Paul B. Chretien

Lymphocyte reactivity in cancer patients: correlation with tumor histology and clinical stage.

The in vitro reactivity of peripheral blood lymphocytes and the effect of serum on normal lymphocyte reactivity was determined in 89 patients with non‐lymphoid tumors by quantitation of phytohemagglutinin (PHA)‐induced tritiated thymidine incorporation. The reactivity of lymphocytes from patients with sarcomas and squamous carcinomas was impaired, and their sera suppressed normal lymphocyte reactivity. The cellular and serum abnormalities coexisted in patients with sarcomas but occurred independently in patients with squamous carcinomas. Patients with melanomas and adenocarcinomas did not differ from controls by these parameters. With the exception of patients with melanomas, a similar incidence of abnormalities occurred in patients with localized tumors and those with metastases. These data indicate that this test system assays certain early and tumor histology‐related aspects of the hosttumor relationship and is potentially useful for the study of factors associated with development of cancer and monitoring effect of tumor treatment.

A Method for Dinitrochlorobenzene Contact Sensitization: A Clinicopathological Study

Abstract To facilitate measurement of cell-mediated immune responses, a method for quantitative clinical evaluation of contact sensitization to dinitrochlorobenzene (DNCB) was devised and used in 40 patients with cancer. When a sensitizing dose is applied, the immediate reaction produced expresses a general inflammatory response. Sensitization is expressed by the occurrence of a spontaneous flare seven to 14 days later, or by the reaction to a challenge dose of DNCB. Equivocal reactions require histologic examination. Use of a sensitizing dose of 2000 μg and a relatively weak challenge dose of 50 μg yielded a satisfactory incidence of sensitization with a low proportion of irritative inflammatory reactions.

Abnormalities of quantitative dinitrochlorobenzene sensitization in cancer patients: Correlation with tumor stage and histology

Cellular immune responses in 103 patients with non‐lymphoid cancers were compared with those in 143 healthy controls using quantitative DNCB contact sensitization. Differences were demonstrated between cancer patients and controls at all levels of reactivity measured. Cancer patients had a lower incidence of spontaneous flare reactions (40.8 vs. 96.5 in controls), a higher incidence of impaired reactivity (29.1% vs. 0.7% in controls), and a higher incidence of anergy (30.1% vs. 2.8% in controls). All anergic cancer patients and all but one control developed a chemical irritation reaction to the sensitizing dose of DNCB. While abnormal reactivity occurred in all histologic tumor types studied, a significant relationship was shown between tumor histology and the distribution of abnormalities. Reactivity was most abnormal in patients with squamous cell carcinoma (43% anergic, 27% impaired reactivity), less in patients with melanoma (25% anergic, 44% impaired) and adenocarcinoma (26% anergic, 27% impaired), and least in patients with sarcoma (13% anergic, 25% impaired). With the exception of patients with sarcoma, the incidence of impaired cellular reactivity was similar in patients with clinically localized cancer (61%) and in patients with disseminated cancer (60%).

The ethmoid sinuses: A re-evaluation of surgical resection*

Summary The combined intracranial transfacial approach to the ethmoid, sphenoid, and frontal sinuses has been satisfactory in performing en bloc resection of cancer arising in or involving these anatomic areas. Fifty-four patients have been treated with this procedure, using the combined expertise of the neurosurgeon and the surgeon interested in the head and neck area. Two postoperative deaths have occurred, both attributed to meningitis. The long range postoperative morbidity is negligible, except as it relates to loss of the palate in all but eight patients and the orbital contents in thirty patients. The cumulative five year survival in this series of patients, forty-two of whom had failure of previous treatment, is 56 per cent. If the procedure is carried out with rigid attention to good surgical technic and the principles of en bloc tumor removal, this combined procedure has the following advantages: (1) allows accurate evaluation of the intracranial tumor extension, (2) protects the brain, (3) avoids cerebrospinal fistulization, (4) provides adequate hemostasis, (5) facilitates en bloc tumor resection, and (6) selectively conserves the orbital contents.

Antibodies to Herpesvirus Nonvirion Antigens in Squamous Carcinomas

Serums from tumor-bearing patients, cured patients, and normal subjects were examined for antibodies to the separated complement-fixing reactive components of nonvirion antigens of herpesvirus type 1 and type 2. The occurrence of antibodies to the antigens was similar in serums from tumor-bearing patients and cured patients. Antibodies to the antigens were observed among 21 of 24 (87 percent) cervical cancer cases, 44 of 49 (90 percent) laryngeal cancer cases, 15 of 24 (62 percent) cases of squamous cell carcinomas of the head and neck excluding the larynx, 2 of 24 (8 percent) nonsquamous cell cancer cases, and 3 of 51 (6 percent) normal subjects. By contrast, no differences were found in the titers of neutralizing antibodies to the virus in serums from laryngeal cancer patients and controls. The observations support an etiologic role of herpesviruses in cervical cancer and in laryngeal cancer, and possibly other squamous cell cancers of the head and neck.

