Phase II trail of didemnin B in previously treated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group (ECOG) Study.

Patients with non-Hodgkin's lymphoma (NHL) who fail initial therapy have a poor prognosis. We conducted a phase II study to determine the efficacy and toxicity of didemnin B, a non-myelosuppressive marine compound, in patients with NHL who relapsed or progressed after receiving one or two previous chemotherapy regimens. Fifty-one eligible patients were registered on this phase II study. Twenty-nine patients had intermediate or high grade (IG/HG) disease and 22 patients had low grade (LG) disease. Twenty-five patients received didemnin B at a dose of 6.3 mg/m2 and the remainder received 5.6 mg/m2, administered intravenously every 28 days. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and biopsy-proven relapsed disease. Objective responses were observed in two (7%) patients (one complete remission [CR] and one partial remission [PR]) with IG/HG disease and five (23%) patients (one CR and four PR) with LG disease. Patients with IG/HG disease had a median time to treatment failure (TTF) of 1.6 months and a median survival of 8.0 months. In contrast, the group with LG disease had a median TTF of 4.6 months and a median survival of 2.7 years. There were five grade V, 12 grade IV, and 57 grade III toxicities. Didemnin B appears to have modest activity in low grade NHL. However, the drug has considerable toxicity in this population of patients.

Phase II study of etoposide (VP-16) in patients with thyroid cancer with no prior chemotherapy: an Eastern Cooperative Oncology Group Study (E1385).

This study of etoposide in thyroid cancer was designed to determine the activity and toxicity of etoposide in a variety of inoperable, thyroid hormone insensitive, and radio-iodine resistant primary cancers of the thyroid. The patients were required to have an ECOG performance status of at least 3 and no previous exposure to chemotherapy. The etoposide was given at a dose of 140 mg/m2 daily for 3 days and every 3 weeks until progression. The study was closed after 18 months because of poor accrual. There were no responses seen among the 10 patients accrued. The toxicity was primarily hematologic. There was no evidence of activity of etoposide in thyroid carcinoma, although this study lacked significant power because of the poor accrual.

Morphology and other prognostic factors of hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma is a malignancy found worldwide that has typically poor prognosis despite treatment. Although several studies have dealt with prognostic factors, just a few detailed analyses of large series correlating the pathology of hepatocellular carcinoma with prognosis are available. The present study was undertaken to address this limitation. PATIENTS AND METHODS: Our prior clinical study described 432 patients, but sufficient tissue was available for evaluation in only 299 patients. Of these, 224 samples contained primary hepatocellular carcinoma, while the remainder contained only metastatic tumor. Characteristics evaluated included degree of tumor differentiation, associated cirrhosis or hepatitis, presence of cytoplasmic inclusion bodies, and blood vessel invasion by the neoplasm. RESULTS: Of the 224 patients, 71% were male, 65% white, and 73% over the age of 45 years. Ninety-one percent were from North America. A total of 42 patients were found to have cirrhosis. Thirty-five percent had cytoplasmic inclusion bodies, and 25% showed evidence of blood vessel invasion. Tumor response rates (tumor shrinkage) were low (8%) regardless of treatment. Presence of cytoplasmic eosinophilic inclusion bodies and blood vessel invasion were not associated with increased survival. Some histopathologies (pelioid, spindle cell, fibrolamellar) were associated with a better prognosis. Patients with a predominant trabecular pattern (43%) did particularly poorly. Although sex was significantly associated with survival using a univariate analysis, this effect disappeared in a multivariate Cox model that adjusted simultaneously for other factors. CONCLUSION: This investigation suggests that histologic subtype and clinical features may provide useful prognostic information in hepatocellular carcinoma. Poorer survival was observed in males, older patients with poorly differentiated tumors, or when associated with cirrhosis. Age younger than 45 years was a good prognostic factor, and presence of cirrhosis had an adverse effect on survival.

Coexistence of granular cell tumor and ipsilateral infiltrating ductal carcinoma of the breast.

