John D. Crissman

Concomitant Cisplatin Chemotherapy and Radiotherapy in Advanced Mucosal Squamous Cell Carcinoma of the Head and Neck Long-Term Results of the Radiation Therapy Oncology Group Study 81-17

One hundred twenty‐four eligible patients with advanced mucosal squamous cell carcinoma of the head and neck were entered into a pilot study of concomitant cisplatin (100 mg/m2 given every 3 weeks for three doses) and standard irradiation. The initial complete response (CR) was 71% with an additional two cases salvaged by surgery for an overall 73% CR. When no keratin was identified in the histologic specimen (41 patients) the CR was 90%. The nasopharynx showed the best CR (89%) among the sites. At 4 years after treatment, the estimated locoregional tumor control rate was 43% and the survival, 34%. When no keratin was present in the specimen, the estimated locoregional control of tumor was superior (56% versus 38% with keratin identified, P = 0.02) and the estimated survival was also superior (48% versus 26%, P = 0.008). Acute treatment‐related toxicities included one death due to renal damage and two patients with life‐threatening renal damage. The delivery of radiotherapy was not altered. Late toxicity included necrosis −3%, fibrosis −4%, and one fistula. The results of this study justify a randomized trial for the comparison of this combination of cisplatin and radiotherapy versus radiotherapy alone in advanced mucosal carcinomas of the head and neck.

A comparative immunohistochemical study of peritoneal and ovarian serous tumors, and mesotheliomas

The distinction between serous neoplasms of the peritoneum in women and conventional mesothelioma can be difficult. In order to determine any significant immunohistochemical differences, formalin-fixed, paraffin-embedded sections of 10 peritoneal serous tumors (PST), 10 ovarian serous tumors (OST), and 10 epithelial mesotheliomas were evaluated with a panel of 10 antibodies directed against carcinoembryonic antigen (CEA: polyclonal, monoclonal), high molecular weight keratin (34 beta E12), low molecular weight keratin (35 beta H11), Leu-M1, TAG-72 (monoclonal antibody B72.3), human milk fat globulin (HMFG-2), vimentin, placental alkaline phosphatase (PLAP), and S-100 protein. The antibodies CEA, Leu-M1, and B72.3 had the most discriminatory value in differentiating serous tumors from mesothelioma. Eighty-five percent of PSTs and OSTs (17 of 20) were positive with CEA, Leu-M1, and/or B72.3. None of the mesotheliomas stained for CEA or Leu-M1; three mesotheliomas had very focal positivity with B72.3 (1% or less). Vimentin, PLAP, HMGF-2, keratin, and S-100 had no significant discriminatory value. Epithelial mucin was present in 80% of serous tumors, while the mesotheliomas lacked epithelial mucin. Leu-M1, CEA, and/or B72.3 positivity in a peritoneal tumor supports a diagnosis of serous tumor. However, since some PST do not stain for any of the three antibodies and the focal nature of positive reactions in some cases may be difficult to interpret, exclusion of mesotheliomas is enhanced by the use of mucin stains.

Inhibitory properties of low molecular mass cysteine proteinase inhibitors from human sarcoma.

Elevated activities of cysteine proteinases such as cathepsins B and L and cancer procoagulant have been linked to tumor malignancy. In the present study we examined the hypothesis that these elevated activities could be due to impaired regulation by the endogenous low molecular mass cysteine proteinase inhibitors (cystatins). Inhibitors from human sarcoma were compared to those from human liver, a normal tissue in which the inhibitors had been characterized previously. An extract of cystatins from sarcoma was less effective against papain and cathepsin B (liver or tumor) than was an extract from liver. This reduced inhibitory capacity in sarcoma was not due to a reduction in either the concentrations or specific activities of the cystatins or an absence of any family or isoform of cystatins. We purified two members of the cystatin superfamily (stefin A and stefin B) to homogeneity and determined their individual inhibitory properties. Stefins B from liver and sarcoma exhibited comparable inhibition of papain and cathepsin B. In contrast, stefin A from sarcoma exhibited a reduced ability to inhibit papain, human liver cathepsins B, H and L and human and murine tumor cathepsin B. The Ki for inhibition of liver cathepsin B by sarcoma stefin A was 10-fold higher than that for inhibition of liver cathepsin B by liver stefin A, reflecting a reduction in the rate constant for association and an increase in the rate constant for dissociation. Cancer is now the third pathologic condition reported to be associated with alterations in cystatins, the other two being amyloidosis and muscular dystrophy.

