Normal sister chromatid exchange and cell cycle progression in cultured lymphocytes from patients with malignant lymphoma.

Twenty patients with malignant lymphoma were examined; all but 2 were untreated or had not recently received therapy. Sister chromatid exchange (SCE) and cell progression through to the third mitotic cycle after phytohemagglutinin stimulation did not differ according to lymphoma type or disease stage, and the lymphoma group as a whole did not differ from 20 normal controls. These findings are contrary to other recent studies of SCE in malignant lymphoma. The only patient who had received recent chemotherapy had the highest SCE score and a greatly accelerated cell cycle response.

Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978-1994.

PURPOSE: The incidence of germ cell testicular tumors (GCTTs) is increasing world wide, and with effective treatment, the majority of patients are being cured. Thus, the clinical and social impact of a second testicular tumor is becoming more important. The frequency, cumulative risk, and relative risk of developing a second testicular cancer in New Zealand have been documented and compared with other reports. PATIENTS AND METHODS: The records of 741 men presenting with germ cell testicular cancer in Auckland and Christchurch between 1978 and 1994 have been reviewed, and these data have been compared with data from other published studies. Cumulative risk was assessed by the Kaplan-Meier method. RESULTS: Over 2% of the study population developed a second germ cell testicular cancer. The cumulative risk was 5.2% over 15 years. The relative risk of developing a contralateral testicular tumor is 27.5 times higher than age-matched New Zealand peers. These results match the only comparable report in the literature. Five of the 16 bilateral tumors (31%) were synchronous, which is a higher incidence than in any other reported series. There was no concordance of histology in the first and second tumors. Prior exposure to cisplatin combination chemotherapy did not prevent the development of a second tumor. CONCLUSION: Men who are cured of a germ cell testicular cancer have a greatly increased risk of developing a second testicular cancer. Such patients should be informed of this risk and ideally kept under long-term surveillance.

Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors.

PURPOSE: Elevated total serum cholesterol levels have been reported recently in a group of patients with metastatic testicular cancer after treatment with cisplatin combination chemotherapy. We have studied the lipid profile of a similar group of patients in an attempt to confirm this observation. PATIENTS AND METHODS: Fasting plasma lipid concentrations were measured in 47 patients with advanced germ cell tumors who were previously treated with a cisplatin combination chemotherapy. The values obtained for mean total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1, and apolipoprotein B concentrations were compared with those obtained from a control group of 59 patients with germ cell tumors who were not treated with chemotherapy and with data from the New Zealand male population. Median time from the completion of chemotherapy to lipid measurement in the treated group was 50 months (range, 2 to 138 months). The median total dose of cisplatin given was 720 mg (range, 300 to 1,625 mg). RESULTS: Mean total plasma cholesterol concentrations in the cisplatin group (5.87 mol/L) and the control group (5.70 mmol/L) did not differ significantly (P > .4). There was no significant difference for any of the variables between the chemotherapy and control groups and those of the New Zealand male population. There was a trend toward higher mean triglyceride concentrations in the chemotherapy group, but this did not reach significance. CONCLUSIONS: We have not demonstrated an elevation in total plasma cholesterol after cisplatin chemotherapy as has been reported by previous investigators. Our results suggest that in these patients, cisplatin-containing combination chemotherapy is not associated with a significant adverse effect on plasma lipid profile.

Elevated frequency of a SstI polymorphism of the Ets-1 oncogene in non-Hodgkin's lymphoma patients.

We studied the frequency of a SstI polymorphism of the Ets-1 oncogene in 100 patients with non-Hodgkin's lymphoma, 44 patients with Hodgkin's disease, 49 patients with chronic myeloid leukemia, and 100 controls. There was no difference in the genotype frequency between the controls and patients with either Hodgkin's disease or chronic myeloid leukemia. In contrast, there was a highly significant difference in the distribution of the three genotypes between the patients with non-Hodgkin's lymphoma and the controls (X2 = 10.76, 2df, p = 0.004) with the C2 allele being more frequent in the lymphoma patients. Molecular cloning indicated that the polymorphic SstI site lay 304 bp from exon 7. This is the second association of the SstI polymorphism of the Ets-1 oncogene with a lymphoid disorder and suggests that the presence of the C2 allele is associated with a predisposition to develop a lymphoid malignancy.

Amelioration of cytotoxic-induced emesis with high-dose metoclopramide, dexamethasone and lorazepam.

