HER-2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel.

PURPOSE: To evaluate the predictive value of HER-2 in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin (A) or with single-agent docetaxel (T). EXPERIMENTAL DESIGN: Patients from this study participated in a phase III clinical trial in which doxorubicin or docetaxel was administered for advanced disease. HER-2 was evaluated by IHC. In all positive cases, FISH was used to confirm the HER-2 positive status. The different cohorts of patients identified by HER-2 were examined to assess a possible relationship between HER-2 status and treatment effect. RESULTS: Tumor samples were available for 176 of the 326 patients entered in the clinical trial (54%). HER-2 positivity was observed in 20% of the study population. A statistically significant interaction was found between response rates to the study drugs and HER-2 status, with HER-2 positive patients deriving the highest benefit from the use of T (odds ratio for HER-2 positive patients treated with T = 3.12 (95% CI 1.11-8.80), p = 0.03). The interaction between HER-2 and response rates to A and T was also confirmed by a multivariate analysis. No statistically significant interaction was found between HER-2 and drugs efficacy evaluated in terms of time to progression and overall survival, although in the HER-2 negative cohort A was at least as effective as T in term of overall survival. CONCLUSIONS: These results suggest that in HER-2 positive breast cancer patients docetaxel might be more active than doxorubicin, while in HER-2 negative patients doxorubicin might be at least as effective as docetaxel. Although the present results cannot have an impact on current practice, they allow us to formulate the hypothesis that HER-2 positive breast cancer is a heterogeneous disease with regard to sensitivity to anthracyclines and taxanes, and that this might be dependent upon other molecular markers including the p-53 and topoisomerase II alpha genes. This hypothesis is currently being tested prospectively in two different 'bench to bed-side' clinical trials.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

Staphylococcal bacteremia in cancer patients: risk factors and outcome in 134 episodes prior to and after introduction of quinolones into infection prevention in neutropenia.

A total of 134 episodes of staphylococcal bacteremia (SBE) appearing among 9987 admissions, and 979 episodes of bacteremia in cancer patients within 5 years, were analyzed for risk factors, clinical course and outcome; 64 were monomicrobial and 70 polymicrobial. The most frequent risk factors were acute leukemia, catheter insertion, long-lasting neutropenia, and prior prophylaxis with quinolones. There was no significant difference between polymicrobial and monomicrobial SBE in risk factors. The two groups differed only in the source of bacteremia (gastrointestinal and respiratory-tract infections were more common in monomicrobial SBE) and etiology-Staphylococcus aureus appeared more frequently in monomicrobial than in polymicrobial bacteremia (20.3% compared to 4.3%, P < 0.05). More complications (14.3%) such as abscesses, endocarditis, etc. appeared in the group of polymicrobial SBE (P < 0.05). No difference was observed in clinical course and outcome between monomicrobial and polymicrobial SBE. The incidence of SBE has increased since 1991, when quinolones were first used in prophylaxis in afebrile neutropenia at our center; however, the infection-associated mortality in monomicrobial SBE was low (4.3%).

Treatment of cancer chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma.

BACKGROUND: Chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (C-TTP/HUS) is a condition involving thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal dysfunction that develops in 2-10% of patients with a history of malignant neoplasms treated with certain chemotherapeutic agents. Pathogenesis of the disease may depend on the following: (1) generation of endothelial lesions in the kidney microvasculature, resulting from drug toxic effects and/or generation of small soluble circulating immune complexes (CIC), and (2) generation of autoantibodies and/or CIC that trigger aggregation and deposition of platelets around the lesions. METHODS: Extracorporeal immunoadsorption treatment of plasma (PROSORBA columns, IMRE Corporation, Seattle, WA) to remove immunoglobulin G and CIC was evaluated in 55 patients for the potential to induce significant clinical benefits (increase in platelet count, decrease in hemolysis, stabilization of renal function) and longer survival. RESULTS: Response to therapy was achieved in 25 of 55 patients examined. Response was associated with an estimated 1-year survival rate of 61%, as compared with an estimated survival rate of only 22% in those who did not respond (P = 0.0001). Patients whose malignant neoplasms were in complete or partial remission at the time of development of C-TTP/HUS had a significantly higher estimated 1-year survival rate (74%) as compared with a historic control group of patients receiving other treatments (22%, P = 0.0161). Clinical responses were correlated with normalization of serum levels of CIC and complement components C3c and C4. There were no side effects associated with 75% of treatments. Immunoadsorption therapy was associated with generally mild to moderate manageable side effects, such as fever, chills, nausea/vomiting, respiratory symptoms, pain, hypertension, and hypotension, which were reported in 25% of procedures. CONCLUSIONS: This multicenter study establishes protein A immunoadsorption as an effective and safe treatment for cancer chemotherapy-associated TTP/HUS, an otherwise fatal disease.