Granular cell tumor is a benign neoplasm that is rarely seen in the breast and can mimic carcinoma, both clinically and by gross pathologic examination. The coexistence of a granular cell tumor with a primary mammary carcinoma can potentially pose diagnostic and therapeutic problems. In this report, we document a granular cell tumor of the breast coexisting with an ipsilateral infiltrating ductal carcinoma in a 74-year-old woman and discuss its clinical significance.

Parotid involvement by desmoplastic melanoma.

Desmoplastic malignant melanoma often arises in sun damaged skin of the head and neck and shows frequent neurotropism. Although metastatic melanoma frequently involve the parotid, direct spread to the parotid has been rarely reported. We evaluated five cases of desmoplastic malignant melanoma involving the parotid gland with clinical and pathological evidence of precursor cutaneous lesions in four of the five cases. The parotid involvement in four cases was tumoural, and three of these were not clinically suspected to be melanoma. The histological appearance in all five cases was that of a sarcomatoid tumour. Immunohistochemistry and electronmicroscopy performed on three of the cases showed only evidence of schwannian differentiation: the tumour cells were positive for S-100 protein and vimentin, and negative for cytokeratin and HMB-45. Electronmicroscopy showed no evidence of melanogenesis. All five tumours showed histological evidence of prominent neurotropism with one case demonstrating extension from overlying skin along cutaneous nerves to the superficial parotid. Thus, desmoplastic malignant melanoma may involve the parotid by neurotropic spread and can be pathologically indistinguishable from malignant schwannoma, a diagnosis which may be made erroneously in the absence of clinical information.

Benztropine identification and quantitation in a suicidal overdose.

For a human fatality involving suspected overdose with the anticholinergic agent benztropine, GC-MS analysis was utilized for identification, quantitation, and investigation of metabolism. Organic extracts of blood and urine were analyzed by a capillary-column gas chromatograph interfaced with an ion-trap mass spectrometer, which was programmed for wide-spectrum data acquisition. Electron impact and chemical ionization were used for benztropine detection. The chemical structures of the ion fragments are proposed. Benztropine-d3 was synthesized and used as an internal standard. Quantitative determinations of benztropine revealed 0.183 mg/L in blood and 7.12 mg/L in urine from the decedent. Drug concentrations were interpreted relative to the case findings, published data, and a limited evaluation of the therapeutic concentrations in psychiatric patients. In addition, the possible metabolic conversion to norbenztropine was investigated by the synthesis of the norbenztropine derivative. Chromatographic evaluation of samples from the case study did not reveal significant bioconversion via the N-desmethylation pathway.

Ovarian endometriotic cysts. An analysis of cytologic atypia and DNA ploidy patterns.

Cytologic atypia may be seen in the glandular epithelium that lines ovarian endometriotic cysts. The significance of this atypia has not been fully elucidated. The authors studied the morphologic appearance and DNA ploidy of the glandular epithelium from 36 ovarian endometriotic cysts by image analysis on formalin-fixed paraffin-embedded tissue sections. In 29 of the cases the corresponding endometrium proper also was studied. The DNA content was diploid in all eutopic endometrium and in the lining epithelium of all endometriotic cysts without atypia or with only mild cytologic atypia. DNA aneuploidy was observed in 3 of 6 endometriotic cysts with severe atypia. Our findings indicate that mild cytologic atypia in the glandular epithelium of endometriotic cysts is associated with normal DNA ploidy patterns, whereas severe atypia may be associated with aneuploidy. These findings support the hypothesis that cytologic atypia represents the precursor lesion for the invasive epithelial malignancy that may arise in ovarian endometriotic cysts.

Renal angiomyolipoma. DNA content and immunohistochemical study of classic and multicentric variants.

