Frank J. Liu

Differential Diagnosis of Monoclonal Gammopathies

Several disorders are associated with a monoclonal immunoglobulin detected by serum or urine electrophoresis, the most common being a monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenstroms macroglobulinemia, and amyloidosis. The clinical features of these conditions, as well as other similar entities, are described in this review. The objective is to demonstrate the importance of electrophoretic studies in the differential diagnosis of plasma cell dyscrasias and in guiding the decision for rational therapies.

An immunologic profile of young adults with head and neck cancer

Numerous reports have suggested, although never demonstrated, a suppressed immune defense mechanism as a contributing factor in the development of head and neck cancer in the young adult. Twenty‐four previously untreated adults > 40 years of age with squamous cell carcinoma were examined for lymphocyte function (natural killer cell activity and in vitro lymphocyte blastogenesis response to mitogens), total lymphocyte number and percentage of lymphocyte subsets, and humoral immune status (circulating IgA, IgG, and IgM). As compared with 33 healthy young adults, no significant immunologic deficit could be identified. On the contrary, the young adult cancer population had significantly increased lymphocyte numbers (P < 0.05) and serum IgA, IgG, and IgM levels (P < 0.001, respectively). These young cancer patients cannot be considered to be immunosuppressed. Alternative biologic mechanisms must be defined to account for the increasing incidence of head and neck cancer over the last decade among young adults in the United States.

Lactate Dehydrogenase Isoenzyme 1 is the Most Important LD Isoenzyme in Patients with Testicular Germ Cell Tumor

We examined the clinical utility of serum lactate dehydrogenase (LD) isoenzyme catalytic concentrations in 58 patients with testicular germ cell tumors (TGCT) (13 with seminoma and 45 with non-seminomatous tumors). Twenty-one patients with no evidence of disease (NED) all had serum LD isoenzyme 1 catalytic concentrations (LD-1) and LD-1/LD fractions below the upper limit of the reference values (ULR). LD-1 and the LD-1/LD fraction discriminated significantly between evidence of disease (ED) and NED (p=0.00009 and pWe examined the clinical utility of serum lactate dehydrogenase (LD) isoenzyme catalytic concentrations in 58 patients with testicular germ cell tumors (TGCT) (13 with seminoma and 45 with non-seminomatous tumors). Twenty-one patients with no evidence of disease (NED) all had serum LD isoenzyme 1 catalytic concentrations (LD-1) and LD-1/LD fractions below the upper limit of the reference values (ULR). LD-1 and the LD-1/LD fraction discriminated significantly between evidence of disease (ED) and NED (p = 0.00009 and p = 0.028, respectively, Mann Whitney U-test). Twenty of the 37 patients with ED had raised values of LD-1. The 17 patients with an LD-1 < 1.0 x ULR had a better survival than the 10 patients with LD-1 between 1.0 and 2.9 x ULR, the 7 with LD-1 between 3.0 and 5.9 x ULR, and the 3 patients with LD-1 > 6.0 x ULR (p = 0.006, log-rank test, chi2 test for trend)). Twenty-three patients with an LD-1/LD fraction < or = 0.25 had a better survival than the 14 with an LD-1/LD fraction > 0.25 (p = 0.013). Nineteen patients with LD-5 < 105 U/L and the 15 with LD-5 > 105 U/L had a similar rate of survival (p = 0.85). Our findings add to the evidence showing LD-1 in preference to LD as a serum tumor marker of TGCT.

The relationship of circulating IgA to cellular immunity in head and neck cancer patients

The relationship of circulating IgA titers and multiple parameters of cell‐mediated immunity was examined in 97 patients with head and neck cancer. In 26% of the patients, IgA titers were above one standard deviation of controls, with highest levels noted in patients with advanced disease. In 40 patients for whom multiple immune parameters were tested in vitro, increasing concentrations of IgA were associated with an enhanced immunologic helper state defined by a generalized hypergammaglobulinemia, increased percentage of T4+ lymphocytes, higher T4/T8 ratio, and an increased lymphocyte blastogenesis response to mitogens. IgA concentrations were inversely related to percentages and absolute number of Leu 11+ natural killer cell subsets, and also to disease‐free survival (p < 0.005 by Cox proportional hazards model). The immune correlations identified here are similar to those noted in many autoimmune diseases. Head and neck cancer patients are an immunologically heterogeneous population, among whom elevated IgA blood levels may reflect the autoimmune nature of cancer, an immunologic state defined by its tumor‐promoting capacity.

Serum and acute phase protein modulation of the effector phase of lymphokine-activated killer cells

An understanding of the role that immunomodulatory factors play in the effector phase of lymphokine‐activated killer (LAK) activity is essential for the development of biologic response modifiers for use in the treatment of advanced carcinoma. Fifteen head and neck cancer patients were studied. Single‐donor killer cells activated by recombinant interleukin‐2 (10 U/mL) and induced in either a complete medium or complete medium plus a 10% autologous serum solution were used. Effector phase solutions of 25% autologous serum were used in chromium 51 release assays to determine sera immunomodulation of LAK cell cytotoxicity. Both K562 and squamous carcinoma (MDA686‐Ln) tumor cell lines were tested.