Ceftriaxone versus ceftazidime plus aminoglycoside therapy for infections in patients with neutropenia after cytotoxic chemotherapy. Short communication.

One hundred and one patients undergoing anticancer chemotherapy due to hematologic malignancy were retrospectively divided into two groups: 67 patients were treated with ceftriaxone plus amikacin, receiving once daily (od) 2-4 g ceftriaxone, 1-1.5 g amikacin (those without a peripheral or central venous catheter) and 34 patients with central or peripheral venous catheter (CPVC) receiving ceftizidime 2 g three times daily (tid) plus amikacin 0.5 g tid i.v. Both groups were similar as to their isolated pathogens, localization of infection, and basic diagnoses of hematologic malignancies. There was no significant difference in efficacy between ceftriaxone plus amikacin versus ceftazidime plus amikacin, but the toxicity was lower in once daily ceftriaxone plus amikacin group.

Ciprofloxacin plus vancomycin versus ceftazidime plus gentamicin in the treatment of pneumonia in granulocytopenic patients with or without venous catheters. Short communication.

58 granulocytopenic patients with confirmed bronchopneumonia were divided retrospectively into two groups for this pilot study: group 1 included neutropenic patients with venous catheters who were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) + vancomycin (VAN; 0.5-1 g, i.v. b.i.d.), and group 2, which included patients without venous catheters treated with ceftazidime (2 g, i.v. t.i.d.) + gentamicin (1 mg/kg, i.v. t.i.d.). Pneumonia was diagnosed clinically and radiologically in all patients; 92.3% in group 1 and 46.8% in group 2 were also microbially confirmed. Mixed infections were present in most patients. 3 of 26 patients (11.5%) in group 1 and 9 of 32 (20.1%) in group 2 did not recover while 88.5% in group 1 and 71.9% in group 2 recovered. CIP + VAN seems to be more effective in treating pneumonia in neutropenic patients, with only 1 patient in the group suffering an adverse effect compared with 5 in group 2.

Dynamic CT vs 0.5 T MR imaging in the detection of surgically proven hepatic metastases.

Seventeen patients with 52 surgically proven hepatic metastases were studied preoperatively with dynamic CT and 0.5 T magnetic resonance (MR). Dynamic CT detected 38 metastases (73%), and the combination of short echo time (T1-weighted) and T2-weighted pulse sequences detected 46 lesions (88%). Magnetic resonance was also superior at assessing potential resectability. This study suggests that MR excels in detecting and anatomically localizing individual hepatic metastases.

Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry.

A registry of suspected cases of cancer-associated hemolytic-uremic syndrome (C-HUS) was established in May 1984. Records of 85 patients from the registry, all with history of cancer, hematocrit less than or equal to 25%, platelet count less than 100,000, and serum creatinine greater than or equal to 1.6 mg/dL were subjected to in-depth analysis. Eighty-nine percent of patients had adenocarcinoma, including 26% with gastric cancer. Microangiopathic hemolysis was reported in 83 patients; coagulation studies were normal with rare exception. Bone marrow examination ruled out chemotherapy-induced myelosuppression in 68 of 85. Thirty-five percent of patients were without evident cancer at time of syndrome development. Mitomycin (MMC) was part of the treatment regimen in 84 patients; all but nine received a cumulative dose greater than 60 mg. Pulmonary edema, generally noncardiogenic, developed in 65% of patients, often after blood product transfusions. C-HUS has a high mortality: over 50% of patients died of or with syndrome, most within 8 weeks of syndrome development. Conventional treatment was ineffective, although ten of 21 treated with staphylococcal protein A (SPA) immunopheresis showed significant responses. Statistical analysis found only absence of obvious tumor and treatment with SPA to suggest favorable prognosis. C-HUS is distinguishable from related syndromes such as childhood HUS, thrombotic thrombocytopenic purpura (TTP), consumption coagulopathy, and microangiopathic hemolysis associated with advanced carcinoma. MMC is likely involved in the development of C-HUS; the risk of developing C-HUS after treatment with MMC is between 4% and 15%. However, possible bias in patients referred to the registry and reports of non-MMC C-HUS cases must be remembered. Recommendations include careful monitoring of renal and hematologic function in patients treated with MMC, aggressive nontransfusion in patients with suspected C-HUS, and consideration of treatment with SPA immunopheresis in patients with definite syndrome.

