Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of investigations was employed to determine if metastases of intraocular melanomas could be induced by experimental manipulations. Syngeneic B16F10 melanoma cells transplanted intracamerally into C57BL/6 mice produced progressively growing intraocular tumors, yet formed only occasional pulmonary metastases. Neither enucleation nor mechanical manipulation of the melanoma-containing eye promoted a significant increase in the incidence of metastases. Likewise, immunologic impairment in the form of natural killer cell deficiency, T-lymphocyte deficiency, or gamma-irradiation-induced lymphopenia failed to produce spontaneous metastases in intraocular melanoma-bearing mice. However, enucleation in consort with immune impairment (T-cell deficiency) produced a sharp increase in the incidence and number of pulmonary metastases in intraocular melanoma-bearing mice. Further studies showed that external pressure to the tumor-containing globe (without enucleation) produced extensive metastases in athymic, nude mice. By contrast, atraumatic enucleation of rapidly frozen eyes prevented metastasis of intraocular melanomas in similar hosts. Collectively, the results indicate that induction of distant metastases in hosts harboring intraocular melanomas requires two simultaneous processes: (1) mechanical manipulation of the melanoma-containing eye, and (2) concomitant impairment of T-cell-dependent immune processes. The data strongly suggest that mechanical manipulation of melanoma-containing eyes produces intravascular showers of melanoma cells that are rejected by T-cell-dependent immune processes in the immunocompetent host. In the absence of these normal T-cell-dependent immune mechanisms, enucleation-induced showers of blood-borne melanoma cells gain a foothold in the lung and form progressive metastases.
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PMID:Enucleation in consort with immunologic impairment promotes metastasis of intraocular melanomas in mice. 638 75

Some biologic, hematologic, and immunologic aspects of the growth and metastasis of the MC-2 fibrosarcoma indicated its suitability as a model for the study of lymphogenous metastasis. The tumor was maintained in syngeneic female BALB/c mice by the serial sc passage of 10(5) viable tumor cells. It metastasized macroscopically in all mice to regional lymph nodes (RLN) and to the lungs. Both forward and retrograde node-to-node metastases were found. Tumor growth and metastasis were associated with splenomegaly, thymus atrophy, cachexia, neutrophilia, lymphopenia, and anemia. Tumor excision at various times after inoculation showed that all mice whose tumors were excised when there was histologic evidence of metastasis in all RLN (day 13; mean of tumor wt, 122 mg) died subsequently from metastases, whereas no animals died whose tumors were excised on or before day 8 (mean of tumor wt, 15 mg). The onset of metastasis was seen in some RLN on day 8. All survivors were immune to challenge with 10(5) viable tumor cells, which demonstrated the immunogenicity of the tumor. Concomitant tumor immunity could be demonstrated prior to the onset of metastasis (days 6 and 7) but not early (days 0--2) or late (days 15, 19, and 20) in primary-site tumor growth. The early immune response to the tumor demonstrable as concomitant tumor immunity appeared to be abrogated by the progressive growth and metastasis of the neoplasm. Tumor cells passaged in adult thymectomized, X-irradiated, syngeneic recipients produced larger RLN metastases and smaller primary tumors than those passaged in control mice.
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PMID:Biologic and immunologic studies on a murine model of regional lymph node metastasis. 692 75

A survey of the lymphocyte status is reported for 25 patients given routine radiotherapy for carcinoma of the cervix or carcinoma of the breast and other tumours. After an initial lymphopenia there was a return to the initial value of the lymphocyte count by the end of a 12 month period of observation. The PHA index was also measured in these patients and this also showed a progressive rise during the 12 month period following a minimal change after radiotherapy. There was no significant difference between the lymphocyte status of patients given radiotherapy above or below the diaphragm nor between patients with or without knwon metastases at the end of the 12 month period. An additional sample of eight patients with carcinoma of the breast showed a rise in lymphocyte count after surgery before the usual fall after radiotherapy.
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PMID:Recovery of lymphocyte status after radiotherapy. 696 62

Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application is restricted by associated toxicities. Previous studies implicate tumor necrosis factor (TNF) as an important mediator of certain IL-2-induced toxicities. We hypothesized that soluble TNF receptor (sTNFr), a TNF antagonist, would alter lymphocyte trafficking into normal tissues and ameliorate IL-2-induced toxicity. Four groups of C57BL/6 mice were treated for 4 days with intraperitoneal injections of 100,000 IU IL-2 alone, 100,000 IU IL-2 and 30 micrograms sTNFr combined, 30 micrograms sTNFr alone, or equal volumes of saline. Animal activity was graded and blood obtained for SGPT and SGOT. At necropsy, organs were harvested for wet:dry ratios as a measurement of organ edema. The lung, liver, and thymus were examined histologically for lymphocytic infiltration and graded on a scale of 1 to 5. IL-2-treated groups had a statistically significant increase in organ edema, lymphocytic infiltration into the lung and liver, liver enzyme elevation, and pancytopenia when compared with controls. Soluble TNFr significantly suppressed IL-2-induced pulmonary lymphocytic infiltration and associated serum lymphopenia without significant alteration of other IL-2-induced effects. These data implicate TNF as a mediator of the pulmonary lymphocytic infiltration and of lymphopenia that accompanies IL-2 therapy and further suggest that alternative mechanisms are involved in other IL-2-induced deleterious effects.
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PMID:Interleukin-2-induced lymphocyte infiltration of multiple organs is differentially suppressed by soluble tumor necrosis factor receptor. 812 Nov 66

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.
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PMID:Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. 950 93

Malignant melanoma is rapidly increasing in the United States. Metastatic disease responds poorly to currently available chemotherapy. Pyrazine diazohydroxide (PZDH) is a new agent inhibiting DNA synthesis that is active in mouse tumor models and human xenografts and lacks cross resistance with multiple standard agents. In this phase II trial, patients with no prior chemotherapy or immunotherapy for metastatic disease and performance status (SWOG) of 0-1, were treated with pyrazine diazohydroxide at a dose of 100 mg/m2/day by i.v. bolus injection over 5-15 minutes for 5 consecutive days every 6 weeks. There were 23 eligible patients entered on this trial with 74% having PS of 0 and 91% having visceral metastases. There were no confirmed anti-tumor responses. The overall response rate is 0% (95% CI 0%-15%). Median overall survival is six months (95% CI 5-8 months). The most common toxicities were hematologic and consisted of lymphopenia, thrombocytopenia, anemia, and leukopenia. Fatigue. and nausea and vomiting were the next most common toxicities. Pyrazine diazohydroxide by this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.
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PMID:A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest Oncology Group study. 1200 85

Hepatocellular carcinoma (HCC) generally arises in a cirrhotic liver and, in most cases, is multifocal and bilobar. Although trans-hepatic artery chemoembolization (TACE) can be highly affective in shrinking tumors, it is limited by virtue of the damage that it can cause to the liver that is already damaged by chronic disease. A high priority in HCC research, after primary prevention and early detection, is to find new treatment modalities that are both effective and non-toxic to the underlying cirrhotic liver. A cohort of 65 patients with biopsy-proven unresectable HCC have been treated with hepatic arterial 90Yttrium microspheres (Therasphere), and the interim results are reported here. Only 1 cycle of Therasphere treatment ever was performed on 46 patients, 17 patients had 2 cycles, and 2 patients had 3 cycles of therapy. The median dose delivered was 134 Gy, typically as either 5 or 10 GBq (2-4 million microspheres). Clinical toxicities include 9 episodes of abdominal pain and 2 episodes of acute cholecystitis, requiring cholecystectomy. A main lab toxicity was elevated bilirubin which increased by more than 200% in 25 patients (30.5%) during 6 months of therapy, although 18 of these patients had only transient elevation. A prominent finding was prolonged and profound (>70%) lymphopenia in more than 75% of the patients, but without clinical significance. Forty-two patients (64.6%) had a substantial decrease in tumor vascularity in response to therapy, and 25 patients (38.4%) had a partial response, by computed tomography scan. Median survival for Okuda stage I patients (n=42) was 649 days (historical comparison 244) and for Okuda stage II patients (n=23) was 302 days (historical comparison 64 days). All patients were followed after therapy for a minimum of 6 months. There were 42 deaths, 21 due to liver failure, 6 from HCC progression, and 3 from metastases. Therasphere appears to be a relatively safe and effective therapy for advanced-stage unresectable HCC.
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PMID:Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients. 1476 49

