beta(2)-microglobulin in Hodgkin's lymphoma: prognostic significance in patients treated with ABVD or equivalent regimens.

PURPOSE: Serum beta-2 microglobulin (sbeta(2)m) is an established prognostic factor for several lymphoproliferative disorders. Because its significance in Hodgkin's lymphoma (HL) is controversial, we determined sbeta(2)m levels in pretreatment serum samples of patients with HL in order to elucidate its prognostic value in this condition. PATIENTS AND METHODS: Pretreatment sbeta(2)m levels were determined in 379 HL patients who were treated with ABVD or equivalent regimens with or without radiotherapy (RT), using a radioimmunoassay (upper normal limit 2.4 mg/l). Sbeta(2)m levels were correlated with several clinical and laboratory parameters. RESULTS: Elevated sbeta(2)m levels were detected in 138/379 (36%) patients and correlated with all clinical and laboratory baseline features except gender, lung involvement and mediastinal bulk. They also correlated with serum soluble CD30 and interleukin-10 levels. The 8-year failure-free survival (FFS) was 78 -/+ 4% for patients with normal versus 65 -/+ 7% for patients with elevated sbeta(2)m levels (p=0.003). The corresponding rates among early-stage patients were 83 -/+ 53% versus 71 -/+ 9% (p=0.003), while for advanced stages they were 70 -/+ 6% versus 64 -/+ 8% (p=0.54). In multivariate analysis of the whole patient population elevation of sbeta(2)m levels was not predictive of FFS, but it was strongly predictive among early-stage patients. The 8-year overall survival (OS) rates were 91 -/+ 3% for patients with normal versus 59 -/+ 11% (p <0,0001) for patients with elevated sbeta(2)m levels, while unrelated mortality at 8 years was 1 -/+ 1% versus 27 -/+ 12% (p<0.0001). CONCLUSION: Our data suggest that sbeta(2)m levels may be a potent prognostic factor for FFS in patients with early stage HL treated with ABVD and equivalent regimens. Their effect on OS is confounded by the higher unrelated mortality in patients with elevated baseline sbeta(2)m levels, probably due to the strong association between sbeta(2)m and older age.

Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group.

PURPOSE: To determine clinical features and patterns of outcome of primary testicular diffuse large B-cell lymphomas (DLCL). PATIENTS AND METHODS: A retrospective international survey of 373 patients with primary testicular DLCL. RESULTS: Most patients presented with localized disease (stage I to II), and the median age at diagnosis was 66 years (range, 19 to 91 years). Anthracycline-based chemotherapy was administered to 255 patients (68%), and prophylactic intrathecal chemotherapy was given to 68 patients (18%); 133 patients (36%) received prophylactic scrotal radiotherapy. Median overall survival was 4.8 years, and median progression-free survival was 4 years. The survival curves showed no clear evidence of a substantial proportion of cured patients. A favorable international prognostic index score (IPI), no B-symptoms, the use of anthracyclines, and prophylactic scrotal radiotherapy were significantly associated with longer survival at multivariate analysis. However, even for patients with stage I disease and good-risk IPI, the outcome seems worse than what was reported for DLCL at other sites. At a median follow-up of 7.6 years, 195 patients (52%) had relapsed. Extranodal recurrence was reported in 140 cases. Relapses in CNS were detected in 56 patients (15%) up to 10 years after presentation. A continuous risk of recurrence in the contralateral testis was seen in patients not receiving scrotal radiotherapy. CONCLUSION: Testicular DLCL is characterized by a particularly high risk of extranodal relapse even in cases with localized disease at diagnosis. Anthracycline-based chemotherapy, CNS prophylaxis, and contralateral testicular irradiation seem to improve the outcome. Their efficacy is under evaluation in a prospective clinical trial.

Primary cutaneous non-Hodgkin's lymphoma with aggressive histology: inferior outcome is associated with peripheral T-cell type and elevated lactate dehydrogenase, but not extent of cutaneous involvement.