Angiomyolipomas (AMLs) are polymorphic renal tumors that are composed of mature tissues and frequently associated with tuberous sclerosis; AMLs have long been considered hamartomatous in nature. We report the routine histologic and immunohistochemical features and DNA content analysis of two fatal cases of renal giant multicentric AML with distant organ involvement, and we contrast the findings with those of four similarly studied cases of classic solitary AML. Severe nuclear pleomorphism, significant mitotic activity, and necrosis, which are all characteristics of multicentric AML, were not seen in the cases of classic AML. Quantitation of DNA by image analysis of Feulgen-stained slides from paraffin-embedded blocks revealed an aneuploid pattern in the two cases of multicentric AML and an aneuploid pattern in one of the four cases of classic AML. Tumors in the liver, spleen, and lungs in one of the cases of multicentric AML were diploid. Immunohistochemical analysis revealed positive staining reaction of vascular and adipose tissue components with HMB-45 antibody in three of the six cases of AML. We conclude that AMLs may occur in a sarcomatous, infiltrating multicentric form involving multiple organs, that aneuploidy may be seen in lesions of both the multicentric AML and classic AML variants, that AMLs may feature DNA ploidy heterogeneity in multiple-organ sites, that HMB-45 immunoreactivity may be encountered in AMLs without evidence of nevomelanocytic differentiation, and that continued study of AMLs is needed to clarify further the histogenesis, lineage, clonality, and malignant potential of these tumors.

Expression of colorectal carcinoma-associated antigens in colonic polyps.

Immunohistologic techniques were used to study the expression of colorectal carcinoma-associated antigens in colonic polyps and to compare this with expression in the normal colonic epithelium. Forty-nine polyps were studied using monoclonal antibodies to 16 different blood group and differentiation antigens and carcinoembryonic antigen epitopes. With the Lewis(a) antigen and the two epitopes of CEA recognized by 3D6 and COL-4 expression in polyp tissue was the same as that in the normal colon. Five types of alteration of antigen expression in polyps were seen. The blood group antigens A, B, and Lewis(b), which are expressed only on the right side of the normal adult colon, were detected in both neoplastic and nonneoplastic polyps from the distal colon. The Lewis(x) antigen and the antigen epitopes detected by the antibodies COL-12, CA19-9, ME491, and GA73.3 showed an increased frequency of expression in all types of polyps in comparison with the normal colonic epithelium, while H-type 2, ND4, and the antigen epitope detected by CO29.11 showed a slightly decreased frequency of expression in polyp tissue. The X-like antigen which was expressed in only 7% of normal colon specimens showed increased frequency of expression in polyp tissue with significantly greater expression in neoplastic than hyperplastic lesions (P = 0.003). The TAG-72 antigen was detected only in adenomas with severe dysplasia (P = 0.01), correlating well with premalignant histology. These findings have helped us clarify the variation of antigen expression in colonic polyps and allowed us to define which antigens are worthy of further investigation as markers of possible malignant transformation.

Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphoma.

PURPOSE: To determine the toxicity, response, and survival rate of orally administered combination chemotherapy in patients with AIDS-related intermediate- and high-grade non-Hodgkin's lymphoma. Secondary objectives included prospective quality-of-life assessment and quantitation of cell-associated p24 antigen (p24 Ag) by flow cytometry. PATIENTS AND METHODS: Eighteen patients with biopsy-proven lymphoma were treated with oral chemotherapy consisting of lomustine (CCNU) 100 mg/m2 on day 1, etoposide 200 mg/m2 on days 1 through 3; cyclophosphamide 100 mg/m2 on days 22 through 31, and procarbazine 100 mg/m2 on days 22 through 31 at 6-week intervals. A variety of clinical assessments were performed: prospective quality-of-life assessment using the Functional Living Index-Cancer (FLIC) and Brief Symptom Inventory (BSI) instruments; indirect immunofluorescence with flow cytometry to measure cell-associated p24 antigen; and price of the oral regimen compared with two other intravenous combination chemotherapy regimens. RESULTS: The overall objective response rate using Eastern Cooperative Oncology Group (ECOG) criteria was 61% (95% confidence interval, 39% to 84%), with seven complete remissions (39%) and four partial remissions (22%). The median survival duration was 7 months, with a range of 11 days to 36 months. The treatment-related mortality rate was 11%. One patient developed CNS progression. Myelosuppression was the most frequent and severe toxicity encountered. Predictor variables of performance status (PS), prior history of thrush, and CD4 lymphocyte count were found to be of prognostic value. In a separate analysis, scores on the three subscales of the BSI were also found to be predictive of complete response. The price of this regimen is several thousand dollars less than that of other intravenous combination chemotherapy regimens. CONCLUSION: This regimen is active in patients with AIDS-related non-Hodgkin's lymphoma. Because it is important to design systemic cytotoxic chemotherapy regimens that are cost-effective, considerate of quality-of-life issues, and efficacious in this patient population, this approach should be compared with standard intravenous combination chemotherapy regimens in randomized controlled clinical trials.