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p < 0.001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.
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PMID:Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. 1525 46

Regulatory T cells (Treg) are important regulators of anti-cancer immune responses, and an increase in Treg frequency was observed in the blood of cancer patients. Blood samples from 112 patients with head and neck squamous cell carcinoma antigen (HNSCC) were obtained at the time of tumour diagnosis, and lymphocyte subpopulations (CD3(+); CD3(-)CD16(+)CD56(+); CD4(+); CD8(+); CD19(+); CD4(+)CD45RA(+)) with emphasis on Treg counts (CD3(+)CD4(+)CD25(+)), complete blood count and tumour markers (squamous cell carcinoma [SCC]; CEA; alpha-1-antitrypsin [AAT]; Cyfra 21-1; C-reactive protein [CRP]) were analysed. The data were grouped according to TNM classification, and their significance for the course of the disease at an interval of 1 year after the end of the therapy was determined. The percentage of CD8(+) cells increased and the CD/D8 ratio decreased with tumour grade. The ratio of B lymphocytes decreased in patients with locoregional metastases (11.25%versus 9.22%). Treg (15.2%) and CD4(+) cells (45.3%) increased, while NK cells (11.8%) decreased in HNSCC patients compared to controls (9.0%, 38.1% and 15.8%, respectively). The data obtained at time of diagnosis were used to assess the significance of tumour markers (SCC, Cyfra 21-1 and AAT) for evaluation of prognosis. The erythrocyte counts (4.64 x 10(12)/l versus 4.45 x 10(12)/l) and haemoglobin levels (14.58 g/dl versus 14.05 g/dl) decreased, while Treg counts (8.91%versus 15.70%) increased in patients with early recurrence. Our results show that examination of these parameters could be helpful for prognostication in HNSCC patients and aid improvement of treatment strategy.
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PMID:Regulatory T cells and their prognostic value for patients with squamous cell carcinoma of the head and neck. 1918 42

Treatment of C57BL/6 mice with cyclophosphamide (100 mg/kg) and fludarabine (200 mg/kg) induced nonmyeloablative lymphodepletion without inhibiting D5 melanoma tumor growth. Using this model, we found that induction of lymphopenia before adoptive transfer of ex vivo anti-CD3/CD28 activated and interleukin-2 expanded D5-G6 tumor draining lymph node cells enhanced the antitumor efficacy of the infused cells in both pulmonary metastases and subcutaneous D5 bearing mice. However, induction of lymphopenia did not promote intratumoral or extratumoral proliferation or accumulation of the infused cells. We have previously shown that radiotherapy enhances the therapeutic efficacy of intratumoral unpulsed dendritic cell vaccination in subcutaneous murine tumor models by augmenting the induction of antitumor cellular immune responses. Here, we confirmed this finding in a murine metastatic melanoma liver tumor model. Furthermore, local tumor irradiation combined with intratumoral dendritic cell administration significantly enhanced the therapeutic efficacy of tumor-reactive T cell adoptive transfer in this lymphodepleted liver tumor model. This was evident by reduced liver tumor size, decreased incidence of spontaneous intra-abdominal metastasis, and prolonged survival, resulting in 46% of mice cured. This enhanced antitumor activity was associated with a selective increase in proliferation, accumulation, and function of CD4+ rather than CD8+ infused cells. This multimodality regimen may have translational applications for the treatment of human cancers.
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PMID:Radiotherapy combined with intratumoral dendritic cell vaccination enhances the therapeutic efficacy of adoptive T-cell transfer. 1948 49


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