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Biomedical subjects

K R Hande

Publications and source records attributed to K R Hande.

At least 91 records · Page 5Linked to original sources
PubMed1984

Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency.

A life-threatening toxicity syndrome consisting of an erythematous, desquamative skin rash, fever, hepatitis, eosinophilia, and worsening renal function in 78 patients receiving allopurinol is described. In a majority of cases, the development of this syndrome was associated with the use of standard (200 to 400 mg per day) doses of allopurinol in patients with renal insufficiency. In pharmacologic studies, it was demonstrated that the renal clearance of the major metabolite of allopurinol, oxipurinol, is directly proportional to the renal clearance of creatinine (oxipurinol clearance = 0.22 X creatinine clearance -2.87). An inverse linear relation was noted between the serum oxipurinol half-life and the renal creatinine clearance [( serum oxipurinol half-life in hours]-1 = 0.00034 X creatinine clearance in milliliters per minute + 0.0045). Long-term use of 300 mg per day of allopurinol was found to result in elevated steady-state serum oxipurinol concentrations in patients with renal insufficiency (serum oxipurinol concentration in micromoles per liter = -2.5 X creatinine clearance in milliliters per minute + 326). Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity.

Adult↗
PubMed1984

The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation.

Forty patients with limited-stage small cell carcinoma of the lung were prospectively evaluated for adjuvant surgery after intensive chemotherapy to determine resectability. All patients giving informed consent and having a Karnofsky performance status greater than or equal to 50% were included in the study, which ran from May, 1980, to September, 1982. Ages ranged from 40 to 70 years (median, 59 years). One patient was lost to follow-up. Thirty-nine patients were evaluated for operation 9 to 15 weeks after diagnosis and after having received two to four cycles of chemotherapy intravenously every 3 weeks (cyclophosphamide, 1,000 mg/m2; doxorubicin, 50 mg/m2; vincristine, 1 mg/m2; VP-16, 300 mg/m2). Two patients had clinical Stage I tumors; 12 patients, Stage II; and 25 patients, Stage III. At the time of reevaluation there were 13 (33%) complete responders, 21 (54%) partial responders, and 5 (13%) with stable disease. Eleven (28%) of the 39 patients underwent thoracotomy using standard resection criteria for non-small cell carcinoma. Eight of these 11 had resectable lesions (2, Stage I; 3, Stage II; 3, Stage III); five pneumonectomies and three lobectomies were performed. Tumor was present in six of eight specimens. Twenty-eight patients were not candidates for operation for various reasons: poor pulmonary function, 5; unresectable tumors, 10; refusal, 6; very poor medical condition, 6; and primary site not identified, 1. Median survival for complete responders was 17 months and for partial responders, 11 months. We have prospectively identified suitable candidates for adjuvant surgery among the total group (denominator population) of patients with limited-stage small cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Potential utility of serum neuron-specific enolase levels in small cell carcinoma of the lung.

To assess the value of neuron-specific enolase (NSE) as a possible biomarker of small cell lung cancer, serum levels were determined by radioimmunoassay in 93 newly diagnosed untreated patients and were compared to the NSE levels of 20 healthy adult controls [9.6 +/- 0.7 (S.E.) ng/ml]. Serum NSE was elevated (greater than 20 ng/ml) in 73% of all patients including 23 of 39 (59%) with limited-stage disease and 45 of 54 (83%) with extensive-stage disease. The mean serum NSE was significantly higher in extensive-stage disease (94.5 +/- 13.8 ng/ml) compared to the mean value for limited-stage disease (33.7 +/- 4.7 ng/ml) (p less than 0.001). NSE was elevated in all patients with three or more sites of metastatic disease. Serial NSE determinations were obtained on 57 small cell lung cancer patients. NSE levels fell in 40 of 50 (80%) of patients responding to treatment, increased in 5 of 7 (71%) of patients with progressive disease, and increased in 30 of 35 (86%) of patients who relapsed. A persistent rise in serum NSE occurred as many as 12 weeks before the clinical recognition of relapse in 15 of 23 (65%) of patients for whom adequate serial NSE data were available. These findings indicate that serum NSE may be a useful marker for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer.

Carcinoma, Small Cell↗
PubMed1984

Inhibition of etoposide-induced DNA damage and cytotoxicity in L1210 cells by dehydrogenase inhibitors and other agents.

