The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2–4-h intervals of culture over 24–48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2–4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

Forty-three dogs with lymphoma that had relapsed or had failed to achieve complete remission to previous chemotherapy were treated with lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea [CCNU]) at a dosage of 90-100 mg/m2 body surface area p.o. every 3 weeks. Durable complete or partial responses occurred in 11 dogs for a median of 86 days. The acutely dose-limiting toxicosis was neutropenia 7 days after administration, resulting in a recommended dosage of 90 mg/m2. Cumulative thrombocytopenia occurred in dogs receiving continued CCNU treatment, and a dose interval of 3 weeks may be too short for continued administration of this drug. Toxicoses evident as fever or central nervous system signs or renal damage were uncommon or rare. CCNU is effective in the treatment of relapsed lymphoma.

Thirty-eight cats with lymphoma were treated with vincristine, cyclophosphamide, and prednisone (COP). They were randomized at entry to receive maintenance chemotherapy consisting of either single-agent doxorubicin or continued COP therapy, starting on week 4 of treatment and continuing for 6 months or until relapse. Eighteen cats achieved complete clinical remission after COP induction chemotherapy. The median remission duration for 11 cats continuing to ymphoma is the most common cancer in cats.' Although L considerable advances have been made in the treatment of lymphoma in dogs with combination chemotherapy protocols, relatively little information is available regarding the treatment of lymphoma in cats.When treated with vincristine, cyclophosphamide, and prednisone (COP) protocol, 79% of cats with lymphoma achieved a complete remission (CR) for a median of 150 days2 The addition of methotrexate andor L-asparaginase did not improve remission rates or duration of remission in 2 studies'; however, in 1 of these studies, the median survival was 21 0 days.' The duration of chemotherapy necessary to provide the longest remission has yet to be determined. Cats treated with COP induction chemotherapy alone relapsed more rapidly (median 42 days)4 than did those that received maintenance COP chemotherapy for 1 year (median 150 days).' Other reports recommend treating cats for 2 years' or for more than 3 years.' Doxorubicin is considered to be the most effective single agent in the treatment of lymphoma in dogshX; however, it has yet to be evaluated as a single agent for the treatment of cats with lymphoma. Another anthracycline derivative (idarubicin) was found to be effective when administered as a single maintenance agent to cats with lymphoma that had achieved a CR with COP chemotherapy. ' The purposes of this study were to determine the efficacy of doxorubicin when compared with COP chemotherapy for the maintenance of CR attained after COP induction, and to determine if cats treated with chemotherapy for 6 months had remission times similar to those reported for cats treated for 1 year or more.

Ninety-eight dogs with lymphoma treated with a 5-drug combination chemotherapy regimen (vincristine. L-asparaginase. cyclophosphamide. doxorubicin, prednisone [VELCAP-L]) were evaluated for pretreatment characteristics predictive for response and remission duration. The complete remission rate was 6970, with a median remission duration of 55 weeks. Dogs with advanced stage of disease, constitutional signs, dogs that were older, and dogs that were dyspneic were less likely to achieve remission. Once in remission, small dogs and dogs without pretreatment thrombocytopenia were likely to have longer remission duration. Toxicoses were frequent, but rarely fatal. and no predictitive factors were found for a dog developing toxicoses. VELCAP-L is an effective treatment for dogs in stage 1-111 lymphoma, particularly in young, small animals.Key words: Cancer: Remission; Treatment.ymphoma is the most common hematopoietic neo- Although maintenance therapy may be important for duration of remission, it appears that an aggressive induction protocol may also be important in determining both remission rate and duration. The ACOPA-11' protocol had an induction period designed to decrease toxicity and minimize patient visits; this protocol had a low remission rate, possibly due to its decreased dose intensity. The protocol VELCAP-L was designed to provide an intense induction period, followed by a maintenance protocol identical to that used in the ACOPA-I1 protocol (see Fig. 1). Materials and Methods Criteria for Selection of CasesOne hundred eleven dogs with a histologic or cytologic diagnosis of multicentric lymphoma and that had not received prior chemotherapy other than prednisone were eligible for entry into this study. Of these 1 I 1 dogs, 13 were excluded because of poor adherence to protocol or a change in diagnosis (from lymphoma to leukemia). The remaining 98 dogs were treated with the VELCAP-L combination chemotherapy protocol.

Eighty-two dogs with lymphoma received a single 15-week course of chemotherapy, after which treatment was ceased until relapse. Fifty-six dogs (68%) achieved complete remission for a median 1st remission duration of 20 weeks. Forty-eight dogs relapsed, of which 30 repeated the induction cycle. In 22 of these dogs, 1st remission had been short, and they received maintenance chemo-therapy; the other 8 dogs received 2 or 3 cycles of induction chemotherapy. Second remission rate for these 30 dogs was 87% (26 dogs). Overall disease control for the 38 dogs that remained on protocol was 44 weeks, which was not markedly shorter than for dogs treated with a previously reported protocol in which maintenance chemotherapy was instituted in all dogs after an identical 1st induction (VELCAP-L). Dogs that were febrile and dogs that were dyspneic were less likely to achieve a complete remission to induction chemotherapy. Of dogs that achieved a complete remission, those that were thrombocytopenic at entry had a shorter 1st remission, and dogs that were anorexic at entry had shorter overall disease control. There was a correlation between 1st remission duration and length of any subsequent remission obtained. The incidence of toxicity was high, particularly after the combination of doxorubicin and vincristine. Dose reductions because of toxicity did not markedly reduce remission duration. We conclude that discontinuous chemotherapy may reduce patient visits in a small number of patients because of long-term disease control. Delaying maintenance chemotherapy until after 2nd remission is achieved does not markedly affect overall disease control.