Gamma delta T-cell neoplasms: a clinicopathological study of 11 cases.

BACKGROUND: The majority of T-cell neoplasms express T-cell antigen receptor (TCR) alpha beta on their cell surface, and a few cases show the TCR gamma delta phenotype. Recently, a variety of gamma delta T-cell neoplasm was recognized; however, its clinicopathological features have not been extensively analyzed. Here we report the results of a clinicopathological study of 11 cases of gamma delta T-cell neoplasm. PATIENTS AND METHODS: During the 11-year period from 1989 to 1999, 104 patients with T-cell neoplasms were examined by flow cytometric analysis and/or immunohistochemical analysis. Tumor cells from all 104 patients expressed one or more of the T-cell antigens-CD2, CD3, CD5 and CD7. Forty-nine of the 104 cases of T-cell neoplasms were examined immunophenotypically for TCR alpha beta/gamma delta subsets. RESULTS: Expression of TCR gamma delta on tumor cells was found in five (33%) of 15 patients with precursor T-cell lymphoblastic leukemia/lymphoma, one (25%) of four with T-cell granular lymphocytic leukemia and five (26%) of 19 with peripheral T-cell lymphoma (PTCL), whereas no expression was found in 11 patients with adult T-cell leukemia-lymphoma. Primary sites of the five patients with gamma delta PTCL were as follows: lymph node, three; skin, one and liver, tonsil and skin, one. The courses of the three patients with gamma delta PTCL of nodal onset were very short (3, 5 and 9 months, respectively), and they were all resistant to combination chemotherapies. CONCLUSIONS: Although gamma delta T-cell neoplasm constitutes a heterogeneous population, it is important to examine the expression of TCR with the view to identifying possible poor prognostic subgroups, such as primary nodal gamma delta T-cell lymphoma.     

Adjuvant therapy of cutaneous melanoma: the interferon debate.

Despite the use of a variety of cytotoxic and immunotherapeutic agents in adjuvant trials in patients following resection of high-risk early cutaneous melanoma, only interferon-alpha2b (IFN-alpha) has shown reproducible efficacy. High-dose IFN-alpha (HDI) is superior to observation in prolonging relapse-free survival. There is still no formal proof of a statistically significant advantage of HDI in prolonging overall survival. For this reason the continued use of observation-only control arms is justified and desirable in adjuvant melanoma trials, and, wherever possible, patients with resected high-risk and intermediate-risk melanoma should be entered on these studies. The toxicity of HDI is high, but the majority of patients complete treatment with dose modification and nearly all toxicity is rapidly reversible. There is now a useful body of information on the supportive care of patients receiving HDI, and data on cost and quality-adjusted time without symptoms and toxicity (Q-TwiST) to support its use in certain high-risk patients. Interim results from a trial of intermediate-dose IFN-alpha are promising. These, and ongoing studies of pegylated IFN-alpha, and of shorter induction-only HDI promise refinements in treatment which may improve efficacy:toxicity ratios.     

Interferon-alpha as maintenance therapy in patients with multiple myeloma.

BACKGROUND: The effect of interferon-alpha 2b (IFN-alpha-2b) on progression-free and overall survival as well as quality of life (QoL) was studied in mainly elderly patients with multiple myeloma (MM), who reached a plateau phase after melphalan/prednisone induction. PATIENTS AND METHODS: In an open phase III trial, 262 patients, median age 69 years (range 34-91), received at least 10 monthly courses of melphalan/prednisone followed by response evaluation. Plateau phase was reached by 128 patients. Next, 90 patients were randomized between IFN-alpha-2b and no maintenance therapy. Reasons for non-randomization were: refusal (18), concomitant disease (nine), protocol violation (six), WHO performance status >2 (four) and allogeneic transplantation (one) RESULTS: At a median follow-up from diagnosis of 97 months (0-140) for those patients alive, IFN-alpha-2b therapy was associated with improved progression-free survival (median 13.5 versus 8.4 months from randomization), although this did not translate in a better overall survival (41 versus 38.4 months). One-third of patients discontinued IFN-alpha due to toxicity. No differences were observed between patient groups in QoL. CONCLUSIONS: IFN maintenance therapy in MM prolongs progression-free survival and, provided that the burden of toxicity is not too high, does not adversely affect QoL.     