Modified vincristine, doxorubicin, and dexamethasone regimen in the treatment of resistant or relapsed chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group study.

BACKGROUND: Thirty-six patients with relapsing or refractory chronic lymphocytic leukemia were entered into a Phase II study of the Eastern Cooperative Oncology Group. METHODS: A modified VAD regimen was given: a 96-hour infusion of 1.6 mg vincristine and 36 mg/m2 doxorubicin with dexamethasone 40 mg by mouth daily for 4 days every 3 weeks. The treatment was continued until two cycles beyond maximal response, which was evaluated after two and six cycles. RESULTS: Of the 33 evaluable patients, 7 (21%) achieved a partial response (PR), with no complete remissions. One-third of the patients (11 of 33) had progressive disease and 15 of 33 (45%) had stable disease, as defined by the National Cancer Institute Working Group criteria. The median duration of PR was 6.5 months, with a median survival time of 14.8 months. A PR was achieved by 3 of 19 patients (16%) who had received prior vincristine +/- doxorubicin and 4 of 14 patients (28%) who had not received vincristine or doxorubicin. Of the nine patients whose disease was refractory to prior therapy, five (55%) achieved a PR. The neurotoxicity of VAD was reduced by decreasing the frequency of the dexamethasone, but 22 of 36 (61%) patients still became infected. Only on infection (2.8%) was life threatening, and there were no infectious deaths. CONCLUSIONS: Because fludarabine has shown superior responses, VAD should be reserved for patients who do not respond to alkylating agents and fludarabine and in whom alternative treatments are not appropriate.

Immunohistochemical analysis of small cell tumors of the thyroid gland: an Eastern Cooperative Oncology Group study.

The majority of small cell anaplastic tumors of the thyroid gland are generally believed to be non-Hodgkin's lymphomas, including most of those formerly classified as small cell carcinomas. Using a panel of antibodies capable of detecting epithelial, neuroendocrine, and B and T cells in paraffin-embedded tissue sections, we studied 68 thyroid neoplasms in which the original diagnosis was small cell carcinoma or lymphoma. Sixty-three of the tumors were identified as lymphomas of B-cell origin on the basis of L26 reactivity used in conjunction with light chain restriction and MB2 immunostaining. Two additional tumors were classified as lymphomas of indeterminate phenotype. Immunophenotyping indicated an epithelial origin in the remaining three tumors. No cases of medullary carcinoma were detected by immunostaining. Histologic review revealed a predominance of large cell and immunoblastic lymphomas, with low-grade lymphomas of mucosa-associated lymphoid tissue histology accounting for only five cases. Our findings indicate that the majority of small cell anaplastic tumors of the thyroid are B-cell lymphomas. Although primary small cell carcinoma of the thyroid may rarely occur, this diagnosis should not be made without immunohistologic confirmation.

A comparison between the Rappaport Classification and Working Formulation in cooperative group trials: the ECOG experience.

The Working Formulation (WF) for the classification of non-Hodgkin's lymphomas was shown to be reproducible and clinically relevant in the original study. However, it has not yet been tested by an NCI-supported cooperative clinical oncology group. As a result, the Hematopathology Subcommittee of the Eastern Cooperative Oncology Group (ECOG) undertook a retrospective study to compare concordance and practical utility between the WF and the Rappaport Classification (RC). Data indicate that with appropriate modifications to minimize unclassifiable lymphomas, the WF can be effectively utilized in cooperative clinical oncology groups.

The predictive value of bone marrow morphologic characteristics and immunostaining in primary (AL) amyloidosis.

