Correlated response to selection for litter size environmental variability in rabbits' resilience.

Resilience is the ability of an animal to return soon to its initial productivity after facing diverse environmental challenges. This trait is directly related to animal welfare and it plays a key role in fluctuations of livestock productivity. A divergent selection experiment for environmental variance of litter size has been performed successfully in rabbits over ten generations. The objective of this study was to analyse resilience indicators of stress and disease in the divergent lines of this experiment. The high line showed a lower survival rate at birth than the low line (-4.1%). After correcting by litter size, the difference was -3.2%. Involuntary culling rate was higher in the high than in the low line (+12.4%). Before vaccination against viral haemorrhagic disease or myxomatosis, concentration of lymphocytes, C-reactive protein (CRP), complement C3, serum bilirubin, triglycerides and cholesterol were higher in the high line than in the low line (difference between lines +4.5%, +5.6 µg/ml, +4.6 mg/ml, +7.9 mmol/l, +0.3 mmol/l and +0.4 mmol/l). Immunological and biochemical responses to the two vaccines were similar. After vaccination, the percentage of lymphocytes and CRP concentration were higher in the low line than in the high one (difference between lines +4.0% and +13.1 µg/ml). The low line also showed a higher increment in bilirubin and triglycerides than the high line (+14.2 v. +8.7 mmol/l for bilirubin and +0.11 v. +0.01 mmol/l for triglycerides); these results would agree with the protective role of bilirubin and triglycerides against the larger inflammatory response found in this line. In relation to stress, the high line had higher basal concentration of cortisol than the low line (+0.2ng/ml); the difference between lines increased more than threefold after the injection of ACTH 1 to 24, the increase being greater in the high line (+0.9 ng/ml) than in the low line (+0.4 ng/ml). Selection for divergent environmental variability of litter size leads to dams with different culling rate for reproductive causes and different kits' neonatal survival. These associations suggest that the observed fitness differences are related to differences in the inflammatory response and the corticotrope response to stress, which are two important components of physiological adaptation to environmental aggressions.

Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors.

BACKGROUND: Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with advanced cancer and performance status ECOG < or = 2. The starting dose was paclitaxel 175 mg/m2 day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m2 daily day 1-5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. RESULTS: Fifty-one patients were entered; men: women ratio 30:21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m2/carboplatin AUC 5/topotecan mg/m2 (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/ 1.0 for four days. G-CSF 5 microg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. CONCLUSIONS: The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.

Simultaneous presence of t(2;8)(p12;q24) and t(14;18)(q32;q21) in a B-cell lymphoproliferative disorder with features suggestive of an aggressive variant of splenic marginal-zone lymphoma.

We report a case of an aggressive variant of splenic marginal-zone lymphona (SMZL) with circulating villous lymphocytes. The karyotype of all examined cells had multiple structural and numerical abnormalities, including two lymphoma characteristic translocations, t(2;8)(p12;q24) and t(14;18)(q32;q21). Based on a literature review of cytogenetic aberrations of splenic lymphoma with villous lymphocytes (SLVL) and SMZL, this is apparently the first documentation of these two translocations in a case of SMZL, and could reflect the heterogeneity of the disorder.

Transfusions of granulocyte-colony-stimulating factor-mobilized granulocyte components to allogeneic transplant recipients: analysis of kinetics and factors determining posttransfusion neutrophil and platelet counts.

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is a safe and effective agent for mobilization of neutrophils in normal donors, consistently resulting in cell yields per leukapheresis (LA) procedure that are superior to those with other agents. LA components also contain platelets, whose clinical relevance is unknown. STUDY DESIGN AND METHODS: This study describes the kinetics of and analyzes the factors determining the ANC and platelet count increments seen with each of three transfusions of granulocytes collected from HLA-matched sibling donors receiving G-CSF (n = 10; maximum of 3 LA procedures/donor). The transfusions were given to recipients (n = 10) on alternate days beginning. Day 1 after allogeneic bone marrow transplant (BMT). RESULTS: Significant, sustained increments in the recipient ANCs were observed after the transfusion of G-CSF-mobilized LA components. The mean peak posttransfusion increments in the ANCs were 1195, 729, and 631 per microL with transfusion of donor LA components on Days 1, 3, and 5, respectively. The length of time that the mean posttransfusion ANC was at or above the baseline (pretransfusion) value was 25 to 37 hours, depending on the post-BMT day when the component was administered. No consistent relationship was observed between LA component granulocyte dose, baseline recipient ANC, or temperature elevation and post-transfusion ANC increments. Large numbers of platelets (mean, 2.55 x 10(11)) were present in LA components, and this resulted in significant increments from baseline in the mean platelet count 1 hour after LA component transfusions. Between Days 1 and 7, the duration of severe neutropenia was shorter and the percentage of patients requiring nondonor platelet transfusions was less in study patients who received LA component transfusions than in a similar historical control group who did not. CONCLUSION: The transfusion of G-CSF-mobilized, HLA-matched LA components to allogeneic BMT recipients resulted in significant and sustained increments in the ANC and the platelet count. Within the range examined, a relationship between neutrophil dose and an increment in the ANC was not demonstrated.