Colony inhibitory effect of recombinant human tumor necrosis factor (rH-TNF) and/or recombinant human interferon (rH-IFN)-alpha, -beta and -gamma on human lung cancer cell lines

This study was conducted to assess, by continuous exposure, the inhibitory effects of rH-TNF and rH-IFN-alpha, -beta and -gamma, either alone or in combination, on the colony formations of human lung cancer cell lines. The cell lines tested were PC-7 and PC-9 (adenocarcinoma), PC-10 (squamous cell carcinoma) and PC-13 (large cell carcinoma). Additional experiments were performed with L929 (transformed murine fibroblast), because of its known high sensitivity to TNF. rH-TNF inhibited the colony formations of PC-10 and L929 even at a low concentration (10 U/ml). However, PC-7, PC-9 and PC-13 were resistant to rH-TNF. rH-IFN-alpha, -beta and -gamma inhibited the colony formation of PC-10 (less than 50% of control) at the highest concentration tested (10(4) U/ml), but only rH-IFN-beta inhibited that of PC-7. PC-9, PC-13 and L929 were insensitive to all three rH-IFNs, even at the highest concentrations tested. Combination effects of rH-TNF and rH-IFN-alpha or -gamma were synergistic only at the highest concentration combinations tested in PC-9. However, the maximum inhibition of colony formation of PC-7, PC-9 or PC-13 in any concentration combination treatment was less than 50%.     

Phase II trial of branched peginterferon-alpha 2a (40 kDa) for patients with advanced renal cell carcinoma.

BACKGROUND: Peginterferon-alpha 2a (40 kDa), PEGASYS(TM) (PEG-IFN), is a modified form of recombinant human interferon (IFN)-alpha 2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase II trial was conducted in previously untreated patients with advanced renal cell carcinoma (RCC) to assess efficacy, toxicity and pharmacokinetic profile. PATIENTS AND METHODS: Forty previously untreated patients with advanced RCC were enrolled on this multicenter trial. The median age was 60 years and 63% had prior nephrectomy. PEG-IFN was administered at a dose of 450 micro g/week on a weekly basis by subcutaneous injection. Serial venous blood samples were drawn to assess concentrations of PEG-IFN. RESULTS: Five (13%) patients achieved a major response (four partial and one complete). The median time to progression was 3.8 months, and 63% of patients were alive at 1 year. The toxicity profile was mostly mild to moderate in intensity. Toxicity higher than grade 2 included neutropenia (six patients), fatigue/asthenia (four patients), nausea/vomiting (three patients) and elevated hepatic transaminase concentrations (four patients). Serum drug levels were studied in all patients; mean C(max) at week 1 was 19 ng/ml, and levels were sustained at close to peak over 1 week. With chronic dosing, drug concentration was increased 3-fold, and steady state was achieved in 5-9 weeks. CONCLUSIONS: The sustained maintenance of serum levels of PEG-IFN allows once-weekly dosing. The efficacy and tolerability profile was qualitatively similar to standard IFN-alpha, and adverse events were mostly mild to moderate in nature.     

Serum Cytokine Level Fluctuations in Chemotherapy-induced Myelosuppression

We have reported that serum granulocyte colony-stimulating factor(G-CSF) and interleukin-6 (IL-6) levels rise in patients withchemotherapy-induced myelosuppression. The aim of the presentstudy was to determine whether other cytokines that functionat different hematopoietic stages also fluctuate during chemotherapy-inducedmyelosuppression and whether the extent of cytokine level fluctuationscorrelate with myelosuppression severity. Fifteen patients participatedin the study. Serum levels of stem cell factor (SCF), interleukin(IL)-1, IL-6, IL-3, granulocyte-macrophage CSF (GM-CSF) andG-CSF were analyzed before chemotherapy and during the myelosuppressivestage and correlations between cytokine levels and myelosuppressionseverity were examined. The results showed that both serum G-CSFand IL-6 levels rose in patients with chemotherapy-induced myelosuppression.The prechemotherapy serum G-CSF and IL-6 levels correlated wellwith their respective elevated levels during the myelosuppressivestage. The myelosuppression severity also correlated well withthe extent of serum G-CSF level elevation. The serum IL-6 andG-CSF levels during the myelosuppressive stage correlated significantly.Serum SCF levels did not fluctuate significantly during myelosuppression,and IL-1, IL-3 and GM-CSF were rarely detected in serum evenafter chemotherapy. In the present study, the roles of IL-1,SCF, IL-3 and GM-CSF chemotherapy-induced myelosuppression werenot clear.     