Cortical echogenicity in the hemolytic uremic syndrome: clinical correlation.

The initial renal sonograms of 15 patients, aged 8 months to 5 years, with hemolytic uremic syndrome (HUS) were reviewed. Ultrasound studies were graded according to cortical echogenicity relative to the liver, they were compared to the severity of the clinical syndrome at admission and to the ultimate outcome of the disease. The degree of cortical echogenicity correlated with the clinical outcome of HUS in 12 of the patients, whereas clinical assessment alone predicted outcome in 13 patients. Sonography overestimated severity in three patients with mild disease correctly assessed clinically, whereas clinical assessment overestimated severity in two patients with moderate disease in whom the sonographic assessment proved correct. The sonographic changes are most likely multifactorial. They appear to reflect a combination of platelet-thrombus deposition in the renal cortex, as well as the general fluid status of the patient. Ultrasound is useful in ruling out other causes of acute renal failure such as obstruction or congenital diseases. It cannot replace laboratory tests and clinical judgement, but nevertheless provides another index of severity in patients with HUS.

Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein A immunoperfusion.

Plasma perfusion over filters containing staphylococcal protein A (SPA) was used to treat 11 patients with adenocarcinoma who developed a hemolytic uremic syndrome. Immunoperfusion resulted in complete clearance of pretreatment elevated levels of circulating immune complexes in eight of the 11 patients with normalization of complement values depressed at the start of the therapy in seven. A significant rise in platelets and erythrocyte counts was achieved in nine patients, and stabilization of progressive renal impairment was achieved in six. The response was incomplete and short lived in three patients with clinically evident tumor recurrence, whereas long-term control of the syndrome was demonstrated in seven patients in complete tumor remission (no recurrence with median follow-up of 9 months). SPA immunoperfusion appears to be an effective form of therapy for this otherwise fatal syndrome.

Clinical experiences with extracorporeal immunoperfusion of plasma from cancer patients.

We have treated 11 patients having a variety of tumor types and three patients having mitomycin-C-associated thrombotic thrombocytopenic purpura (TTP) with extracorporeal plasma perfusion through filters containing immobilized protein A from Staphylococcus aureus. In performing more than 140 procedures we observed only minimal toxicity, of which fever, chills, nausea, and vomiting were the most common symptoms, occurring in 25% of the patients. Significant decrease in blood pressure and bronchospasm were rare complications. However, none of these side effects were severe enough to require therapeutic intervention. The antitumor effect of immunoperfusion was modest. In 10 adequately treated patients there was one measurable tumor reduction (40% decrease of original tumor mass). Two patients had correction of total small bowel obstruction, with return to normal food intake and restoration of normal bowel habits, lasting for 6 and 3 months; and two of the two adequately treated TTP patients had dramatic hematological improvement after four and five immunoperfusion treatments and are well at present. We found direct correlation between extent of complement activation and clinical toxicity. By temperature manipulation of the perfusion procedure we were able to control the above-mentioned side effects caused by complement activation.

Cytostasis of tumor cell lines by granulocytes from cancer patients and normal human donors.

Granulocytes of normal human donors were previously shown to have cytostatic activity in vitro against a variety of tumor cell lines. In the present study, we have compared the levels of granulocyte-mediated cytostatic activity in cancer patients and normal donors. In an initial study of 25 tumor-bearing patients and 21 individuals with benign or no disease, decreased cytostatic activity was observed in 84% of the cancer patients. Nine cancer patients with no evidence of disease had reactivity in the normal range. Granulocytes separated by a one-step method on a double Ficoll-Percoll gradient showed decreased reactivity. This procedure eliminated the differences previously detected between tumor-bearing patients and controls. Addition of either pooled normal AB human serum or autologous serum to the assay restored the reactivity. Only with autologous serum and not with allogeneic serum, were the differences between tumor-bearing patients and controls again seen. Therefore, in a subsequent study, we examined the effect of serum on cytostasis by normal granulocytes that were isolated on double gradients. We observed lowered serum restorative activity (SRA) in 41 of the 46 (89%) tumor-bearing patients tested. Fractionation of sera by Sephadex G-200 chromatography indicated that SRA of both cancer patients and normal donors was in the 100,000 molecular weight region.

Chédiak-Higashi gene in humans. II. The selectivity of the defect in natural-killer and antibody-dependent cell-mediated cytotoxicity function.