Randomized comparison of G-CSF + GM-CSF vs G-CSF alone for mobilization of peripheral blood stem cells: effects on hematopoietic recovery after high-dose chemotherapy.

Fifty patients with either lymphoid or selected solid tumor malignancies were apheresed an identical number of times for PBSC collection after being randomized to receive either G-CSF 10 microg/kg/day alone (arm I), or G-CSF at the same dose with GM-CSF 5 microg/kg/day (arm II). Growth factor(s) was/were given as the stem cell mobilizing agent for 5 days before the start of PBSC collection, and were continued throughout the 4 days of apheresis. Aspiration and cryopreservation of autologous bone marrow occurred on day 3 or 4 of growth factor(s). Thirty-one of 50 patients received one cycle only at time of evaluation, and 19 patients received two cycles of HDCT, each supported with PBSC with or without autologous bone marrow. No patients received growth factors post-autologous stem cell transplant, unless the absolute neutrophils count (ANC) failed to recover to > or = 100/microl by day +18 post-transplant. The median number of days to recovery of ANC to 100/microl, 500/microl and 1000/microl, and of platelet counts to 20000/microl, 50000/microl and 100000/microl after either cycle 1 or cycle 2 of HDCT and the number of febrile days and platelet and PRBC transfusion requirements was not significantly different between the two arms of the study. The duration of hospitalization was similar between study arms for cycle 1 of HDCT, but was 3.5 days less with arm II compared to arm I (P = 0.0248) for cycle 2 of HDCT. The bone marrow buffy coat and PBSC product mononuclear cell count (x 10(8)/kg) and CD34+ cell count (x 10(6)/kg) collected by each method of stem cell mobilization was not significantly different. There is questionable clinical benefit with PBSC products mobilized with the combination of G-CSF and GM-CSF vs G-CSF alone. Perhaps different dosages, schedules, or other growth factor combinations with G-CSF might enhance these differences.

Atypical prolymphocytic variant of hairy-cell leukemia: case report and review of the literature.

The prolymphocytic variant of hairy-cell leukemia (HCL-V) is relatively rare and differs from typical hairy-cell leukemia (HCL) both clinically and morphologically. Recognition of HCL-V is important due to therapeutic impact. We report on a case of HCL-V, atypical in its degree of marrow fibrosis, IgM/lambda monoclonality, expression of CD24, and the ultrastructural presence of ribosomal lamellar complexes. The patient was treated with splenectomy followed by pentostatin, and he achieved a partial response.

Antifungal effects of yeast-derived rhu-GM-CSF in patients receiving high-dose chemotherapy given with or without autologous stem cell transplantation: a retrospective analysis.

Systemic fungal infections (SFI) in patients receiving high-dose chemotherapy (HDC) are a frequent cause of morbidity and mortality. Preclinical studies have reported augmented antifungal activity of monocytes, macrophage cells, and neutrophils exposed to certain colony-stimulating factors (CSF), including GM-CSF. We conducted a retrospective descriptive epidemiologic study to examine the characteristics of 145 consecutive patients receiving HDC administered with or without autologous stem cell transplantation (ASCT) and who subsequently received either GM-CSF and G-CSF, G-CSF alone, GM-CSF +/- IL-3 or no CSF. The analysis of this patient population sought to define the incidence of SFI and its relationship to therapy with monocyte/macrophage-stimulating (MMS group) cytokines (GM-CSF and G-CSF; GM-CSF +/- IL-3) or to cytokines which do not result in monocyte/macrophage stimulation (NMMS group, G-CSF alone or no CSF). Risk factors for the development of SFI were balanced between the MMS (n = 70) and NMMS (n = 75) groups. Two patients (2.9%) in the MMS and nine patients (12%) in the NMMS groups developed SFI. The risk ratio for developing SFI in the NMMS group compared to the MMS group was 4.20 (P = 0.023). This relationship was confounded, however, by the diagnosis of hematologic tumor or solid tumor (RR = 3.15, P = 0.082). SFI was the primary cause or major contributing factor in five of the 10 total deaths in our study population. Four SFI-related deaths occurred in the NMMS group and one SFI-related death occurred in the MMS group. Our data suggest a protective role for GM-CSF, IL-3 or other MMS cytokines in preventing SFI in patients receiving HDC. This should be further investigated as a potential complementary approach to conventional strategies in antifungal prophylaxis for patients receiving HDC.