BACKGROUND: The aim of this study was to explore the association between extent of cutaneous involvement, presenting features and progression-free survival (PFS) in patients with primary cutaneous non-Hodgkin's lymphoma (PCNHL) of aggressive histology. METHODS: Previously untreated patients with localized or extensive PCNHL of aggressive histology, treated with combination chemotherapy, but excluding lymphoblastic lymphoma and mycosis fungoides and its variants, were reviewed retrospectively. RESULTS: We identified 53 patients, of whom 52 (35 males, 17 females) were treated with doxorubicin-based regimens. Median age was 52 years (range 25-81 years), and disease was localized and extensive in 37 and 16 patients, respectively. Twenty-four patients had diffuse large B-cell lymphoma, nine had grade 3 follicular lymphoma, 13 had peripheral T-cell lymphoma (PTCL; not otherwise specified) and seven had anaplastic large cell lymphoma (WHO classification). With a median follow-up of 101 months (range 2-237 months) for survivors, the 10-year PFS was 65 +/- 7% and overall survival was 72 +/- 8%. The first failure involved the skin in 33% of B-cell and 91% of relapsing T-cell lymphomas. Univariate analysis revealed that PTCL (P = 0.005), lymphopenia (P = 0.01) and high serum levels of beta(2)-microglobulin (P = 0.0006) and LDH (P = 0.002), but not extent of skin involvement, were associated with inferior PFS. Multivariate analysis revealed that only PTCL and high serum lactate dehydrogenase (LDH) were independently associated with inferior PFS. CONCLUSIONS: PTCL and elevated serum LDH level, but not extent of cutaneous involvement are associated with inferior PFS in aggressive PCNHL treated with combination chemotherapy.

Irinotecan in relapsed or refractory non-Hodgkin's lymphomas. Indications of activity in a phase II trial.

Because irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity, we investigated its activity in relapsed or refractory non-Hodgkin's lymphomas (NHLs). Irinotecan at 300 mg/m2 i.v. was administered every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 44 registered patients, 32 are evaluable for response. Seventeen patients had received one previous regimen, and 15 patients had received two. Disease was refractory to the regimen preceding irinotecan in 12 patients. At baseline, serum lactate dehydrogenase levels were high in 47% (14/30), and beta-2-microglobulin levels were higher than 3.0 mg/L in 29% (8/28) of patients. Responses were seen in 12 of 32 (38%) patients (95% confidence interval [CI] = 21%-56%). Response rates were 43% for seven indolent (95% CI = 10%-82%), 0% for three mantle cell (95% CI = 0%-71%), 44% for 18 relapsed aggressive (95% CI = 22%-69%), and 20% for five refractory aggressive NHLs (95% CI = 1%-72%). Grade 3/4 toxicities included myelosuppression, neutropenic fever, and diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive or indolent NHL. Accrual to this study is continuing for better determination of response rates in all histologic subtypes of NHL.

Trimetrexate in relapsed T-cell lymphoma with skin involvement.

PURPOSE: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated. PATIENTS AND METHODS: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus. TMTX (200 mg/m(2)) was given intravenously every 14 days without topical or systemic corticosteroids. Patients who responded received up to 12 doses. RESULTS: Twenty patients were assessable for response. Median age was 59 years (range, 45 to 87 years); 13 patients were men. Three patients had anaplastic large-cell lymphoma, 15 had mycosis fungoides or Sézary syndrome (14 with large-cell transformation), and two had peripheral T-cell lymphoma. Serum lactate dehydrogenase was high in 35%, and beta-2 microglobulin was more than 3.0 mg/L in 35% of patients. The median number of previous regimens was three (range, two to 15) and included MTX in five patients. Disease was refractory to the regimen immediately preceding TMTX in 85% of patients. Responses were complete in one and partial in eight patients (overall response rate, 45%). Two of five patients previously treated with MTX responded. Grade 3 or 4 mucositis was observed after 4%, infection after 3%, neutropenic fever after 6%, neutrophils less than 100/microL after 4%, and platelets less than 10,000/microL after 3% of TMTX doses. CONCLUSION: TMTX is active with acceptable toxicity in this population and merits further investigation.

Non-Hodgkin's lymphoma affecting the testis: is it curable with doxorubicin-based therapy?