Antibody-dependent cell-mediated cytolysis (ADCC) of human tumor cells by FcR(+) nonadherent effector lymphocytes as well as natural killer (NK) activity was markedly impaired in Chediak-Steinbrinck-Higashi Syndrome (C-HS) patients. Compared to a more than 400-fold defect in NK activity in terms of lytic units, the abnormal ADCC response in C-HS donors was 24-fold below normal suggesting a partial but not complete overlap of lymphocytes or lytic mechanisms responsible for ADCC and NK. The ADCC mechanism against erythrocyte targets, however, was normal, thereby suggesting a qualitative difference in these two forms of ADCC. Other effector-cell functions against tumor-cell targets were normal as measured by (a) spontaneous cytolysis mediated by monocytes, (b) spontaneous cytostasis mediated by neutrophils, and (c) lectin-dependent cytolysis mediated by neutrophils. Although one C-HS patient was low in lectin-dependent cytolysis mediated by lymphocytes, the other C-HS patient was normal, thereby suggesting that cytolytic T function was not linked to the NK-ADCC defect. In addition, the proliferative response to T-dependent mitogens was also relatively normal. These results, combined with other studies showing normal cell-mediated and humoral immunity in these same patients, suggest that patients with C-HS have an immunodeficiency which is selective for NK and ADCC activity.

A new immunodeficiency disorder in humans involving NK cells.

Immunodeficiency disorders have provided much information on the development and interaction of the various B and T lymphoid components in the immune system of man. As the lymphoid system becomes increasingly divided into functional subsets of cells it will be important to find immunodeficiencies affecting newly discovered cell types. Natural killer (NK) cells are a recently described but ill-defined subpopulation of lymphocytes which is thought to play an important part in surveillance against tumour development. Mice homozygous for the beige gene were found to have a selective deficiency in NK function and were more susceptible to transplantation of syngeneic tumours as predicted. We report here that patients carrying the analogous, autosomal recessive Chediak-Higashi (CH) gene have a profound defect in their ability to spontaneously lyse various tumour cells in vitro by either antibody-dependent or independent mechanisms. Since other cell-mediated cytolytic functions were relatively normal, these results suggest that the beige or Chediak-Higashi gene in both man and mouse controls NK function.

Significance of radioimmunoassay of human chorionic gonadotropin and alpha fetoprotein in nonseminomatous germ cell tumors of the testis.

Radioimmunoassays of human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) made in 49 patients with nonseminomatous testicular tumors have shown that these investigations make the diagnosis more precise, permit to follow up the dynamics of the course of the disease and the effectiveness of treatment and may help to reveal the presence of otherwise undetectable tumorous metastases. The significance of the these assays is enhanced if the two tumorous proteins are investigated in parallel. The results proved rightly positive in 43 (87.8%) and falsely negative in 6 (12.2%) of the patients. The absence of HCG and AFP production in some of the patients with an active disorder has not as yet been elucidated.

The response rate at chemotherapy in advanced Hodgkin's disease reflected by peripheral lymphocyte count.

Forty patients with advanced Hodgkin's disease stage III and IV were treated with combination chemotherapy. Absolute lymphocyte count in the peripheral blood was determined before start to chemotherapy. Higher levels of lymphocytes in the peripheral blood were associated with higher chemotherapy response rates. This difference was statistically significant (P less than 0.05).

Change in the proportion of T and B lymphocytes in human malignant neoplasia in relation to the clinical stage.

Formation of spontaneous (E--erythrocyte) and immune (EAC--erythrocyte, antibody, complement) rosettes of sheep red blood cells (SRBC) with peripheral blood T and B lymphocytes, respectively, was used for quantitative assessment of these lymphocytes populations in tumor patients and control subjects. Relative counts of T and B lymphocytes have been correlated with lymphocyte survival in short-term cultures using standard subtoxic doses of phytohemagglutinin (PHA). The mean values and SE in normal control subjects for E rosettes (T lymphocytes) were 72.8 +/- 1.2%, for EAC rosettes (B lymphocytes) 23.8 +/- 2.5% of lymphocyte population. The survival of lymphocytes in short-term cultures with PHA in control subjects was 55.3 +/- 1.1%. In tumor patients the counts of E, EAC rosettes and percentage of lymphocyte survival in short-term PHA cultures were dependent upon the clinical stage. In patients with localized tumors the values were similar to controls. In patients where dissemination of the tumorous process could be ascertained a decrease of T lymphocyte counts, an increase of B lymphocyte counts and a higher survival of peripheral blood lymphocytes in short-term cultures with PHA was found.