The authors previously demonstrated that bone marrow plasmacytosis in primary (AL) amyloidosis may be monoclonal or polyclonal. However, the clinical implications of the degree of plasmacytosis and its clonality have not been studied. The authors evaluated 62 patients with AL amyloidosis, 40 of whom had monoclonal medullary plasma cells. There was complete concordance between the light chain class of the plasma cells in the monoclonal cases and that of the circulating paraprotein in the 22 cases associated with a paraprotein. The remaining 22 patients had polyclonal plasma cells, although a paraprotein was detected in 6. The degree of plasmacytosis was significantly higher among patients with monoclonal plasma cells and correlated inversely with length of survival. The authors' findings indicate that the quantitation of bone marrow plasma cells in AL amyloidosis by immunoperoxidase studies may predict the clinical course.

An evaluation of immunohistologic stains for immunoglobulin light chains in bone marrow biopsies in benign and malignant plasma cell proliferations.

Bone marrow specimens from 226 patients with a variety of benign and malignant plasma cell proliferations were studied to assess the reliability of immunohistologic studies in their evaluation. The clonality of the bone marrow plasma cells was compared with results of serum and urine electrophoreses. Discordance was observed most frequently in cases in which a paraprotein was demonstrated, but no monoclonality was detected by immunoperoxidase (16 cases). Of these 16 cases, 9 had 5% or less bone marrow plasma cells. In only one case was the light chain class of the bone marrow plasma cells different from that of the paraprotein. If discordant cases with 5% or less plasma cells are eliminated, the overall concordance was 97%. The authors' findings indicate that immunohistologic studies for immunoglobulin light chains in Zenker-fixed decalcified bone marrow biopsy sections are reliable in the evaluation of patients with plasma cell proliferations when the marrow contains more than 5% plasma cells.

Inhibition of sialic acid incorporation prevents hepatic metastases.

It has been hypothesized that the metastatic capacity of tumors may be correlated with hypersialylation of the cell surface. We used a novel inhibitor of sialic acid incorporation, KI-8110, to determine the effect of depletion of cell surface sialic acid on the metastatic behavior of three human colorectal cancer cell lines, in which hepatic seeding was related to tumor cell differentiation. Treatment of tumor cells with KI-8110 prior to intrasplenic injection prevented liver colonization. Total cellular sialic acid was reduced, as was that of the cell surface. Secreted forms of carcinoembryonic antigen also were depleted of sialic acid by this treatment. These data show that depletion of sialic acid from cell surface glycoconjugates reduces the incidence of hepatic metastases from human colorectal primary tumors and adds to the mounting evidence of the importance of sialic acid in determining the biological behavior of tumor cells.

The detection of Epstein-Barr virus in hairy cell leukemia cells by in situ hybridization.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of several B-cell lymphoid proliferations. Because patients with hairy cell leukemia (HCL) have a high incidence of seropositivity for EBV antigens, we studied the cells of HCL for evidence of EBV infection using in situ hybridization techniques. EBV mRNA was detected in the tumor cells in four of six cases using a radiolabeled RNA probe. Confirmatory serologic data were available in three cases in which the viral DNA was detected and in one negative case. Our results suggest that EBV infection may have a pathogenetic role in this disorder.

Non-Hodgkin's lymphomas of the gastrointestinal tract. An evaluation of paraffin section immunostaining.

Although the gastrointestinal (GI) tract is the most common site of primary extranodal lymphomas, the lineage of these tumors has been controversial. The authors used paraffin-reactive antibodies detecting markers of B-, T-, histiocytic, and epithelial cells to study 34 non-Hodgkin's lymphomas of the GI tract for which unequivocal frozen-section immunophenotypine was available as a control to determine whether these antibodies are reliable in the study of these tumors. Frozen-section studies revealed 31 tumors of B-cell origin and three T-cell tumors. Paraffin-reactive antibodies confirmed B-cell lineage in 28 of the 31 cases, with equivocal results in the remaining three. Only one of the T-cell lymphomas was identified in paraffin studies. Our results indicate that paraffin-reactive antibodies can reliably identify most B-cell lymphomas in the GI tract but may be unreliable in the detection of lymphomas of T-cell origin.