Serum lactate dehydrogenase isoenzyme 1 as a prognostic predictor for metastatic testicular germ cell tumours

Serum lactate dehydrogenase isoenzyme 1 as a prognostic predictor for metastatic testicular germ cell tumours

Serum biomarkers in metastatic renal cell carcinoma

To identify possible clinically valuable markers of metastatic renal cell carcinoma, we measured the serum concentrations of several commercially available biomarkers in 117 patients with this disease. The alpha-fetoprotein level was measured in 75 patients and was elevated in 8 (11%); elevation did not correlate with the presence of liver metastasis. Beta subunit of human chorionic gonadotropin levels increased in 8 of 83 patients tested (10%). C-terminal parathyroid hormone levels were measured in 79 patients and were elevated in 15 (19%); their serum creatinine level was normal. Thirteen of this group had normal serum calcium levels, whereas 7 patients with hypercalcemia and no clinically evident bone metastasis had normal parathyroid hormone levels. In only 2 of 72 patients, serum lactate dehydrogenase and its isoenzyme 1 were elevated. Only 1 of 85 patients had mildly elevated serum carcinoembryonic antigen, in contrast to 3 of 7 patients with metastatic transitional cell carcinoma of the renal pelvis who had moderately elevated carcinoembryonic antigen. Elevations in alpha-fetoprotein, human chorionic gonadotropin, and parathyroid hormone correlated with the course of the disease in 13 patients for whom follow-up measurements were available; measurement of these markers, however, is only useful in a small proportion of patients with metastatic renal cell carcinoma.

Serologic determinants of survival in patients with head and neck cancer: Validating a clinical prediction model

Quantitative measurements of serum C1q‐binding macromolecules (C1qBM) and immunoglobulin A (IgA) were done on 162 patients using previously described methodology. The measurements were compared to a previously described head and neck cancer population. Using the Cox Proportional Hazards model, the prognostic implications regarding high ClqBM and subsequent death with disease (P = .02), and regional recurrence (P = .0094) were validated, but not our previous IgA‐related prognostic implications. When both study populations were combined, ClqBM was predictive of survival in those patients treated with induction chemotherapy (P = .0001). ClqBM was not a significant predictor of survival in patients treated with surgery plus postoperative radiation therapy in either this second “test” population or in the original “training” population. The findings demonstrate the confounding influence of treatment modalities and the importance of model validation.

Serologic determinants of survival in patients with squamous cell carcinoma of the head and neck

Specific circulating serum proteins may reflect unique properties governing the growth and progression of head and neck cancers. One hundred three previously untreated patients with squamous cell carcinoma of the head and neck were prospectively evaluated for serum IgA, IgG, and IgM and C1q-binding macromolecules. Immunoglobulins were assessed by the immunoturbidimetric technique. C1q-binding macromolecules (C1qBM) were measured utilizing the iodine-125 assay of Zubler et al (J Immunol 1976; 116: 232-5). Neither the level of serum immunoglobulins nor C1qBM values were correlated with the primary site, AJC (American Joint Committee on Cancer) stage of disease, or size of primary lesion. Likewise, comparison of serum IgA with C1qBM values demonstrated that these laboratory parameters were independent variables (r = 0.15 by Pearson linear regression). Univariate statistical analysis, utilizing the Cox proportional hazard model, showed serum IgA and C1qBM values to each contribute significantly to the ability to predict survival in patients with advanced squamous cell carcinoma of the head and neck (p = 0.01 and 0.003, respectively). Furthermore, multivariate analysis reveals that both C1qBM and serum IgA levels contribute significantly to the hazards model beyond staging in predicting survival (p less than 0.001). Predictive results were most apparent in patients with stage IV disease and related to the probability of both regional and distant metastatic recurrences. Conversely, serologic analysis provided no information in patients who were staged early. These results support pretreatment multiparametric serologic analysis of patients with squamous cell carcinoma of the head and neck.

Immunomodulation of the induction phase of lymphokine-activated killer activity by acute phase proteins

Effective treatment of head and neck cancer with biologic response modifiers may be benefitted by an understanding of in vivo factors capable of modulating the lymphokine-activated killer (LAK) cell phenomenon. Eighteen patients with squamous cell carcinoma of the head and neck were studied. Killer cells from each patient, activated by recombinant interleukin-2 (10 U/ml), were induced in either complete medium alone or complete medium plus 10% autologous serum solution and analyzed. Cytotoxicity against both K562 and squamous cell carcinoma (MDA686-Ln) cell lines was determined by use of standard chromium-release assays. The immunomodulatory capacity of serum was correlated with levels of various acute phase proteins. Autologous serum significantly inhibited the induction phase of the LAK phenomenon in 61% of patients and stimulated it in 22%. No patients with early stage I or II disease had significant inhibition of induction. No direct correlation between inhibition and serum acute phase protein levels were seen. An inverse relationship was seen between the C, component of complement and induction inhibition (r = −0.6). These findings suggest that advances of in vivo immunomodulatory therapy will require elucidation of mechanisms of serologic inhibition of the induction phase of the LAK phenomenon. Such studies may lead to serologic modification to enhance treatment efficacy of biologic response modifiers.