The mechanism of action of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16), an important antitumor agent, is unclear. There is evidence that DNA may be the target of action because VP-16 causes single-strand and double-strand breaks in DNA and produces cytotoxicity over a similar dose range. We have hypothesized that an enzyme system, such as dehydrogenase, catalyzes an oxidation-reduction reaction involving the pendant phenolic group which forms an active metabolite that causes the DNA damage and cytotoxicity. To test our hypothesis, we investigated the effect of disulfiram, an aldehyde dehydrogenase inhibitor, and its metabolite, diethyldithiocarbamate, on VP-16-induced DNA damage in L1210 cells. Using the alkaline elution technique to assay DNA damage, we found that disulfiram and diethyldithiocerbamate inhibited VP-16-induced single-strand breaks. Both compounds were also capable of significantly reducing VP-16-induced cytotoxicity. Oxalic acid, pyrophosphate, and malonic acid, competitive inhibitors of succinate dehydrogenase, and the naturally occurring dehydrogenase substrates, succinic acid, beta-glycerophosphate, and isocitric acid, also blocked the effects of VP-16. Free-radical scavengers were also studied. While sodium benzoate was particularly effective in preventing drug-induced DNA damage and cytotoxicity, a number of other scavengers were not. Our data are consistent with the hypothesis that VP-16 is activated by an enzyme such as a dehydrogenase which transforms it into an active intermediate resulting in DNA damage and, consequently, cell death.

Aldehyde Dehydrogenase↗
PubMed1984

Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients.

Plasma urine, and cerebrospinal fluid etoposide concentrations have been measured in 12 adult patients after administration of high-dose (400 to 800 mg/sq m) etoposide in order to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27 to 114 micrograms/ml) and total areas under the concentration-time curve (9,200 to 48,000 micrograms/ml X min). The etoposide mean (+/- S.D.) terminal half-life of 8.05 +/- 4.3 hr and plasma clearance of 28.0 +/- 9.7 ml/min/sq m, however, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 +/- 4.3 ml/min/sq m, representing from 35 to 40% of the total clearance of this drug from plasma. Cerebrospinal fluid etoposide concentrations ranged from 0.1 to 1.4 micrograms/ml, as measured in 6 patients at 1 to 8 hr after high-dose etoposide therapy, and were 1.8 +/- 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hr posttherapy contained etoposide at 1.8 micrograms/ml. Our data, combined with data published previously, indicate that the pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the cerebrospinal fluid.

Etoposide↗
PubMed1983

High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.

Adolescent↗
PubMed1982

Randomized study of high-dose versus low-dose methotrexate in the treatment of extensive small cell lung cancer.

Forty patients with extensive small cell lung cancer randomly received either high-dose or low-dose methotrexate with leucovorin rescue in combination with cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine. Nineteen patients were treated with the high-dose methotrexate regimen, and 21 received the low-dose methotrexate treatment protocol; both treatment groups were similar in median age, performance status and spread of disease. Response rates (74 percent for high-dose therapy; 67 percent for low-dose therapy), median survival (nine months versus nine months), and overall survival were similar for the two treatment groups. Myelosuppression was equivalent in both treatment groups but moderate to severe mucositis developed more often when patients were treated with the high-dose methotrexate regimen as compared with low-dose methotrexate therapy (p less than 0.001). Central nervous system recurrences developed after three patients received high-dose methotrexate therapy. This study indicates that when used with other antineoplastic agents, high-dose methotrexate therapy does not improve the remission rate or survival nor does it decrease central nervous system metastasis in patients with small cell lung cancer when compared with standard doses of methotrexate; high-dose methotrexate is associated with greater cost and toxicity.

Carcinoma, Small Cell↗
PubMed1982

Effects of high-dose cytarabine.

Plasma, urine, cerebrospinal fluid, and tear concentrations of cytarabine (ara-C) were measured in 15 patients receiving 3 gm/m2 IV ara-C given as a 1 hr infusion every 12 hr for 6 days. The two assay methods used for measuring ara-C concentrations (high-pressure liquid chromatography and radioimmunoassay) gave much the same results. Peak plasma ara-C concentrations (2.0 microM) after high-dose therapy were 50 times those achieved with more conventional (100 to 300 mg/m2) doses. High doses of ara-C were not sufficient to saturate cytidine deaminase; plasma ara-C half-lifes (t1/2) after high-dose therapy (distribution t1/2 = 6.2 min; elimination t1/2 = 154 min) were much the same as those after conventional ara-C doses. Kinetics of ara-C were not altered by repeated dosing over a 6-day period. Cerebrospinal fluid ara-C concentrations after high-doses (mean = 7.8 microM) were 10 times those after conventional intravenous dosing, bot were 0.5% to 1.0% those achieved by intrathecal ara-C doses. Tear concentrations of 22 and 38 micro M were measured in two patients who developed conjunctivitis after high-dose therapy so that the presence of ara-C in tears may be a cause of the conjunctivitis seen in some patients.

Adult↗
PubMed1981

Cancer and the kidney: complications of neoplasms.

Various renal complications occur during the course of neoplastic disease. The therapeutic and prognostic implications differ according to the reversibility of both the underlying malignancy and the superimposed complications in the kidney. Since the mechanisms of renal failure vary significantly in patients with different types of malignancy, it is essential to avoid generalizations about etiologic factors or likely outcomes of the disease processes. The pathophysiologic abnormalities should be determined in each patient, and the reversibility of both the neoplastic and problems assessed before therapeutic decisions are made. This often requires a team effort by the internist, oncologist, nephrologist, urologist and, most importantly, the patient.

