Posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than is percent reduction in M-protein in patients with IgG myeloma.

We conducted a retrospective study of patients with IgG or IgA myeloma who attained plateau to evaluate the relationships between survival and posttreatment nadir M-protein levels and between survival and the response to treatment evaluated by the percent reduction in M-protein. Of the 127 patients comprising 92 IgG and 35 IgA myeloma patients with disease stages II or III, 51 (40.2%) attained plateau. For IgG myeloma patients who attained plateau, survival time was not affected by the percent reduction in M-protein (median survival, 59.5 months for responding patients versus 54.4 months for nonresponding patients, P = .6910). Posttreatment nadir M-protein level, however, did affect survival time (median survival, 61.2 months for <3000 mg/dL versus 25.7 months for >3000 mg/dL, P = .0439). These findings suggest that the posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than the percent reduction of M-protein in patients with IgG myeloma.

Posttreatment M-protein nadir level is a significant prognostic factor associated with survival in multiple myeloma. Nagoya Myeloma Cooperative Study Group.

In the present study 142 patients with myeloma (102 with IgG M-protein and 40 with IgA) treated with either VMCP (65 patients) or MMCP (77 patients) as remission induction therapy were retrospectively analyzed. Response to treatment was evaluated in terms of a more-than-50% fall of pretreatment M-protein and the posttreatment M-protein nadir. Though significantly more patients treated with MMCP achieved partial response (PR) as compared with those treated with VMCP (P=0.019) and though patients achieving PR showed a significantly longer survival than those with less responsiveness (P=0.0091), the difference in survival curves between the two treatment groups was not significant (P=0.1871). The difference in response between the treatment groups evaluated in terms of posttreatment nadir was not significant (P=0.507). Multivariate analysis identified posttreatment M-protein nadir as a significant prognostic factor associated with survival, along with 3 other factors: sex, performance status, and hemoglobin. The lack of difference between the survival curves for patients treated with the 2 regimens despite the significantly different response rates evaluated in terms of percent fall of pretreatment M-protein levels was considered to be due to the lack of a difference in the ability to induce a deep posttreatment nadir between the regimens. Posttreatment M-protein nadir is an important prognostic factor associated with survival and should be included in the evaluation of the efficacy of chemotherapy.

[Analysis of elderly patients, aged 60 years old or over, with acute lymphoblastic leukemia].

In order to obtain the realistic background information on clinical features, and the present status of treatment and outcome in elderly patients with acute lymphoblastic leukemia (ALL), we carried out random survey of patients with ALL aged 60 or over who had been admitted to 13 general hospitals in the Nagoya region from January 1990 through December 1995. Among the 20 cases collected, ages ranged from 60 to 88 (median age 68), and the male to female ratio was 11:9. Nineteen cases were L2 subtype in FAB classification. Among 17 patients, 13 had B cell series surface phenotypes (76%), 2 had T cell series (12%), one had stem cell type (6%) and one had an undetermined phenotype (6%). Ph chromosomes were detected in 4 cases among 15 analyzed (27%), whereas 5 were found to have no chromosomal abnormality. Half of the patients had some concurrent disease at diagnosis, including two with treatment-limiting complications. Common induction regimens were the combination of adriamycin (ADM) + vincristine (VCR) + cyclophosphamide (CPM) + mitoxdn trone + L-asparaginase [4 patients]. ADM + VCR + PSL [4 patients]. VCR + PSL [4 patients] and others [8 patients]. The overall remission rate was 55.0% (11/20) without any significant difference according to age. The median survival time (MST) for all cases was 205 days. (1-year survival rate:17.9%, 2-year survival rate:10.8%). There was no significant difference in survival times among patients with the Ph chromosome, those with other chromosomal abnormalities and those without them. All the patients aged 75 or over were treated with attenuated induction therapy, and they had a shorter survival than those aged less than 75, but with no statistical significance [MST:121 days versus 276 days, p = 0.307 (generalized Wilcoxon test)].

Acute myeloid leukemia in the elderly:--159 Nagoya case studies--Nagoya Cooperative Study Group for Elderly Leukemia.