A double-blind randomised controlled trial comparing the antiemetic effects of sublingual lorazepam combined with high-dose, short course metoclopramide (3 mg/kg) infused twice 3 h apart with or without i.v. dexamethasone is reported. Sixty patients receiving a total of 209 cycles of potentially severely emetic cytotoxic chemotherapy were randomised to receive one or other antiemetic regimen. In those receiving platinum-based chemotherapy the addition of dexamethasone was associated with an improvement in freedom from nausea (P less than 0.01) and freedom from vomiting (P less than 0.05). In the non-platinum-based chemotherapy group the addition of dexamethasone led to a reduction in the duration and severity of nausea, and duration of vomiting (P less than 0.05 in each case). Both antiemetic regimens were well tolerated with a low incidence of adverse effects and could be administered easily in an outpatient setting.

Serum profiles and safety of intermediate-dose (500-1,000 mg) methotrexate following IV and IM administration.

Despite extensive clinical experience with methotrexate there is no consensus of opinion as to the ideal method of administration. This study tested the hypotheses that intermediate-dose (500-1,000 mg) methotrexate can safely by administered to outpatients as an IM injection, and that similar serum profiles of methotrexate result from IM and IV administration. Fourteen patients received 500 mg methotrexate, and nine of these received 1,000 mg as an IM injection. Methotrexate levels at 24 and 48 h were below the levels at which toxicity can be expected. Six patients received 500 mg both IM and IV and 1,000 mg both IM and IV. Serum methotrexate profiles over 48 h were similar following both IM and IV administration. This study showed no evidence of significant toxicity in terms of bone marrow, gastrointestinal, or renal impairment.

Carboplatin is ototoxic.

For assessment of the ototoxic potential of carboplatin [cis-diammine-1,1-cyclobutane dicarboxylate platinum(II); CBDCA], pure-tone audiograms were evaluated in 27 patients receiving a total of 119 doses of carboplatin in the range of 300-400 mg/m2. Pure-tone audiometry (PTA) was done immediately prior to and 4 weeks after the administration of 80 doses (67%). Defining carboplatin ototoxicity as an increase of greater than or equal to 30 dB in auditory thresholds that was unexplainable by other causes, we identified 5 examples (19%). Hearing loss tended to be cumulative with increasing dose and was always maximal at 8,000 Hz. Two patients had an increase in auditory thresholds at 1,000 Hz, but this only amounted to 10 dB in each case. Patients developing ototoxicity tended to be older. Sex, the pre-treatment creatinine clearance, the pretreatment audiogram, the number of doses, and the cumulative dose did not emerge as being reliable predictors of subsequent ototoxicity. We conclude that although carboplatin is ototoxic, clinically significant deafness does not occur with conventional dosing and routine audiometric monitoring is therefore unnecessary. However, we suggest that caution should be exercised when carboplatin is given either at higher doses or for longer periods when there is concomitant use of other potentially ototoxic agents or when there is significant pre-existing auditory impairment.

Circadian pharmacokinetics of methotrexate.

Six patients with intermediate- and high-grade non-Hodgkin's lymphoma were treated with 400 mg/m2 i.v. methotrexate (MTX) at 0600 and 1800 hours. Despite evidence of circadian rhythms in renal function, the pharmacokinetics of total and free serum MTX showed no significant difference between these two times. The marked two-fold circadian variation in MTX pharmacokinetics previously reported in rats was not observed in these patients.

Hemorrhagic lymphadenopathy as a presenting feature of primary al amyloidosis.

Lymphadenopathy associated with hemorrhage as a presenting feature of primary (AL) amyloidosis has not previously been described. We report two such cases one of whom had an acquired factor X and IX deficiency. The clinical presentations were characterized by sudden spontaneous enlargement of lymph nodes followed by partial regression. In both cases significant delay in diagnosis, and hence treatment, occurred due to the mode of presentation. One patient died with rapidly progressive disease but the other has had an excellent response to therapy with high-dose melphalan (HDM, 200 mg/m2) and peripheral blood stem cell rescue. AL amyloid should be considered in all patients presenting with hemorrhagic lymphadenopathy.

Hodgkin's cells express CD83, a dendritic cell lineage associated antigen.