This study was designed to determine response, outcome, and patterns of failure of patients with non-Hodgkin's lymphoma who presented with a testicular mass. Consecutive patients presenting to M.D. Anderson Cancer Center between 1969 and 1999 treated with doxorubicin-based regimens and with radiotherapy and/or intrathecal therapy were considered for this study. We identified 43 patients whose median age was 61 years. Ann Arbor stage (AAS) was I in 22 patients, II in 7 patients, III in 1 patient, and IV in 13 patients. All 43 patients had intermediate-grade lymphomas according to the Working Formulation, and all 31 tumors assessed immunophenotypically were large B-cell lymphoma according to the World Health Organization classification. The International Prognostic Index score was > or = 2 in 18 patients (42%). Thirty-four patients achieved complete remission, 19 of whom relapsed, and 5 failed initial therapy. At 10 years, progression-free survival (PFS) was 20% +/- 9% and survival was 33% +/- 9%. Progression-free survival for patients with AAS I/II vs. III/IV was 36% +/- 13% vs. 0%, respectively (P = 0.004). At 10 years, the actuarial probability of failure in the central nervous system was 34% +/- 9% and was 21% +/- 9% in contralateral testis. Using the intent-to-treat method, patients receiving cyclophosphamide/doxorubicin/ vincristine/prednisone (CHOP), with additional scrotal radiotherapy and intrathecal methotrexate, had a 5-year PFS of 91% +/- 9% vs. 30% +/- 15% vs. 41% +/- 12% for those receiving only one or neither of these additional modalities (P = 0.053). Doxorubicin-based regimens alone appear unable to cure most patients with lymphoma involving the testis, but CHOP with prophylactic intrathecal therapy and adjuvant scrotal radiotherapy appears promising. This should be confirmed with prospective clinical trials and longer follow-up.

Anaplastic lymphoma kinase (ALK) is not expressed in Hodgkin's disease: results with ALK-11 antibody in 327 untreated patients.

The t(2;5)(p23;q35) or other rare chromosomal abnormalities involving 2p23 upregulate the ALK gene, which is not expressed in normal lymphocytes. Thus, detection of ALK protein is presumptive evidence of these 2p23 abnormalities. The t(2;5) and ALK immunoreactivity are common in anaplastic large cell lymphoma of T/null-cell lineage. However, a small subset of cases of Hodgkin's disease (HD) have been reported to either carry the t(2;5) or express ALK. In this study, we have immunohistochemically evaluated 327 cases of HD with the ALK-11 antibody. ALK-11 is a well characterized polyclonal antibody raised against an intracellular portion of the ALK protein. We detected ALK-11 immunoreactivity in 8 (2.4%) cases of HD. We further studied these positive cases with ALK-1 monoclonal antibody, which reacts with an intracellular portion of ALK, similar to ALK-11. All 8 ALK-11 positive cases were negative for ALK-1. These results indicate that rare cases of HD may react with ALK-11 antibody, similar to previous reports by others using different polyclonal anti-ALK antibodies. However, the absence of ALK-1 expression in these HD cases suggests that ALK protein is not truly present and that polyclonal anti-ALK antibodies may rarely yield non-specific cross reactivity. These results further support the use of anti-ALK antibodies in the differential diagnosis of HD from ALCL.

Differential expression of BCL-2 family proteins in ALK-positive and ALK-negative anaplastic large cell lymphoma of T/null-cell lineage.

Anaplastic large-cell lymphoma (ALCL) of T- or null-cell lineage, as defined in the revised European-American lymphoma classification, includes a subset of tumors that carry the t(2;5)(p23;q35) resulting in overexpression of anaplastic lymphoma kinase (ALK). Patients with ALK+ ALCL are reported to have a better prognosis than patients with ALK- ALCL. Because the mechanisms for this survival difference are unknown, we investigated the hypothesis that apoptotic pathways may be involved. We therefore assessed expression levels of the anti-apoptotic proteins BCL-2 and BCL-XL and the pro-apoptotic proteins BAX and BCL-XS in T/null-cell ALCL using immunohistochemical methods and correlated the findings with ALK expression and apoptotic rate (AR), the latter assessed by a modified Tdt-mediated dUTP nick-end labeling assay. ALK was detected in 21 of 66 (31.8%) ALCLs. BCL-2 was not detected in 21 ALK+ ALCLs but was present in 26 of 45 (57.8%) ALK- ALCLs (P < 0.0001). ALK+ and ALK- ALCLs also showed significant differences in expression of BCL-XL, BAX, and BCL-XS. ALK+ tumors less commonly had a high level of BCL-XL (1 of 17 versus 14 of 35, P = 0.01), and more commonly had high levels of BAX (13 of 18 versus 15 of 36, P = 0.05), and BCL-XS (11 of 16 versus 12 of 31, P = 0.05) compared with ALK- tumors. ALK+ tumors also had a higher mean AR than ALK- tumors (3.4% versus 1.1%, P = 0.0002). Differential expression of BCL-2 family proteins may be responsible for the higher AR observed in ALK+ ALCL and provides a possible biological explanation for the better prognosis reported for patients with ALK+ ALCL.