To obtain background information on elderly acute myeloid leukemia (AML), unselected data covering 159 patients aged 60 years or over with AML from 14 hospitals in Nagoya, Japan was analyzed retrospectively. Among these patients, 119 had de novo acute AML, 32 had AML which evolved from myelodysplastic syndrome (MDS-AML), and 8 had other types of leukemia. The survey showed that MDS-AML tended to be more prevalent in patients aged 70 years and older and that MDS-AML showed a significantly more severe degree of leukopenia and anemia than de novo AML. MDS-AML also showed a significantly lower complete remission (CR) rate than that of de novo AML [6.9% (2/29) vs 58.3% (67/11), P < 0.01] and significantly shorter survival times than those of de novo AML [median: 3.6 months vs 9.6 months, P < 0.01 (generalized Wilcoxon test; GW]. In de novo AML, the proportion of patients treated with conventional therapy (CT group) decreased significantly, and that of those with attenuated therapy (AT group) increased significantly as age elevated (P < 0.01). The CT group showed a significantly higher CR rate (65.4% vs 41.2%, P < 0.05) and a significantly longer survival period than those of the AT group [median: 11.6 months vs 4.8 months, P < 0.05 (GW)]. Overall survival rates of the older age groups became significantly shorter with aging [P < 0.01 (GW)].

[Characteristics of bedridden elderly people living at home and in a hospital].

We compared bedridden elderly people living at home to others who were hospital inpatients. Questionnaires regarding medical status and care were returned by 85 of 116 people caring for a bedridden elderly person at home in Obu city, Aichi prefecture and by 62 of 64 nurses and family members caring for bedridden inpatients at Chubu National hospital. All subjects were at least 65 years old. The median age in both groups was 81 years, neither age distribution nor female sex predominance differed between both groups. The percentage of subjects with only one underlying disease was 62.5% among those living at home and 64.4% among inpatients. In both groups the most common disease was cerebrovascular disease (42.5% among those at home and 39.0% among inpatients), followed by dementia (31.3%), infirmity of old age (17.5%) and bone fracture (13.8%) among those at home, and by bone fracture (27.1%), dementia (20.3%) and infirmity of old age (16.9%) among inpatients. The median durations of bedridden status were 2 years and 3 months among those at home and 3 months among inpatients. The proportion of subjects bedridden for less than 6 months was greater among inpatients (p < 0.0001). The percentage who needed medical treatment was 60.0% among those at home and 67.7% among inpatients. The most common conditions for which drugs were taken were hypertension, dementia, chronic cerebrovascular dysfunction, and osteoporosis. Among inpatients, 54.8% were ambulatory before admission, 24.2% were almost completely bedridden, and 17.7% were completely bedridden. The most common cause rending the patients bedridden was infection (usually pneumonia). The degree of disability did not differ between groups. Decubitus ulcers were present in 25.9% of those at home and 17.7% of inpatients.

A randomized study comparing VMCP and MMPP in the treatment of multiple myeloma.

PURPOSE: To compare VMCP, a multidrug combination chemotherapy comprising vincristine (VCR), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL), with MMPP comprising MPH, ranimustine (MCNU), procarbazine, and PSL as induction, to elucidate the value of alternating combination chemotherapy, and to search for an appropriate maintenance therapy in multiple myeloma. METHODS: At 16 institutions in the Nagoya City area, we carried out a randomized trial of VMCP versus MMPP as the initial treatment. Patients who were refractory or resistant to the initial therapy were crossed over into the other arm (crossover trial). For patients who achieved a partial response (PR) or a minor response (MR) and in whom the paraprotein level ceased to decrease, the maintenance therapy was randomized either to an MPH/PSL combination (MP) or to alternating combination therapy (AT) with VMCP and MMPP. RESULTS: In the 94 evaluable patients of the 111 enrolled, the response rate (PR rate) was 27.7% (13/47) in the VMCP arm and 44.7% (21/47) in the MMPP arm (P = 0.0859). The crossover trial resulted in a PR rate of 15.8% (3/19) for the VMCP-->MMPP crossover and 14.3% (2/14) for the MMPP-->VMCP crossover. The median survival time was 23.4 months for those initially begun in the VMCP arm and 24.9 months for those in the MMPP arm, showing a tendency for better survival during a follow-up of 2-6 years with MMPP treatment, but without statistical significance. The survival time of patients with progressive disease was significantly shorter than that of patients with PR, MR or no change (NC). However, there was no significant difference in the survival rate among those who achieved PR, MR, or NC. As to the maintenance therapy, there was no significant difference in survival between MP therapy and AT. Patients who reached a plateau phase survived significantly longer than those who did not. Except for six cases of grade 3 or 4 neurotoxicity in the VMCP arm, there was no significant difference in the hematologic or gastrointestinal toxicity between the two arms. CONCLUSIONS: We conclude that VMCP is less effective for myeloma than MMPP as the induction treatment, that alternating noncrossresistant chemotherapeutic combinations do not offer an advantage in multiple myeloma, and that patients who reach a plateau phase have a significantly longer survival time.