Hodgkin's cells (HC) are considered to be the malignant cells of Hodgkin's disease (HD), but despite extensive studies, no conclusive evidence has emerged regarding their non-malignant counterpart and the ontogeny of these cells remains controversial. The analysis of a possible dendritic cell (DC) origin of HC has been hampered to date by the lack of a DC lineage specific marker. The expression of the two DC-associated antigens CD83 and CMRF-44, the B lymphocyte restricted molecule CD79, and the costimulator molecule CD86, was examined in lymph nodes from 23 HD patients using immunohistological techniques. The majority of HC expressed the CD83 (22/23) and CD86 antigens (20/23), whereas expression of the CMRF-44 antigen was variable (10/23) and usually only a subpopulation of HC stained. In contrast, the CD79 antigen was absent from most HC (17/23). The presence of the CD83 antigen on HC in the absence of the CD79 antigen supports a possible DC lineage origin for some HC. Regardless of its role in lineage assignment, CD83 may become a useful immunohistological marker for HD as the CD83 antigen was present on most HC.

Severe hypertriglyceridaemia and hypercholesterolaemia associated with tamoxifen use.

A patient who was given tamoxifen as adjuvant treatment for breast cancer developed very severe hypertriglyceridaemia, hypercholesterolaemia and acute pancreatitis after being treated for 4 months. The hyperlipidaemia was corrected after cessation of the tamoxifen and the institution of gemfibrozil treatment. This patient appears to have type IV hyperlipidaemia. It is suggested that, in such patients, tamoxifen should be used with extreme caution because the weakly oestrogenic effect of this agent can cause severe and life threatening hyperlipidaemia.

The management of Hodgkin's disease in a regional centre over an eight-year period.

The staging and management of Hodgkin's disease has been discussed in relationship to experience obtained over an eight year period in a regional centre. Eighty cases were shown to be evaluable and the data pertaining to them has been discussed. A complete remission has been achieved by either wide-field radiotherapy or combnation chemotherapy in 78 percent of these cases. Sixty-six percent of the evaluable patients were alive and well five years after their diagnosis. The importance of interdisciplinary co-operation in management and the referral of such patients to a regional centre has been stressed.

Gestational trophoblastic malignancy.

Gestational trophoblastic malignancy, although rare, offers the clinician the opportunity of being able to cure a malignant disease with cytotoxic chemotherapy. Such an opportunity is fulfilled only when the progress of the post-molar patients is monitored and chemotherapy instituted as soon as the malignant transformation of the mole is documented. The management and treatment of nine cases is presented and discussed.

Immunocytoma, cancer and other associations of monoclonal gammopathy: a review of 224 cases.

The clinical, haematological and biochemical correlations of 224 consecutive unselected examples of monoclonal gammopathy have been studied. The paraprotein frequency detedted was IgG 62 percent, IgA 15.2 percent, IgM 10.3 percent, Bence Jones protein 8.9 percent and in 3.6 percent the paraproteins were not identified. In half the monoclonal gammopathy was associated with an immunocytoma (myeloma in 82 and lymphoma in 30). In three cases the associated clinical disease was amyloidosis. In 36 cases (16.1 percent) the associated clincial disease was a nonlymphoproliferative malignant tumour. Monoclonal gammopathy may be a significant marker of malignancy in such cases. In 73 cases (32.6 percent) the associated clinical conditions were unrelated to the gammopathy although only 55 of these cases were sufficiently investigated to warrant classification as examples of benign monoclonal gammopathy. There was a strong correlation between Bence Jones proteinuria and malignancy. Sixty-five patients demonstrated Bence Jones proteinuria and in 59 of these a malignancy was detected. The association was strong between hypercalcaemia and malignancy as this was present in all 27 of the cases who had hypercalcaemia. The relationship between Bence Jones proteinuria and hypercalcaemia was also strong and Bence Jones proteinuria was detected in 73 percent of the hypercalcaemic patients as opposed to 36.7 percent in the whole series. Hypercalcaemia and Bence Jones proteinuria, when found in a patient with monoclonal gammopathy have a grave clinical connotation.

Cis-platinum and distal renal tubule toxicity.