Cellular immunity in cured cancer patients

Cellular immune competence was quantitated in 100 postoperative cancer patients considered clinically free of tumor and compared with that of 200 preoperative cancer patients and over 400 cancer‐free persons. Immunity was assessed by in vitro phytohemagglutinin (PHA)‐induced lymphocyte reactivity and in vivo dinitrochlorobenzene (DNCB) contact sensitivity. The immune reactivity of the cured cancer patients correlated with the histology of the tumor previously excised. Patients cured of squamous carcinomas had high incidences of impairment of lymphocyte reactivity and DNCB contact sensitivity similar to that found in preoperative patients. Patients with sarcomas, melanomas, and adenocarcinomas, however, had lymphocyte reactivity higher than both their preoperative counterparts and normal subjects, and did not display the abnormalities of DNCB contact sensitivity present in the comparable preoperative groups. A suppressant effect on lymphocyte reactivity of sera from preoperative patients with squamous carcinomas and sarcomas also occurred with sera from cured squamous carcinoma patients. The persisting high incidence of impaired cellular immunity in patients cured of squamous carcinomas indicates the need for investigation of genetic and environmental factors which may be responsible for the defects and determination of their relation to tumor induction. Treatment of these tumors may be improved by monitoring immune reactivity during therapy and by regimens that correct these defects. The intact cellular immune competence of patients clinically cured of sarcomas, melanomas, and adenocarcinomas indicates that patients treated for tumors of these histologic types who display abnormalities by the assays used may be suspected of having residual tumor.

CEA levels in head and neck cancer

Serum carcinoembryonic antigen (CEA) levels were determined for 439 patients with squamous carcinoma of the head and neck region, 154 healthy smokers, and 122 nonsmokers. Among nonsmokers 95% of the CEA levels did not exceed 5 ng/ml, but among smokers this discriminatory level was 7 ng/ml. Among tumor‐bearing patients 36% of the CEA levels exceeded 5 ng/ml but only 17% exceeded 7 ng/ml. Both the incidence and magnitude of CEA elevations correlated with clinical stage of tumor; however, excluding patients with clinically apparent advanced malignancies, the incidence and magnitude of elevations were similar among tumor‐bearing patients, tumor‐free treated patients, and smokers. Although not predictive of ultimate survival, elevated preoperative CEA levels declined to the range of normals after resection. Similarly, during palliative irradiation for incurable tumors, CEA levels declined with regression of tumor. Irradiation did not nonspecifically elevate CEA levels. The data indicate that in patients with head and neck squamous carcinomas CEA level is not likely to contribute to a determination of prognosis after therapy; however, serial determinations may have adjunctive value in monitoring tumor response.

Prolonged depression of cellular immunity in cured laryngopharyngeal cancer patients treated with radiation therapy

Immune competence was evaluated in cured patients who had been treated by irradiation for carcinoma of the laryngopharynx, and compared with that of similar patients treated by surgery alone, and normal controls. Cellular immunity was determined by quantitation of in vitro phytohemagglutinin (PHA)‐induced lymphocyte reactivity and peripheral blood thymus‐dependent lymphocyte (T cell) levels. Humoral immunity was assessed by measurement of serum immunoglobulin levels and by the effect of serum on in vitro normal lymphocyte reactivity to PHA. In 21 patients who were studied for 4–23 years (mean 8.4) after surgical treatment alone for laryngopharyngeal carcinoma, neither cellular nor humoral immunity differed from that of 44 controls. In contrast, 14 patients who had been irradiated and subsequently cured for 4–15 years (mean 9.0) prior to evaluation displayed significantly impaired cellular immune competence when compared to normals and patients treated by surgery alone. Since previous determinations of the effects of radiation therapy have been in patients who received irradiation to the thymic region or large area of bone marrow, this study indicates that radiation therapy for cancer administered via portals that encompass a minimal area of the immune system may be associated with prolonged impairment of cellular immunity.

Thymus-dependent lymphocyte levels in bronchogenic carcinoma: Correlations with histology, clinical stage, and clinical course after surgical treatment†

The in vitro spontaneous lymphocyte rosette (T cell) assay was used to determine cellular immunologic competence in 112 patients with bronchogenic carcinoma. Among preoperative patients with localized tumors, T cell levels were significantly lower than in 237 normal controls. With advanced stages of disease, T cell levels declined progressively among patients with squamous cell carcinoma, oat cell carcinoma, and undifferentiated carcinoma, but not among patients with adenocarcinoma. Squamous carcinoma patients considered cured had persisting low T cell levels, but cured adenocarcinoma patients had normal levels. Serial determinations that showed a fall in T cell levels preceded the development of clinically evident metastases by an average of 2.5 months. Postoperative patients with rising T cell levels have remained clinically free of disease. The data indicate that T cell levels correlate with extent of tumor and clinical course of patients with bronchogenic carcinoma. The assay may, therefore, provide a rational basis for the selection of patients who are at high risk for the development of recurrence after surgical resection and who may benefit from the early institution of adjunctive therapy.

High dose methotrexate as a preoperative adjuvant in the treatment of epidermoid carcinoma of the head and neck: A feasibility study and clinical trial☆

Thirty patients with operable epidermoid carcinoma of the head and neck were treated with intravenous high dose methotrexate and leucovorin rescue prior to resection. Their clinical courses were compared with those of thirty randomly selected patients matched for tumors site and clinical stage who were treated by surgery alone. No medical or surgical complications associated with methotrexate were encountered. An objective decrease in tumor size (primary lesion or nodal metastases) was noted prior to resection in twenty-three patients (77 per cent). The number of recurrences in the two groups was similar. However, these was a significantly greater disease-free interval in the methotrexate-treated patients (p less than 0.05). No significant differences in survival have been noted to date between the two groups. In view of the absence of complications, the regressions in tumor size, and the increase in postoperative disease-free interval in this trial, evaluation as preoperative adjuvants of higher doses of methotrexate and of other chemotherapeutic agents in combination with methotrexate appears warranted.