[An preliminary study on Quality of Life Scale for Elderly: an examination in terms of psychological satisfaction].

The purpose of this study was to construct Quality of Life Scale for Elderly (QOLS-E), which was to evaluate the older person's physical, social, and psychological states synthetically, and to find out which factors most influenced the person's psychological satisfaction. Two groups of people, 42 in total who were between 65 and 90 years old, participated in the study, with 25 living in the nursing home, and 17 in the hospital. Although the factor structure of QOLS-E was reasonable, the reliabilities were not very high, meaning further research was necessary to improve the scale. Multiple regression showed that Satisfaction with Activities of Daily Life was apt to be related to psychological satisfaction. Also, enjoying a hobby and positive relationships with institutional staff members appeared important for other facets of psychological satisfaction. As for subscales of psychological satisfaction, enjoying a hobby was significantly related to Acceptance of Own Life, and number of diseases to Mental Stability. Another subscales of QOLS-E, Satisfaction with Family Relationships, was also related to Acceptance of Own Life.

[Awareness and feelings of elderly patients and their families concerning disease during terminal hospitalization--malignancy versus non-malignancy].

We conducted a questionnaire survey on the awareness and feelings of elderly patients and their families concerning their diseases and prognosis during terminal hospitalization. Sixty-five families of 177 patients who died at our hospital in 1992 answered questions concerning estimation of the prognosis, understanding of the disease, satisfaction regarding explanation of the disease, wish to be informed of the diagnosis, feelings during hospitalization, and whether the family revealed the diagnosis to the patient. Patients with malignancy were not informed of the true diagnosis at this time. As to estimation of the prognosis, patients aged 70 or older who did not expect "cure" of their diseases at first were significantly fewer, and those anticipating "death" just before dying were significantly more frequent than those under age 70. In patients with malignancy, those aged 70 or older foresaw "incurability" at first significantly more frequently than those under age 70. Patients with malignancy knew the diagnosis in significantly fewer cases, believed the false diagnosis significantly more frequently, and showed dissatisfaction with the explanation of the disease significantly more frequently, than those with non-malignancy. Proportions of the family who told the diagnosis to the patient were 11.8% in malignancy and 38.8% in non-malignancy with statistical significance. These data indicate that medical care during terminal hospitalization should be modified principally based on informed consent, if that is the wish of the patient.

[A survey on elderly patients' knowledge of management of health care].

We conducted a questionnaire survey on the awareness of elderly patients in our hospital concerning medical management. As to the recognition of their own diseases, patients aged 80 or older, showed a lower degree of understanding than those under age 80. The proportion of patients who wished to known about their diagnosis decreased with age, although no statistical significance was recognized. Those who wished to known about their diagnosis, even if it were malignant, reduced significantly depending on the increase in age. In addition, the proportion of patients who would not like to know their diagnosis, if it were malignant, increased significantly as age increased. Proportions of patients who wanted to know other information, such as prognosis, the aims, methods and results of medical examination, the methods and adverse effects of treatment, and the names, effects and side effects of drugs, also decreased significantly as age increased. However, there were no statistical significant differences in the proportion of answers between cases of malignant and non-malignant disease. These data show that elderly patients had more anxiety or fear about malignancy, and wished to know less about medical management than non-elderly patients.

