Barry M. Colls

Carboplatin is ototoxic

SummaryFor 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 ⩾ 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.

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

Summary Hodgkins cells (HC) are considered to be the malignant cells of Hodgkins 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.Abbreviations: HC, Hodgkins cells; HD, Hodgkins disease; DC, dendritic cell; LP, lymphocyte predominant; MC, mixed cellularity; NS, nodular sclerosing; LD, lymphocyte depleted; MoAb, monoclonal antibodies; UPN, unique patient number.

Hodgkin's cells express a novel pattern of adhesion molecules

Adhesion molecules play an important role in the functioning of the immune system, particularly with regard to cell‐cell interactions and antigen presentation. Several adhesion molecules are expressed on Hodgkins disease‐derived cell lines and these arc important in their molecular interactions as antigen presenting cells (APC). There are no data regarding the expression of many of these adhesion molecules on Reed‐Slernbcrg cells and its mononuclear variant (Hodgkins cells (HC)) present in pathological material. To obtain this information we undertook an immunohistolo‐gical study on material from 18 cases of Hodgkins disease using a panel of MoAbs to examine the expression of adhesion molecules on HC. The HC were shown to express the integrin /il subfamily molecules. LFA‐I (CDI la) and pi 50,95 (CDI lc)in high density but lacked CR3(CDIIb). All of the immunoglobulin gene superfamily adhesion molecules studied were present to some degree on HC. with ICAM‐2, in particular, showing moderate to strong expression in most cases. The Hermes antigen CD44 was present in high density but leukosialin (CD43), another molecule present on diverse leucocyte types, was. in general, not detected on HC. These new data showing that ICAM‐I, ICAM‐2 and LFA‐3 are. like LFA‐1. expressed on HC emphasize the ability of HC to act as APC. The known adhesion molecule phenotype of the recently defined haematopoietic lineage of human dendritic cells (DC) is broadly similar to that of HC. perhaps supporting the hypothesis that some HC represent a malignancy of an APC (DC) lineage.

Circadian pharmacokinetics of methotrexate

SummarySix patients with intermediate- and high-grade non-Hodgkins 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.

Summary 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.

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

SummaryA 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<0.01) and freedom from vomiting (P<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<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.

Sequential half‐body irradiation in lymphomatoid granulomatosis. Report of a case and an immunohistologic study

A case is presented of a man with ulcerating skin nodules who was diagnosed by histologic and immunohistologic analysis of skin biopsy specimens as having lymphomatoid granulomatosis (LYG). Phenotypic studies showed the majority of the infiltrating cells to be activated CD4+ T‐lymphocytes. The disease followed a rapidly progressive course and did not respond to treatment with cytotoxic chemotherapy. The patient developed life‐threatening systemic symptoms and involvement of both upper and lower respiratory tracts. After treatment with sequential half‐body irradiation he has been in complete remission for 3.5 years.

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-Hodgkins lymphoma, 44 patients with Hodgkins 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 Hodgkins 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-Hodgkins 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.

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

SummaryDespite 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 be adminstered 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.