Glomerular filtration rate (GFR) and plasma electrolyte concentrations were evaluated prospectively in 22 consecutive patients treated with serial courses of cisplatinum combination chemotherapy. In addition, renal distal tubular function was assessed in the first 12 by measurement of overnight urinary concentration after intranasal desamino-d-arginine vasopressin inhalation and by a standard short urinary acidification test following the administration of oral ammonium chloride. Cumulative and dose-related hypomagnesaemia was observed in all patients but was unassociated with clinical symptoms. No significant fall in GFR was seen in the group as a whole but four of the 12 patients studied more comprehensively developed impairment of urinary concentrating and acidifying abilities, independent of any change in GFR. This indicates a selective effect on the renal distal tubule.

The management of small cell lung cancer in Christchurch 1979-89.

The management of 215 consecutive patients with small cell lung cancer referred to the oncology service at Christchurch Hospital, 1979-89, was reviewed. After staging, 118 patients were treated with combination chemotherapy (cyclophosphamide, vincristine and doxorubicin), with (87) or without (31) thoracic irradiation. Patients with other medical problems were treated with alternative chemotherapy (34) or irradiation alone (54). Nine received symptomatic care alone. Eighty-five (40%) had limited disease, with no extrathoracic metastases beyond supraclavicular nodes. The response rate to treatment was 66%. Median survival for the whole group was 33 weeks, 51 weeks for those with limited and 26 weeks for extensive disease. The cumulative risk of developing cerebral metastases was 40% at one year. Patients surviving 26 weeks spent one third of their time as hospital inpatients or outpatients. Twenty-two patients survive, five progression free for 4-8 years, including two who had initial surgical resection. The study supports the policy of reserving intensive staging for fit patients who appear to have limited disease and for those entered into clinical trials. Fit patients with limited disease warrant treatment with combination chemotherapy and thoracic irradiation.

The antiemetic activity of tetrahydrocannabinol versus metoclopramide and thiethylperazine in patients undergoing cancer chemotherapy.

A double blind-cross-over randomised clinical trial has been conducted to compare the antiemetic effects of tetrahydrocannabinol, thiethylperazine and metoclopramide. There were no significant differences in the antiemetic effects of these drugs. The incidence of adverse reactions as recorded by both the staff and the patients was significantly higher in the tetrahydrocannabinol group than in either the metoclopramide or thiethylperazine groups. This trial has established that in the dosages used tetrahydrocannabinol given by mouth has an antiemetic effect of approximately the same order as thiethylperazine and metoclopramide. However, its adverse effects are sufficiently greater than those of the other agents to prevent is widespread usage for this purpose. Tetrahydrocannabinol taken by mouth is not recommended as a routine antiemetic agent in cancer chemotherapy.

High grade nonHodgkin's lymphoma: management with moderate dose combination chemotherapy.

We have reviewed the management of high grade nonHodgkin's lymphoma in a regional cancer centre over an eight year period. Forty-seven patients were referred with diffuse histiocytic, diffuse undifferentiated and lymphoblastic lymphomas or true histiocytic neoplasms. Twenty-six were treated with doxorubicin, cyclophosphamide, vincristine and prednisone (ACOP). The overall complete remission rate was 73%, 83% for stage I and II disease and 62% for stages III and IV. Kaplan-Meier analysis shows 49% surviving at a median follow up time of 23 months (range 1-108 months) with 11 of the 13 survivors continuously disease free. Toxicity was not severe except for one treatment-related death. Most were treated as outpatients. Patients 70 years of age or older were treated less intensively and only 3 of 14 survive. We conclude that treatment with ACOP is simple and effective in the management of high grade nonHodgkin's lymphoma. Currently our protocol includes the same agents, but at higher dosage, with the addition of methotrexate; we believe this should be tested against the recent more intensive, multiagent alternating regimens in a prospective, randomised clinical trial.

Improving the preregistration experience: the New Zealand approach.

There is currently much debate about how to improve undergraduate medical education, and in particular on how best to prepare students for clinical responsibility. For 20 years a period of trainee internship has formed part of New Zealand medical students' undergraduate training, and the model could have much to offer the United Kingdom. Students take their final examinations at the end of the second clinical year; they spend their final year in a series of eight clinical attachments, during each of which they shadow a preregistration house officer or senior house officer. As trainee interns they are paid 60% of a house officer's salary for their clinical work, which is supervised by the firm's registrars and consultants under the overall responsibility of the head of the academic department. The order of the attachments is determined on educational, not service, grounds, and trainees have to attend educational sessions and pass assessments on each attachment. The trainee internship, funded jointly by the education and health departments, offers a more seamless transition from student to house officer and aims at improving both general medical education and clinical training.