[A case of malignant lymphoma, highly suspected to be of pancreatic origin, with multiple nodular hepatic invasions].

We reported a rare case of malignant lymphoma, highly suspected to be of pancreas origin with multiple nodular hepatic invasions. A 63-year-old man visited our hospital on May 24 1990, complaining of anorexia. In spite of high serum levels of LDH and amylase, abdominal ultrasonography (US) showed no significant lesions. Forty days later, he was admitted because of the loss of weight and the appearance of abdominal pain with marked hepatomegaly, exhibiting cachexia. Abdominal US and computed tomography visualized a tumor of pancreas with multiple nodular space-occupying lesions in the liver. In several days, jaundice and ascites appeared with progressive deterioration. Angiography showed no tumor vascularity nor vascular stain in pancreas and liver, suggesting a non-epithelial malignancy. Mitomycin C and Epi-adriamycin, given to the patient via the celiac artery, brought about a remarkable shrinkage of the abdominal tumor. Subsequent systemic chemotherapies and occasional intra-arterial chemotherapies resulted in the disappearance of abdominal tumor clinically. However, at the end of April 1991, signs of CNS involvement were observed, and he died on June 7, 1991. Autopsy revealed that malignant lymphoma, of diffuse large cell type, had invaded the subarachnoidal cavity without any evidence of invasion of the abdomen or other sites except regional necrotic lesion in the pancreas. These findings strongly suggested that the patient suffered from malignant lymphoma of pancreas origin with multiple nodular hepatic invasions.

Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia.

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and without L-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P = 0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P = 0.955 by generalized Wilcoxon test [GW], P = 0.952 by log-rank test [LR]). Median disease-free survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P = 0.141 by GW, P = 0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P = 0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P = 0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Nationwide randomized comparative study of daunorubicin and aclarubicin in combination with behenoyl cytosine arabinoside, 6-mercaptopurine, and prednisolone for previously untreated acute myeloid leukemia.

Aclarubicin was evaluated in combination chemotherapy for adult acute myeloid leukemia in a randomized trial involving 58 institutions throughout Japan. Behenoyl cytosine arabinoside (BH-AC).daunorubicin, 6-mercaptopurine, and prednisolone (DMP) was compared with BH-AC.aclarubicin, 6-mercaptopurine, and prednisolone (AMP). In the 360 evaluable cases among the 433 cases enrolled, complete remission (CR) rates were 63.7% (116/182) for BH-AC.DMP and 53.9% (96/178) for BH-AC.AMP (P = 0.0587). Median survival periods and 7-year survival rates were 15.8 months and 19.3% for BH-AC.DMP and 9.5 months and 20.2% for BH-AC.AMP (P = 0.0091 according to the generalized Wilcoxon test [GW], P = 0.196 according the log-rank test [LR]). Median disease-free survival periods were 15.4 months for BH-AC.DMP and 14.1 months for BH-AC.AMP (P = 0.851 by GW, P = 0.439 by LR). Among the 346 cases of extramurally confirmed FAB subtypes, CR rates were 67.9% (19/28) with BH-AC.DMP and 31.8% (7/22) with BH-AC.AMP for subtype M3 (P = 0.011) and 63.3% (93/147) with BH-AC.DMP and 56.8% (84/148) with BH-AC.AMP (P = 0.254) for subtypes M1, M2, M4, and M5. Diarrhea, ileus, pneumonia, and renal failure were more frequent with BH-AC.AMP than with BH-AC.DMP. The results indicate, at least on the basis of the long-term outcome, that BH-AC.AMP has antileukemic effects on subtypes M1, M2, M4, and M5 that are comparable with those of BH-AC.DMP.

[Dyskinesias as neurologic complications of hematologic disorders].

Dyskinesias as the neurologic complications of hematologic disorders were described in detail on abetalipoproteinemia and ataxia telangiectasia as well as in summary on other hematologic diseases. Dyskinesias as the iatrogenic neurologic manifestations in hematologic disorders were also briefly described. Although the pathogenetic mechanisms of dyskinesias observed in hematologic disorders were quite heterogeneous, they could provide us with good suggestions and clues to clarify the true mechanisms of their own as well as other dyskinesias.