Multimodality therapy for adenocarcinoma of the esophagus.

Few reports exist detailing results of multimodality treatment for adenocarcinoma of the esophagus. We have treated 28 such patients using a preoperative regimen consisting of two courses of cisplatin and 5-fluorouracil with radiation (either 3,000 or 3,600 cGy). There were 25 men and 3 women (mean age, 62.9 years; range, 35 to 86 years), and 16 patients were known to have Barrett's esophagus. Dysphagia was present for a mean of 2.7 months, and the average weight loss was 6.5 kg. Tumors ranged from 2 to 10 cm in length (mean, 5.2 +/- 1.8 cm) with American Joint Committee on Cancer clinical stage I in 2 patients, stage II in 19 patients, and stage III in 7. Dysphagia improved in 23 patients (82%), and in 8 (29%) no tumor was detected during radiologic and endoscopic staging after neoadjuvant therapy. Four patients refused operation. Esophagectomy via standard Ivor Lewis approach was accomplished in 20 of 24 patients (87%) undergoing operation. There were no operative deaths, and mean hospital stay was 15.5 +/- 11.6 days. Four patients (17%) were complete responders with no tumor in the resected specimen. Actuarial survival in the 28 patients at 1, 2, and 3 years is 71%, 28%, and 20% respectively. Of the 20 esophagectomy patients, 6 are alive with no evidence of disease at 10, 50, 54, 70, 77, and 84 months. Three of these were complete responders. Only 1 of the 8 patients no undergoing resection is alive at 16 months with no evidence of disease after further radiotherapy and chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit.

PURPOSE: To evaluate the clinical value of growth factors (GFs) with peripheral-blood stem cells (PBSC) collected following mobilization with GFs, we randomized patients to receive or not to receive GFs following transplant. PATIENTS AND METHODS: Thirty-seven patients were apheresed after receiving the combination of granulocyte colony-stimulating factor (G-CSF) with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses of 10 micrograms/kg/d and 5 micrograms/kg/d, respectively, for 6 days before apheresis and during a median of 4 days of collections. One day after the infusion of autologous marrow and PBSC, patients were randomly assigned to receive no GFs or a combination of G-CSF (7.5 micrograms/kg/d) and GM-CSF (2.5 micrograms/kg/d), both as a 2-hour intravenous (i.v.) infusion twice per day until the neutrophil count was greater than 1,500/microL. RESULTS: The median days to recovery to an absolute neutrophil count (ANC) of 100/microL (9 v 11.5, P = .0005), 500/microL (10 v 16, P = .0004), or 1,000/microL (12 v 21, P = .0008) was shortened with the use of GFs, post-PBSC infusion. In addition, the duration of hospitalization was shorter (19 v 21 days, P = .0112) in the arm receiving GFs post-PBSC infusion. There was no significant difference between the two study arms in the duration of fever, documented septic episodes, or RBC or platelet transfusion requirements. CONCLUSION: Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.

Irreversible, severe congestive cardiomyopathy occurring in association with interferon alpha therapy.