Amyloidosis↗
PubMed1981

The unrecognized extragonadal germ cell cancer syndrome.

Within 3 years we saw 12 patients diagnosed initially as having poorly differentiated or undifferentiated carcinomas who, we believe, actually had extragonadal germinal cancers. Serum levels of the beta subunit of human chorionic gonadotropin (beta-HCG) or alpha-fetoprotein were useful in suggesting and supporting the diagnosis: Levels of one or the other were elevated in six of 10 patients in whom they were measured but levels of both, in only one patient. Staining of histologic specimens for beta-HCG or alpha-fetoprotein showed intracellular localization of one of these markers in the cancer cells of all four patients studied. All patients responded to therapy (11 treated with chemotherapy with or without radiotherapy, one with excision and radiotherapy only), with complete remissions in seven of 12. Two of the patients who had a complete remission have experienced relapse, and five have continued in disease-free remission from more than 8 to more than 56 months. Histologically atypical extragonadal germ cell neoplasms may be commoner than previously supposed. Physicians should consider this treatable and potentially curable cancer in selected patients having poorly differentiated or undifferentiated carcinomas.

Adult↗
PubMed1981

Advanced ovarian cancer: brief intensive combination chemotherapy and second-look operation.

The effects of brief intensive combination chemotherapy have been evaluated in 59 patients with advanced epithelial ovarian cancer. Following surgery and before chemotherapy, 16 patients had limited residual cancer (tumor nodules 3 cm or less in diameter) and 43 had bulky disease (tumor nodules greater than 3 cm). Chemotherapy with hexamethylmelamine, cyclophosphamide or 5-fluorouracil, doxorubicin, and cisplatin was given intensively. Myelo-suppression was the most serious side effect, although gastrointestinal, neurologic, and renal toxicity was also observed. Fifty-five of the 58 (95%) evaluable patients had either a partial clinical response or no clinically detectable tumor following therapy. Forty-five of these 55 patients underwent a second-look surgical evaluation at 6 months; 17 of 45 patients (14 of 16 patients with limited residual disease and 3 of 29 with bulky disease) had no evidence of residual cancer, and 9 patients had all known cancer resected. Sixteen of 17 patients who attained a complete response as judged by laparotomy remain in remission; median follow-up has been 19 months (range, 9 to 30 months) following chemotherapy. This combination chemotherapy produces marked tumor regression as judged by second-look evaluation, and most patients who had limited residual disease have all evidence of cancer eradicated. Longer observations is required to determine how many of these patients will remain continuously free of ovarian cancer.

Adult↗
PubMed1981

Postchemotherapy purine excretion in lymphoma patients receiving allopurinol.

The urinary excretion of hypoxanthine, xanthine, and uric acid was measured prior to and following chemotherapy in 11 patients with rapidly growing chemotherapy-sensitive lymphomas who were receiving concomitant allopurinol therapy. Mean maximal total dairy urinary excretions of these purines postchemotherapy were: uric acid, 807 mg/day; hypoxanthine, 343 mg/day; and xanthine, 638 mg/day. The mean maximal postchemotherapy urinary concentrations of uric acid, hypoxanthine, and xanthine were 288, 115, and 179 mg/liter, respectively. Mean total daily urinary excretion of uric acid, hypoxanthine, and xanthine rose 2.2-, 6.6-, and 6.9-fold, respectively, following initiation of antineoplastic therapy. Although standard doses of allopurinol did not prevent a postchemotherapy increase in the excretion of uric acid or hypoxanthine, the urinary concentrations of both compounds remained below their solubility in urine at pH 7 in all 11 patients studied. However, the urinary concentration of xanthine exceeded its solubility in urine at pH 7 in six of the 11 patients. In three of the six patients whose urinary concentration of xanthine concentration exceeded its solubility in urine, transient renal failure developed in association with the increased excretion of xanthine. These studies indicate that, despite the use of conventional doses of allopurinol, the urinary excretion of uric acid may still increase following massive tumor lysis, and urinary excretion of xanthine can increase to concentrations potentially causing xanthine nephropathy.

Acute Kidney Injury↗
PubMed1980

High-dose methotrexate in combination chemotherapy for small cell lung cancer.

High-dose methotrexate and Leucovorin (calcium folinate) rescue was evaluated as induction chemotherapy in combination with cyclophosphamide, doxorubicin, and vincristine in 21 patients with extensive-stage small cell lung cancer. Nine (42%) of 21 had a complete remission. The median duration of remission has been short (5 months), and attempts are now under way to improve consolidation chemotherapy. In general, the degree of myelotoxicity was not increased by the high-dose methotrexate, although the antitumor activity of the combination appears enhanced. Attempts at further increasing the intensity of this regimen or comparative trials with other therapy appears warranted.

Adult↗