KIT and PDGFRalpha mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study.

BACKGROUND: The prognostic significance of KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations in gastrointestinal stromal tumors (GISTs) is still controversial. PATIENTS AND METHODS: In all, 104 patients were diagnosed with GISTs by KIT immunoreactivity; tumor DNA was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17 and in PDGFRalpha exons 12 and 18. Disease-free survival (DFS) was analyzed in 85 radically resected patients. RESULTS: KIT mutations occurred in exon 11 (69), in exon 9 (11) and in exon 17 (1). PDGFRalpha mutations were detected in exon 18 (10) and in exon 12 (3). Ten GISTs were wild type. Exon 11 mutations were as follows: deletions in 42 cases and point mutations in 20 cases and insertions and duplications, respectively, in 2 and 5 cases. A better trend in DFS was evident for duplicated and point-mutated exon 11 KIT GISTs. There was a significant association between PDGFRalpha mutations, gastric location and lower mitotic index. Moreover, PDGFRalpha-mutated GISTs seemed to have a better outcome. CONCLUSIONS: Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior.     

Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma: results of an open single-armed multicentre phase II study.

OBJECTIVES: Histamine inhibits formation and release of monocyte/macrophage-derived reactive oxygen metabolites and thereby protects natural killer (NK) and T cells against oxidative inhibition. Efficacy and safety of histamine, when given in combination with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), were evaluated in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Forty-eight mRCC patients were included. The self-administered, outpatient regimen included IFN-alpha, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-alpha, 3 MIU s.c., days 1-7, weeks 1-4; interleukin-2, 2.4 MIU/m2 s.c., b.i.d., days 1-5, weeks 1 and 2; and histamine dihydrochloride, 1 mg s.c., b.i.d. days 1-5, weeks 1-4. RESULTS: Forty-six patients were eligible. Forty-two patients were evaluable for response with four partial responses (9% of eligible patients, 10% of evaluable patients). Fifteen patients (36%) had stable disease. After subsequent surgery of residual tumours, three patients (7%) had no evidence of disease at 14+, 21+ and 21+ months. Median survival time for all patients was 16.3 months. One grade 4 toxicity (thrombocytopenia) was observed. Most frequent grade 3 toxicities were fatigue/malaise (26%), dyspnoe (11%), nausea (9%) and stomatitis (9%). Four patients discontinued due to treatment-related toxicity. There were no treatment-related deaths. CONCLUSIONS: The present combination of histamine with IL-2 and IFN-alpha. as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low-dose schedule of IL-2 and IFN-alpha. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-alpha requires further investigation.     

Prognostic implications of the expression of erbB2, topoisomerase II alpha and thymidylate synthase in metastatic gastric cancer after fluorouracil-based therapy

Objective: This retrospective study aimed to ascertain the expressionof erbB2 in relation to topoisomerase II (T2) and thymidylatesynthase (TS) markers in 30 consecutive metastatic gastric cancerpatients with a specimen available for study. Methods: All patients had been entered on consecutive chemotherapeuticclinical trials that were all 5-fluorouracil based. The specimenswere evaluated by fluorescence in situ hybridization to ascertainerbB2 and T2 gene amplification, and by immunohistochemicalstaining for T2 and TS protein expression. Results: erbB2 amplification was detected in 16.7% of specimens,with co-amplification of the T2 gene in 40%, and 44% had undetectableTS protein expression. Kaplan–Meier survival curves showedsignificantly prolonged overall survival in patients with erbB2and T2 gene amplification, T2 protein overexpression and absenceof TS protein expression (P = 0.0011, P = 0.0048, P = 0.0061and P = 0.0267, respectively, by log rank test). There was apositive correlation between erbB2 amplification and T2 amplification,T2 protein overexpression, and a trend towards absence of TSexpression (P = 0.0001, P = 0.003 and P = 0.066 by Fisher'sexact test). Conclusion: High dose fluorouracil/leucovorin-based chemotherapymay have the potential to reverse the adverse effects resultingfrom erbB2 gene amplification in gastric cancer.     

Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome

BACKGROUND: Hypoxia is a common feature of many solid cancers and linked to malignant transformation, metastases and treatment resistance. Hypoxia is known to induce hypoxia-inducible factor-1alpha (HIF-1alpha) expression. The aim of this study is to investigate the impact of overexpression of HIF-1alpha on prognosis and the relationship with clinicopathological characteristics in human osteosarcoma. METHODS: Immunochemistry with digital image analysis was used to determine the HIF-1alpha protein expression in histologic sections from 39 treated patients. RESULTS: According to our study, expression of HIF-1alpha protein were detected in 31 of 39 cases (79%), with signal concentrated primarily within the nuclei of tumor cell. In contrast, non-cancerous adjacent tissues showed no HIF-1alpha immunoreactivity. HIF-1alpha expression was significantly associated with surgical stage, percentage of dead cells and microvessel density (MVD). Surgical stage, percentage of dead cells and HIF-1alpha expression showed significant influence on overall survival (OS) and disease-free survival (DFS) in univariate analysis. In multivariate analysis, surgical stage (IIA versus IIB/III) and percentage of dead cells (<90% versus > or =90%) were significant for DFS and OS. Those patients with HIF-1alpha moderate/strong expression showed significantly shorter OS and DFS compared with HIF-1alpha negative/weak expression. CONCLUSIONS: Overexpression of HIF-1alpha is predictive of a poor outcome and might be a novel therapeutic target in human osteosarcoma.     

Screening for hepatocellular carcinoma: survival benefit and cost-effectiveness.

BACKGROUND: The prognosis for patients with hepatocellular carcinoma (HCC) is poor by the time they present with symptoms. This review examines the usefulness of screening programs from the perspectives of survival benefit and of cost-effectiveness. MATERIALS AND METHODS: Articles were searched through Medline for screening, HCC, treatment and cost-effectiveness. RESULTS: Both ultrasonography and alpha-fetoprotein testing have a low sensitivity for detecting HCC, although a combination of the two investigations can increase sensitivity. They remain the main screening methods because they are convenient, non-invasive and easily assessable. Though earlier studies fail to show improvement in patient management and survival by screening, more recent studies demonstrate that screening can increase the chance of curative treatment and, more importantly, improve survival even after the adjustment of lead-time bias. This is probably due to the improvement in medical treatment and technology. The cost per tumor detected for a region is inversely proportional to the tumor incidence of that region. CONCLUSIONS: In countries with a low prevalence of HCC, screening for HCC is not cost-effective. But in countries with a high prevalence of HCC, especially when screening is directed at older patients with a high risk of HCC, screening programs for HCC become much more cost-effective.     

Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-α be better?

BACKGROUND: The optimal dose of TNF-alpha delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown. PATIENTS AND METHODS: Randomised phase II trial comparing hyperthermic ILP (38-40 degrees ) with melphalan and one of the four assigned doses of TNF-alpha: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2-3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group. RESULTS: One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-alpha. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively. CONCLUSION: At the range of TNF-alpha doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-alpha doses. Efficacy and safety of low-dose TNF-alpha could greatly facilitate ILP procedures in the near future.     

A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.

BACKGROUND: Experimental data had suggested a synergistic effect of histamine with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Forty-one patients with metastatic melanoma received IL-2 9 MU subcutaneously (s.c.) twice daily on days 4-8 and 25-29, and once daily on days 11-15 and 32-36. IFN-alpha-2b was given as 5 MU s.c. on days 1-3 and then daily to day 43. Histamine 1 mg s.c. was administered twice daily, following IL-2 and IFN injections starting on day 4. Efficacy and toxicity were compared with those of 42 patients included on exactly the same criteria and receiving the same regimen but without histamine. RESULTS: Two patients achieved a partial response (PR) for an objective response rate of 5% [95% confidence interval (CI) 1% to 17%]. Median overall survival was 7.8 months (95% CI 6.4-9.1). In the control group, two complete responses and one PR were achieved. Median overall survival was 7.1 months (95% CI 5.4-8.9). CONCLUSIONS: This IL-2 and IFN regimen was well tolerated on an outpatient basis. However, the applied regimen cannot be recommended because of the low clinical efficacy. Histamine did not add efficacy or toxicity in combination with this moderate-dose schedule of IL-2 and IFN.     

