuracy was not significantly superior to the prediction by performance status alone. Serious pessimistic error, defined as AS was at least 28 days and twice as long as CPS, was recognized in 13%, while serious optimistic error, defined as AS was less than 28 days and half as long as CPS, in 15%. The frequency of serious error was not significantly different by physicians' experiences, patients' age, sex, primary disease, and metastatic locations, but was significantly higher in cases with better performance status. Also, unexpected changes resulting in death were experienced in 42% of another 186 cases. The main underlying causes were pneumonia, bleeding, heart failure, intestinal perforation, cerebrovascular disease, hepatic/renal failure, hypoglycemia, sepsis and electrolyte imbalance. Clinical prediction was not sufficiently reliable and must be further improved.

[Treatment of 71 adult acute lymphoblastic leukemia].

From 1975 to 1989, 71 acute lymphoblastic leukemia patients aged 15 to 81 years (median 46 years) were treated at Jichi Medical School. Fifty-eight patients (81.7%) achieved complete remission (CR). Median CR duration was 219 days, and the probability of being in continuous CR at 3 years was 8.9%. Median survival was 462 days, and the probabilities of being alive at 3 and 5 years were 19.8% and 7.3%, respectively. The new regimen introduced from 1987 consisted of remission induction with L-asparaginase, daunomycin, vincristine and prednisolone, followed by intensive consolidation and maintenance. However, the treatment failed to improve outcome. The factor unfavorable for achieving early CR after first-line treatment regimen was the presence of myeloid antigen, and that for achieving final CR after second-line treatment regimen was advanced age. The factors unfavorable for remission duration were high leukocyte count and late CR. Those unfavorable for survival were advanced age and elevated blood urea nitrogen. Further improvement in the design of new protocols which include the use of several cytokines and autologous bone marrow transplantation may result in prolonged disease-free survival.