Osteosarcomas and chondrosarcomas of the jaws: immunohistochemical correlations.

Clinical, microscopic, and immunohistochemical characteristics of 17 jaw sarcomas are reported. Histologic subtypes included chondroblastic (five), fibroblastic (five), osteoblastic (three), telangiectatic (one), parosteal (two), and chondrosarcoma (one). Reactivity for all antigenic markers in decalcified tissue was judged to be comparable to nondecalcified tissue. All neoplasms were nonreactive for muramidase and leukocyte common antigen. alpha-1 Antichymotrypsin and HLA-DR immunoreactivity was found focally. Positive S-100 staining was found predominantly in chondrocytes. All tumors were positive for vimentin. Cells in focal zones of cartilage were positive for keratin. No distinctive pattern emerged relative to clinical recurrence and histologic subtype or immunotype. Leukocyte common antigen determinations were useful because they distinguished between neoplastic and inflammatory cells. S-100 protein stains helped in the subclassification of chondroblastic osteosarcoma, and vimentin stains confirmed mesenchymal origin. Cross-reactive staining of cartilage with keratin antibodies was regarded as a possible diagnostic pitfall.

Applications for Antimetastatic Therapies

The development of therapies directed toward either interrupting the metastatic cascade or decreasing its efficiency is an intriguing concept. For the most part, clinicians and scientists have concentrated their efforts on achieving a cure of malignant neoplasms. Therapies which decrease the efficiency of the metastatic cascade have been viewed as palliative. Surgery and/or radiation therapy are the traditional and most effective methods to excise or sterilize primary and regional disease. However, cure is unlikely if successful metastatic foci have been established prior to or during initial treatment. Small metastases are not often identifiable at the time of initial diagnosis and treatment. Careful clinical staging will usually uncover large metastatic deposits in organs accessible to non-invasive maneuvers. Newer technologies (i.e., CT scans) have resulted in an increased identification of smaller metastases. Cytotoxic chemotherapy was originally reserved for palliative therapy of patients with documented disseminated cancer. Nevertheless, in selected cancers, patients with a high probability of microscopic tumor spread are commonly treated systemically with single or combination cytotoxic chemotherapy. The major exception to this is the use of hormonal therapy for neoplasms arising in the accessory sex organs. In the last decade cytotoxic chemotherapy has improved dramatically resulting in the successful treatment of many types of leukemia, lymphoma and germ cell tumors. Remarkable cytoreduction has occurred in these tumors with a significant number of patients surviving for ≥ 5 years. Unfortunately, similar success has not been evident with the more common carcinomas.

Cathepsin B-Like Cysteine Proteinases and Metastasis

During the process of metastasis tumor cells traverse several extracellular matrix barriers in order to gain entry to the vascular space at the site of the primary tumor and to the perivascular space at the sites of metastatic tumors. A number of in vitro model systems have been designed to study tumor cell invasion through extracellular matrices. Several of these model systems including systems to study the concomitant digestion of these matrices by tumor cells are discussed elsewhere in this volume (see Chapters 18–21). A focus of much recent research is the basement membrane which underlies endothelial cells. The physical location of the basement membrane suggests that it must be traversed for tumor cells to form hematogenous metastases. Since the basement membrane in contrast to other extracellular matrix barriers contains type IV collagen a number of investigators have hypothesized that tumor cells must be able to degrade type IV collagen in order to invade through the basement membrane (see also Chapter 19). Metastatic variants of the B16 melanoma have been shown to secrete a type IV collagenase (1). However, type IV collagenase is secreted by tumor cells in a latent form which requires activation (2) suggesting that type IV collagenase is not by itself sufficient for basement membrane invasion by tumor cells and that additional proteinases or a proteolytic cascade may participate in basement membrane invasion.