The growth promoting effect of transforming growth factor-alpha in human breast cancer cell lines

Two human breast cancer cell lines, BT-20 and ZR-75-1, were examined with the aim of the elucidating the pathological roles of human transforming growth factor (TGF)-alpha in breast cancers. The TGF-alpha receptor was found to be present in both cell lines. A clonogenic assay revealed that concentrations of TGF-alpha greater than 10(10) M induced a significant increase in colony formation, indicating TGF-alpha to be a breast cancer cell growth factor. Northern blot analysis revealed, moreover, that both cell lines expressed TGF-alpha mRNA. Taking these observations together, it is reasonably possible to assume that TGF-alpha is an autocrine growth factor for breast cancer cells. Although it has been proposed that TGF-alpha could be an epidermal growth factor (EGF) superagonist with regard to its colony formation stimulating activity, the present study demonstrated the colony formation stimulating activities of TGF-alpha and EGF not to be all that much different in the two breast cancer cell lines.     

Time-Dependent Cytotoxic Action of Human Recombinant {alpha}-Interferon (Ro22-8181) In Vitro and the Sensitivity of Various Cultured Leukemia and Lymphoma Cell Lines to It

The growth inhibitory activity of human recombinant leucocyteA interferon (Ro22-8181: -interferon) against 23 human culturedcell lines derived from leukemias and lymphomas was measuredquantitatively by regrowth assay. Daudi cells were the mostsensitive to it. Two T-cell lines (RPMI-8402, HUT78), threeB-cell lines (Raji, Ly16, A3/Kawakami), one non-T, non-B acutelymphoblastic leukemia (ALL) cell line (KOPN-1) and three myelomonocytoidcell lines (U937, THP-1, ML-1) were moderately or slightly sensitive.Although the levels of sensitivity of these cell lines weredifferent, cells could be killed by the recombinant -interferon.Morphological changes in the sensitive cells treated with itwere decreases in mitosis, pyknosis and fragmentation of thecells. Thirteen other cultured cell lines were not sensitive.The results indicated that the growth inhibitory activity ofrecombinant -interferon is not always cell lineage-specific.There were only three cell lines whose sensitivity, expressedby the concentration required for 90% growth inhibition, wasless than the several hundred units per milliliter that hasusually been obtained as blood levels in clinical trials. Thesethree included one of 10 T-cell lines and two of seven B-celllines; none of six non-T, non-B ALL and myelomonocytoid celllines were that sensitive. Among virus-associated cell lines,only Epstein- Barr virus-associated B-cell lines were sensitiveto the interferon; adult T-cell leukemia virus-associated T-celllines were not sensitive. It was demonstrated that recombinant-interferon has a time-dependent, but not a concentration-dependentcytocidal action, indicating that optimal therapeutic schedulesof recombinant -interferon for cancer may be daily long-termtreatment, not single or short-term large-dose therapy.     

Elevated alpha-foetoprotein and hepatic metastases--it's not always what it seems!

Gastric cancers that secrete alpha-foetoprotein (AFP) are a rare but well defined entity. These tumours tend to be aggressive with a poor prognosis. Recognition and identification of this group of patients is important in influencing prognosis, treatment options and further clinical research into this entity. We report three cases of gastric cancers associated with elevated AFP. This entity should be considered in patients with hepatic lesions and an elevated AFP without risk factors for hepatocellular carcinoma or in patients with associated gastric symptoms.     

Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes.

BACKGROUND: Anemia occurs frequently in patients with cancer and is associated with impaired health-related quality of life (HRQOL). Treatment of anemia results in significant improvements in energy, activity and overall HRQOL, particularly among patients with mild-to-moderate anemia. Importantly, studies have indicated that anemia may have a negative impact on the success of radiotherapy, reducing survival and locoregional control. Recent preclinical and preliminary clinical data have also suggested that anemia may be associated with poorer outcomes following chemotherapy or surgery. MATERIALS AND METHODS: Data for review were identified and selected from searches of the literature published from January 1990 through to October 2002 using Medline, and searches of proceedings from key international oncology and hematology meetings. RESULTS: A wealth of data indicate that treatment of anemia improves HRQOL in patients with cancer. Prospective studies exploring survival and/or treatment outcomes in anemic cancer patients are currently in their early stages, preventing any firm conclusions from being drawn, although they do indicate a benefit in treating anemia. CONCLUSIONS: Recent studies support the use of erythropoietic agents in anemic cancer patients as a means of raising their hemoglobin levels and consequently improving their HRQOL. Randomized, controlled trials are needed to determine whether treating anemia with erythropoietic agents will improve other outcomes following therapy.