Interferon alpha is a biologic agent with demonstrated anti-tumor activity in a variety of hematologic and solid malignancies. Many patients treated with interferon experience acute toxicity manifested as a flu-like syndrome of fever, chills, myalgias, and malaise. However, fatigue, anorexia, bone marrow suppression, nausea, vomiting, dizziness, and confusion may also occur. Cardiotoxicity is a rare complication of interferon therapy that most frequently presents as transient episodes of hypotension and tachycardia, with few significant life-threatening cardiovascular effects reported. A small number of cases of suspected interferon-induced cardiomyopathy, all of which improved after discontinuing interferon, have recently been documented. We report a patient with multiple myeloma who developed severe congestive cardiomyopathy while receiving interferon alpha that did not reverse subsequent to discontinuation of interferon therapy. Although the patient had previously received doxorubicin, the presence on endomyocardial biopsy of a prominent intracellular lipid accumulation within myocytes and only grade 2 anthracycline cardiotoxicity suggested that other or additional factor(s) contributed to the severity of this patient's cardiomyopathy. Etiologies of cardiac dysfunction other than interferon and doxorubicin were excluded. While a direct cause-effect relationship between interferon alpha and irreversible congestive cardiomyopathy cannot be firmly established in this case report, patients who either concurrently or sequentially receive interferon and anthracyclines should be carefully monitored for evidence of cardiac toxicity.

Demonstration of coexistent B-cell lymphoma and therapy-related acute myelogenous leukemia in lymph nodes by flow cytometry and immunohistochemistry. Case report and review of the literature.

A 58-yr-old white woman, with a 9-yr history of non-Hodgkin's lymphoma with recurrences and multi-modality therapy, presents with acute leukemia and residual lymphadenopathy. By flow cytometric analysis, cytochemistry, and cytomorphology, the leukemia is classified as acute myelogenous leukemia (AML), M4, and the lymph nodes are found to contain residual NHL in addition to an AML infiltrate. Immunohistochemistry performed on the lymph nodes correlates with the flow cytometric data. A review of the literature of AML secondary to therapy for non-Hodgkin's lymphoma is also conducted. There are no documented cases in the English literature of simultaneous involvement of lymph nodes by residual lymphoma and an AML infiltrate. Thus, this report is unique in the simultaneous involvement of lymph nodes by residual lymphoma and therapy-related AML. It emphasizes the application and usefulness of flow cytometry and immunohistochemistry in such cases.

Nutrition support in bone marrow transplant recipients.

Bone marrow transplantation is a complex therapy designed as curative for a variety of malignant and nonmalignant diseases. It is a highly invasive procedure that uses high-dose chemotherapy and may also include radiation treatment. This results in immunosuppression that is often followed by infection, graft-vs-host disease, pulmonary complications, veno-occlusive disease of the liver, and metabolic and nutritional abnormalities. Parenteral nutrition has been the mainstay of nutrition support in patients undergoing bone marrow transplantation. Parenteral nutrition has not been uniformly successful in improving nutritional status or outcome. Enteral nutrition offers many theoretical advantages but is often not well tolerated. Coordinated efforts of the health care team are needed to optimize the nutrition support of these complicated cases.

Design of preparative regimens for stem cell transplantation in breast cancer.

We have evaluated tandem cycles of a tri-drug combination, termed CVP (cyclophosphamide, etoposide [VP-16], and cisplatin [Platinol]), at four levels in more than 300 patients with various types of tumors. Tandem CVP appears to be at least therapeutically equivalent to alternatives. A second potentially non-cross-resistant combination of mitoxantrone and thiotepa (MT), with or without etoposide, has been used in sequence following CVP to improve long-term, disease-free survival in patients who have multiple metastatic sites, who relapse shortly after adjuvant therapy, or who show other unfavorable clinical features. A combination of MT and etoposide (MVT) achieved an overall response rate of 61% in 32 patients with metastatic or refractory breast cancer. The etoposide was then eliminated to decrease the major toxicities of this regimen. MT was subsequently given to 37 evaluable patients prior to bone marrow infusion. The overall response rate was 48.5% Thirty patients with metastatic breast cancer were then treated with induction therapy, a cycle of CVP, and then a cycle of MT. Given the low complete remission (CR) rate to induction therapy in these patients, the CR rate achieved with CVP-MT was encouraging. Further studies are ongoing.

Tandem transplants in solid tumors: marrow versus peripheral stem cell transplant: peripheral blood cells as now practiced are not the whole answer.