Irinotecan in relapsed or refractory non-Hodgkin's lymphoma.

Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity. Various schedules and doses have been studied, and major complications were delayed diarrhea and myelosuppression. We explored the activity of irinotecan in patients with relapsed or refractory non-Hodgkin's lymphoma, using a 3-week schedule of administration. Eligible patients had histologically proven relapse, had received no more than two previous regimens, were > or = 15 years and < or = 75 years old, had normal renal function, neutrophil count > 1,500/microL, platelet count > 100,000/microL, and no human immunodeficiency virus infection or central nervous system involvement. Patients were treated with irinotecan 300 mg/m2 i.v. every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 25 patients registered so far, 22 are evaluable for response. The median age was 67 years (range: 25 to 74 years) and 11 were male. The median number of previous regimens was 2 (range: 1 to 4 regimens), and 16 patients had disease that was refractory to their last regimen. Serum lactate dehydrogenase level was high in 75%, and beta2-microglobulin was > 3.0 mg/L in 26% of patients. Responses were seen in 8 of 22 (36%) patients with non-Hodgkin's lymphoma. Response rates were 40% for indolent, 0% for mantle cell, 45% for relapsed aggressive, and 33% for refractory aggressive lymphomas. Grade 3/4 toxicities included myelosuppression, neutropenic fever, and delayed diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive non-Hodgkin's lymphoma. Accrual to this study is continuing for better determination of the response rate in all histologic subtypes of non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma involving the gynecologic tract: a review of 88 cases.

Non-Hodgkin's lymphoma (NHL) involving the gynecologic tract is unusual and may cause confusion for the pathologist not familiar with its clinical and histologic features. The literature regarding this topic is also confusing, as modern NHL classification systems were not used or patients were not staged according to the Ann Arbor system in many prior reports. In addition, immunophenotypic data is not available for many cases, particularly in older studies. In the past year, there has been an interest in NHL involving the gynecologic tract and 88 cases have been collected. These cases were reviewed in the Pathology Department of M.D. Anderson Cancer Center during the past two decades, and many of these patients were treated at this hospital. In this review, these cases are reported using updated terminology and almost all cases were immunophenotyped using immunohistochemical methods or flow cytometric methods in a small subset of cases. These cases have also been segregated into two groups: 1) localized NHL, that presumably initially arose in the gynecologic tract and therefore are primary; and 2) NHL that involved the gynecologic tract as a part of systemic disease, and therefore most likely represent secondary involvement of the gynecologic tract. The differential diagnosis of NHL involving gynecologic organs is discussed.

Hodgkin's disease in patients infected with human immunodeficiency virus: frequency, presentation and clinical outcome.