Cisplatin, etoposide, and vincristine combination chemotherapy in the treatment of non-small cell lung cancer.

Thirty patients with previously untreated, inoperable non-small cell lung cancer (NSCLC) were treated with cisplatin, etoposide and vincristine. Among twenty-nine evaluable patients, eight patients achieved partial response and the overall response rate was 28%. No patient achieved a complete response. The median survival time was 51 weeks. Myelosuppression was the dose-limiting toxicity. Four patients had a leukocyte nadir of less than 1000/mm3, and one died from severe myelosuppression and sepsis. The other toxicities were nausea/vomiting, peripheral neuropathy, and alopecia. We conclude that cisplatin, etoposide, and vincristine combination chemotherapy offers moderate activity for inoperable non-small cell lung cancer.

A new myeloblastic leukemia cell line with double minute chromosomes. Induction of methotrexate resistance and dihydrofolate reductase gene amplification.

To test the relationship between DMs and drug resistance in newly established AML cell lines, KY821, and its clone KY821A3, the latter had lost DMs during cloning, were cultured in increasing concentrations of MTX. KY821 became resistant against 2 x 10(-4) M MTX, whereas KY821A3 did against 2 x 10(-5) M MTX in a same period. Enhanced enzyme activities of DHFR were correspondent to the increased DMs numbers and DHFR gene amplification in both resistant clones. The amplified DHFR gene was located on DMs by in situ hybridization. These data indicated that the presence of DMs in KY821 would facilitate the acquisition of drug resistance.

[Salvage chemotherapy with a combination of VP-16, ifosfamide, procarbazine, prednisolone, bleomycin and methotrexate (VIPP-BM) for refractory malignant lymphoma].

Twenty patients with refractory malignant lymphoma were treated with a combination of VP-16, ifosfamide, procarbazine, prednisolone, bleomycin and methotrexate (VIPP-BM) as salvage chemotherapy. These patients were either resistant to front-line therapy or refractory in their relapses. Two patients (10%) achieved a complete remission and eleven patients (55%) attained a partial remission. An overall response rate was 65%. Major toxicities were myelosuppression, nausea and vomiting, and mucositis. However they were well tolerated. This regimen has been effective in the treatment for the patients with refractory lymphoma.

[Methotrexate and its drug resistance].

Methotrexate (MTX), a folic acid antagonist, is among the most active known drugs for clinical cancer therapy. The mechanisms of resistance to MTX have been extensively studied, and several mechanisms have been reported so far. Those are decreased cell permeability, increased synthesis of dihydrofolate reductase (DHFR), which is the target enzyme of MTX, decreased polyglutamation of MTX, and decreased binding capacity of MTX to DHFR. Recent basic studies revealed that an increase of DHFR synthesis is the result of a proportional amplification of DHFR gene, and that polyglutamation of MTX plays an important role in its action. High-dose methotrexate (HDMTX) therapy has a good rationale for overcoming MTX resistance. However, many clinical trials of HDMTX during past decade have not demonstrated any apparent clinical efficacy except childhood ALL and ostosarcoma. Further research would be necessary for the improvement of the therapy using MTX.

[Adriamycin, cyclophosphamide, vincristine and methotrexate combination chemotherapy of small cell lung cancer].

Twenty-two patients who had not received previous chemotherapy for small cell lung cancer were treated with a combination of adriamycin (30 mg/m2, i.v., on day 1), cyclophosphamide (500 mg/m2, i.v., on day 1, and 350 mg/m2, i.v., on day 8), vincristine (1 mg/m2, i.v., on day 1) and methotrexate (20 mg/m2, i.v., on days 1 and 8). This chemotherapy regimen was repeated at 3- or 4-week intervals. Among 20 evaluable patients, none showed complete response but 14 (70%) showed a partial response, with a median response duration of 8 weeks (range, 4-20 weeks). The median survival time for the 20 evaluable patients was 28 weeks. Toxicity included mild to moderate hematologic toxicity, alopecia and nausea and vomiting. This combination chemotherapy appears to be suboptimal for the treatment of small cell lung cancer, with no complete responses and a relatively short median survival time.