We have performed sequential studies examining the modification of hematopoietic toxicity after the administration of high-dose cyclophosphamide, etoposide, and cisplatin (CVP). The sequential studies include a comparison of the influence of autologous bone marrow transplantation (ABMT) on hematopoietic recovery after CVP, with or without growth factors. These studies demonstrate a significant shortening of the duration of neutropenia with ABMT, but minimal impact on the number of infectious episodes, when compared to those not receiving ABMT. The addition of mobilized peripheral blood stem cells (PBSC) to ABMT followed by growth factor was found to enhance platelet recovery, but did not significantly further reduce the period of absolute neutropenia. Subsequent studies show that similar early hematopoietic recovery can be achieved by use of peripheral blood stem cells alone, pheresed following several days of subcutaneous administration of recombinant growth factors, but neutrophil recovery is more rapid with use of growth factor after PBSC infusion. Using the product of two phereses for each cycle of recovery appears to result in similar rates of hematopoietic engraftment after each cycle of CVP. In conclusion, the use of peripheral blood stem cells alone following sequential high dose CVP is associated with rapid neutrophil and platelet recovery. Caution should be exercised when using PBSC alone after high dose therapy, due to the lack of platelet recovery in some instances, which can be overcome by reinfusion of backup marrow. Thus, studies evaluating the role of PBSC after high dose therapy should continue.

A new case of IgE myeloma.

We report a case of IgE myeloma in a 78-year-old woman who presented with bone pain in the shoulder and hip and progressive weakness. Except for hypercalcemia, routine chemistry values were within normal limits. Hemoglobin was decreased and the leukocyte count slightly increased. Plasma cells were not observed in the peripheral blood. Serum protein electrophoresis showed a monoclonal protein in the beta-globulin fraction. Immunofixation confirmed the presence of an IgE kappa monoclonal protein. A bone marrow biopsy revealed an interstitial and nodular infiltration of abnormal plasma cells comprising 60% of nucleated cells present. Skeletal roentgenograms and bone scans of this patient showed osteolytic lesions and osteopenia of the thoracic and lumbar spine and osteolytic destruction of the right half of the sacrum. Flow-cytometric analysis of mononuclear cells isolated from peripheral blood showed that 15% of the lymphocytes bound IgE. Using cell-surface markers, we identified 45% of the IgE-positive cells as natural killer cells. Similar results have been found in other diseases marked by increased IgE. The clinical, radiological, and laboratory findings for this patient are compared with previously reported cases of IgE and other types of myeloma.

Preoperative chemotherapy and radiotherapy for esophageal carcinoma.

From October 1986 to January 1991, 47 patients with esophageal cancer (29 squamous, 18 adenocarcinoma) were treated with simultaneous radiotherapy (3000 or 3600 cGy) and chemotherapy (infusional 5-fluorouracil, cisplatin) delivered during a 5-week period. This treatment was well tolerated; 44 patients (94%) completed a full course of therapy, 40 (85%) had relief from dysphagia, and 21 (45%) noted either weight gain or no net weight loss. One patient (2%) died of complications (tracheoesophageal fistula, perforated ulcer) during chemotherapy and radiotherapy. The remaining 46 patients were referred for operation. Six refused because of excellent relief of their dysphagia, and one was denied operation. Thirty-nine patients went to operation, and 34 (83%) had lesions that were resectable. Eight of the 39 surgically treated patients (21%) had no evidence of residual tumor identified in the resected specimens. One of these complete responders died 7 weeks postoperatively after multiple complications (3% operative mortality rate). Three of the remaining seven have also died since the operation, one of recurrent cancer and two with no known recurrent disease. Actuarial survival in this present series was significantly better than that of our 1980 to 1985 historical control patients (p less than 0.005). There was no difference between patients with squamous carcinoma and those with adenocarcinoma with regard to the prevalence of complete response or long-term survival. Survival of the seven patients who did not undergo operation was comparable with that of the 34 patients in whom esophagectomy was performed. This study suggests that combined preoperative chemotherapy plus radiotherapy for esophageal cancer is well tolerated, provides excellent palliation of symptoms, allows for a high rate of resectability, is equally effective for squamous carcinoma and adenocarcinoma, and provides encouraging early results with regard to long-term survival. The data also call into question the role of esophagectomy, particularly in patients who have a complete response to preoperative therapy.

Familial adult T-cell leukemia/lymphoma.

Clinical and laboratory data are described for two siblings who both developed adult T-cell leukemia/lymphoma resulting from infection by human T lymphotropic virus type I (HTLV-I). These findings suggest that genetic factors or virus-specific factors may determine which HTLV-I-infected individuals will develop leukemia.

Parkinsonism induced by high-dose cytosine arabinoside.

We report a severe parkinsonian condition following high dose, parenteral cytosine arabinoside (Cytosar) that persisted for 8 weeks. The drug was used in a patient with acute myelogenous leukemia that was refractory to all other treatment. The syndrome was partially responsive to antiparkinsonian drugs and fortunately remitted completely within 12 weeks.