We report the frequency, presenting characteristics, progression-free survival, event-free survival, overall survival and AIDS-free survival of patients with previously untreated Hodgkin's disease (HD) in the setting of infection by human immunodeficiency virus (HIV). To accomplish this we retrospectively reviewed all untreated patients presenting to the University of Texas M.D. Anderson Cancer Center between July 1985 and August 1999 with HD and HIV infection. All available records were reviewed to determine presentation, clinical characteristics, treatment outcome, progression-free survival and overall survival. We identified 887 patients with HD and 3,500 with Non-Hodgkin's Lymphoma (NHL). The ratio of NHL to HD in HIV-negative versus HIV-positive patients was 3.9 versus 6.9, respectively. There were 14 HIV-positive patients with HD and 97 with NHL. The median age of the HIV-positive HD patients was 33 years, and 13 were male. Three patients had Acquired Immune Deficiency syndrome (AIDS) at the time of HD diagnosis, and seven had B-symptoms. Ann Arbor stage was I in one, II in three, III in four and IV in six patients. Mixed cellularity histology was seen in eight, bone marrow involvement in five and extranodal disease in seven patients. Four patients had elevated serum lactate dehydrogenase, three low serum albumin, and nine elevated serum beta2-microglobulin, The median CD4 count was 160/microl. Eleven patients received ABVD or equivalent regimens, followed by radiotherapy in five. One patient was treated with COPP and radiotherapy, one with NOVP and radiotherapy and one only with radiotherapy. All patients received some antiretroviral therapy, but it was variable over the years. With a median follow-up of 64 months for survivors, the projected 5-year progression-free survival was 64%, event-free survival 45%, overall survival 54% and AIDS-free survival 45%. Six patients died of complications arising from HIV infection, including one patient who had preexisting AIDS at HD presentation. Two patients died of HD, without developing other conditions diagnostic of AIDS. We conclude that in our referral patient population HIV infection is associated with preferential development of NHL rather than HD, which appears curable with standard treatment regimens. Since HIV-related deaths exceed those caused by HD, future investigation should focus on integration of chemotherapy and highly active antiretroviral therapy.

Human recombinant interferon-inducible protein-10: intact disulfide bridges are not required for inhibition of hematopoietic progenitors and chemotaxis of T lymphocytes and monocytes.

Human recombinant interferon-inducible protein-10 (rIP-10), a C-X-C chemokine, inhibits proliferation of human hematopoietic progenitors responsive to co-stimulation by recombinant steel factor (rSLF), is chemotactic for human monocytes and T-lymphocytes, and promotes T-lymphocyte adhesion to endothelial cells. Because chemokines have four conserved cysteines forming two intramolecular disulfide bridges, we decided to investigate their contribution in the biological activity of rIP-10. Since amino acid residues 22-98 of the sequence predicted by the cDNA constitute the naturally occurring IP-10, they were cloned after an initiating methionine into expression vector pET-3d. Subsequently rIP-10 was purified by enzymatic cell lysis, solubilization of refractile bodies with guanidine hydrochloride, renaturation by dialysis against dilute acetic acid, and sequential ion-exchange and reverse-phase high-performance liquid chromatography. Purified rIP-10 was reduced with 20 mM dithiothreitol, and chemically modified with 100 mM iodoacetamide (IAA), or S-methyl-methanethiosulfonate (MMTS), or N-methylmaleimide (NMM). Radiolabeling experiments demonstrated that 95% of the rIP-10 thiols were modified, and this was confirmed with SDS-PAGE. The biological activity of modified rIP-10 was determined in vitro by inhibition of rSLF-responsive human bone marrow hematopoietic progenitor proliferation and by chemotaxis assays using human T-lymphocytes and monocytes. In both assay systems, the biological activity was evident at rIP-10 concentrations of 20-100 ng/ml. The activity was preserved after modification of rIP-10 by IAA or MMTS, but was abolished after modification by NMM. We conclude that disulfide bridges are not essential for the biological activity of rIP-10.

Protein aggregation mediated by cysteine oxidation during the stacking phase of discontinuous buffer SDS-PAGE.

The resolution of complex protein mixtures by discontinuous buffer SDS-PAGE is accomplished by their concentration into thin bands in the stacking gel, followed by their separation during migration through the resolving gel. Recombinant human interferon-inducible protein-10 (IP-10), a 10-kDa C-X-C chemokine with four cysteines, aggregated during the stacking phase of SDS-PAGE and generated a band with an apparent molecular mass of 18 kDa. This aggregation depended on the presence of reduced sulfhydryl residues on IP-10, on the amount of loaded protein, and on the concentration of the ammonium persulfate used to polymerize the stacking gel. The aggregation of IP-10 could be prevented by reduction of its sulfhydryls with dithiothreitol followed by irreversible blockade with iodoacetamide. These methods may be useful in the prevention of aggregation of sulfhydryl-containing proteins during SDS-PAGE, especially when large quantities are analyzed to assess their purity.

Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Interleukin-10 (IL-10) is a pleiotropic cytokine which increases bcl-2 levels and protects cells from steroid or doxorubicin-induced apoptosis. Hodgkin and Reed-Sternberg (HRS) cells bear functional IL-10 receptors. Thus serum IL-10 (sIL-10) might inhibit apoptosis in HRS cells, which could occur as a result of either chemotherapy or the crippled immunoglobulin genes. DESIGN AND METHODS: We determined sIL-10 levels in 122 patients with Hodgkin's lymphoma (HL), treated with ABVD or equivalent regimens with or without radiotherapy, and correlated them with presenting clinical and laboratory features, as well as failure-free survival (FFS) and overall survival. RESULTS: Elevated sIL-10 levels ( > or = 10 pg/mL) were detected in 55 patients (45%), and were correlated with advanced stage and elevated serum b2-microglobulin levels. At 7 years FFS was 85% vs. 63% for patients with normal vs. elevated sIL-10 levels, respectively (p=0.01); overall survival was 97% vs. 73% (p=0.005). Multivariate analysis with Cox's proportional hazards model demonstrated that elevated sIL-10 levels were the strongest independent predictor of FFS, and were also associated with inferior overall survival. INTERPRETATION AND CONCLUSIONS: We conclude that sIL-10 levels are elevated in 45% of patients with HL, and are associated with inferior FFS and overall survival, independently of other established prognostic factors.

Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy.

PURPOSE: Establish frequency, presenting features, response and relapse patterns, and outcome of primary cutaneous non-Hodgkin's lymphoma (PCNHL). PATIENTS AND METHODS: Review of untreated patients, older than 16 years, presenting between 1971 and 1993 with cutaneous lymphoma, not mycosis fungoides, and Ann Arbor stage I. RESULTS: We identified 46 patients, 27 males, with median age of 57 years. Treatment was radiotherapy in 10 patients, doxorubicin-based therapy in 33 patients that was followed by radiotherapy in 25 patients, and other combination with radiotherapy in one patient. The complete response rate was 95%. After a median follow-up of 140 months (range, 61 to 284 months), 18 patients have relapsed, and 14 have died from lymphoma. The first failure was exclusively cutaneous in 50% of relapses. For the 44 treated patients, progression-free survival (PFS; actuarial +/- SE) was 61% +/- 7% and survival was 58% +/- 9% at 12 years. For the 18 patients with diffuse large B-cell lymphoma, after doxorubicin-based regimens, PFS was 71% +/- 12% (P = .0003) versus 0% after radiotherapy; survival was 77% +/- 12% versus 25% +/- 22% (P = 004), respectively. For the nine patients with follicular center-cell lymphoma treated with combined modality, the 12-year PFS was 89% +/- 11% and survival 70% +/- 18%. CONCLUSION: PCNHL is rare, and its first relapse is exclusively cutaneous in 50% of patients. Patients with diffuse large B-cell lymphoma are curable with doxorubicin-based regimens but not with radiotherapy. Prospective studies in PCNHL should define the cytogenetics, the basis for cutaneous tropism, the prognosis of histologic subtypes, and the role of radiotherapy.

Cytokine expression patterns distinguish HIV associated skin diseases.

AIDS is known to cause a shift of cytokines in the periphery. However, predominant cytokines in skin of patients with HIV-associated skin diseases have not been clearly defined. We hypothesized that there are distinct cytokine profiles that distinguish among the different clinical manifestations of AIDS-related skin diseases. To test this hypothesis, lesional and non-lesional skin was biopsied from 53 HIV+ patients with Kaposi's sarcoma (KS), psoriasis, and pruritus due to eosinophilic folliculitis, and from HIV negative controls with psoriasis or KS prior to therapy. Immunohistochemistry was performed with antibodies to tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, interferon (IFN)-gamma, and interferon-inducible protein (IP)-10. HIV positive individuals included 10 with psoriasis, 14 with pruritus, and 15 with Kaposi's sarcoma. HIV negative controls included 12 with psoriasis and two with KS. Semi-quantitative analysis of cytokine staining was confirmed by optical density using a digital imaging system on four representative skin sections from each disease. Optical density analyses were conducted using ANOVA and t-tests. We found that epidermis overlying HIV+ Kaposi's sarcoma was hyperproliferative and was highest in IP-10, IFN-gamma, and IL-10 (P=0.0001). HIV+ pruritus was significantly highest in TNF-alpha (P=0.0001) staining. HIV+ psoriasis represented an intermediate state for all four cytokines. Normal skin adjacent to lesions showed the same relative patterns, with lower intensities. Skin diseases seen frequently in the setting of HIV and immunodeficiency have relatively distinct levels and patterns of cytokine expression that may reflect immune dysfunction, reactivity to HIV and to opportunistic infections.

Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients.

Aggressive mantle cell lymphoma has a poor prognosis with current therapy and occurs frequently in an elderly population which cannot receive stem cell transplantation. Newer aggressive therapies are needed. In this study, 25 consecutive previously untreated patients 65 years or older with MCL were enrolled in two sequential phase II trials. The program included fractionated cyclophosphamide 1,800 mg/m2 administered with doxorubicin, vincristine and dexamethasone (hyper-CVAD), alternating every 3 weeks with high doses of methotrexate and cytarabine (M-A) for up to 8 cycles. Cytarabine was given as 1 gram/m2/dose. Six of 14 patients tested (50%) presented with gastrointestinal (GI) involvement, but only one had GI symptoms. The overall response rate was 92% (95% C.I. 73-99) and the complete remission (CR) rate was 68% (95% C.I. 46-85). With a median follow-up of 17 months, the median FFS for the entire group is 15 months. Hematologic toxicity was significant but only 5% of the cycles were associated with grade 3 infection. Treatment-related death occurred in 2 patients. In conclusion, GI involvement by MCL is common in this age group. Hyper-CVAD alternating with M-A with adjustment of the cytarabine is an active regimen in this elderly group of patients with untreated MCL and the toxicity is manageable. Strategies for eradicating minimal residual disease are still needed.

Molecular response assessed by PCR is the most important factor predicting failure-free survival in indolent follicular lymphoma: update of the MDACC series.

BACKGROUND: We have observed that molecular response, as defined by a PCR-negative status during the first year of therapy, along with beta 2-microglobulin (beta 2M), was the most important variable associated with failure-free survival (FFS) in follicular lymphoma (FL). Herein, we present an update of the previously published MDACC series. PATIENTS AND METHODS: A total of 116 patients (male:female ratio 64:52; median age: 52 years) with indolent FL and BCL-2 rearrangement (at MBR or mcr breakpoints) assessable in peripheral blood (pb) by PCR prior to treatment, and with two or more PCR determinations during the first year, were selected for the present study. RESULTS: Of the 116 patients, 4 who presented with progression and 1 who died of unrelated causes during the first year were excluded from the landmark analysis. One hundred patients (86%) achieved clinical CR and 80 (69%) achieved a negative PCR status within first year. Median FFS was 6.4 years. Five-year FFS was 73% and 28% for molecular responders and nonresponders, respectively (P = 0.001). In spite of this strikingly higher FFS favoring molecular responders, no clearcut plateau was evident in this group. Molecular response assessed in pb (P = 0.001) and serum beta 2M (P < 0.001) were the most important factors to predict FFS in the multivariate analysis. In the subset of patients with normal beta 2M and molecular CR, there was a trend for a plateau in the FFS curve. No significant difference between the groups has been observed so far in terms of survival. CONCLUSIONS: Molecular response assessed in pb using a PCR technique is, along with beta 2M, the most important factor to predict FFS in FL.

Liposomal vincristine in relapsed non-Hodgkin's lymphomas: early results of an ongoing phase II trial.

OBJECTIVE: Vincristine is an active agent in lymphomas, but is often neurotoxic, and the resulting dose reductions have been associated with lower remission and survival rates in Hodgkin's disease. Liposomal vincristine (Onco-TCS) has prolonged half-life, reaches higher concentration in tumors and lymph nodes than in nerves, and administered at full doses appears to be less neurotoxic, and more active then free vincristine in mice bearing L-1210 and P-388 leukemias. We therefore explored its activity in relapsed non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eligible patients had histologically proven relapse, age > or = 16 years, normal renal function, neutrophils > 500/microliter, platelets > 50,000/microliter, and no HIV infection, central nervous system disease, or serious neuropathy. Patients were treated with 2.0 mg/m2 of liposomal vincristine i.v. over 60 minutes q 14 days. Responders received up to 12 injections. RESULTS: Of the 51 registered patients, 35 are currently evaluable for response. Median age was 62 years (range 19-86), and 21 were male. The median number of prior regimens was 3 (range 1-10) and had included vincristine in all patients, of whom 51% were refractory to their last regimen. Serum LDH was high in 46%, and beta 2-microglobulin > 3.0 mg/l in 63% of patients. Of the 155 administered injections, 138 (89%) were at the 2.0 mg/m2 level. The median injected dose was 3.8 mg (range 2.6-4.8 mg), and median number of injections was 4 (range 1-12). Responses were seen in 14 of 34 (41%) patients with NHL (95% confidence intervals (95% CI) 25%-59%). Response rates were 10% for indolent, 71% for transformed, and 47% for aggressive NHL, but the 95% confidence intervals overlapped. Median progression-free survival was 5.5 months for responders. Grade 3-4 motor or sensory neuropathy was seen in 11, and caused termination of therapy in five patients. All five had prior neuropathy, two had previously received paclitaxel, one platinum, and two paclitaxel and platinum. Fever was detected in three patients, but there were no toxic deaths. CONCLUSIONS: Liposomal vincristine is active and well tolerated in this heavily pretreated population with relapsed NHL, but can be neurotoxic in a fraction of patients heavily exposed to prior neurotoxic agents. These data, if confirmed, would suggest a potential role for liposomal vincristine in the combination therapy of previously untreated patients with NHL.

Infusional vinorelbine in relapsed or refractory lymphomas.

Vinorelbine (Navelbine is a semisynthetic vinca alkaloid devoid of serious neurotoxicity. When given weekly vinorelbine has documented activity against many tumors, including lymphomas. Since weekly schedules cannot be easily incorporated in combination regimens, we tested an infusional schedule of vinorelbine given every 21 days in adults with relapsed or refractory lymphoma. Patients with inadequate organ or bone marrow reserve, HIV or other serious infection, central nervous system disease, or prior stem cell or bone marrow transplantation were ineligible. In the phase I part, patients received a constant intravenous bolus of 8 mg/m(2), followed by intravenous continuous infusion over 24 hours daily for four days increasing from 10, 12, to 14 mg/m(2) /d in successive three-patient cohorts. Cycles were repeated every 21 days, and the daily continuous infusion dose was adjusted for toxicity. Dose-limiting mucositis and neutropenia were reached at the continuous dose of 14 mg/m(2) /d. Consequently, for the Phase II trial the starting continuous infusion dose was 12 mg/m(2) /d. After the first 19 patients were entered in the phase II study, the starting infusion dose was reduced to 10 mg/m(2) /d because of frequent grade (3/4) myelosuppression and mucositis. Forty-four patients were entered in the phase II study, of whom 41 are evaluable. Median age was 61 years, 23 were males, with clinically aggressive non-Hodgkin's lymphoma (NHL) in 22, indolent NHL in 18, and Hodgkin's Disease in one patient. The median number of prior regimens was 3 (range 1-11). The lymphoma was refractory to the initial regimen in nine patients, and to the regimen immediately before vinorelbine in 20 patients. Serum LDH was high in 2(1/4)1, and serum beta(2) -microglobulin > 3.0 mg / L in 16/31 patients. Responses were observed in four of 22 patients with aggressive NHL (18%, 95% confidence interval 5%-40%), and in six of 18 with indolent NHL (33%, 95% confidence interval 13%-59%). Median progression-free survival was 6 months for responders. During the Phase II trial 114 vinorelbine courses were administered. Neutrophil nadir was < 1000/microl in 65% and < 100/microl in 35% of courses, respectively. Platelet nadir was < 100,000/microl in 30% and < 20,000/microl in 8% of courses, respectively. Grade (3/4) mucositis was seen in 18% of courses, and neutropenic fever in 13%, and was complicated by death in one patient. We conclude that this dosage and schedule of vinorelbine has modest activity in patients with relapsed or refractory NHL. Myelosuppression is frequent but reversible, but there is no significant neurotoxicity. The role of vinorelbine in combination regimens for patients with relapsed lymphomas, particularly those of indolent histology, should be further investigated.