Edwin B. Cox

Provocative Agents and the Diagnosis of Medullary Carcinoma of the Thyroid Gland

Twenty-six patients with known or suspected medullary thyroid carcinoma (MTC) and 21 normal control subjects were tested intravenously on four separate days with calcium gluconate (CG), 2 mg Ca++/kg/l min.; pentagastrin (P), 0.5 ug/kg/ 5 sec; calcium chloride (CC), 3 mg Ca++/kg/10 min.; and a combination of calcium gluconate and pentagastrin (CG + P). Calcitonin (CT) levels were determined by radioimmunoassay on plasma collected before and immediately following each test infusion. In none of the 21 control subjects was there a clear increase in CT above 200 pg/ml following any of the four provocative tests. Conversely, in all 26 patients with known or suspected MTC, plasma CT levels were markedly increased (>300 pg/ml) following the combined infusion of CG + P. The peak CT response was greater with CG + P than with a) CG alone (22 of 24 patients, p < 0.002), b) P alone (25 of 26 patients, p < 0.002), or c) CC alone (17 of 17 patients, p < 0.002). Of 12 MTC patients with undetectable basal calcitonin levels, all had peak responses greater than 300 pg/ml following CG + P, whereas such responses occurred less often following CG alone (8 of 12) or P alone (8 of 12). The results demonstrate that the combined administration of pentagastrin and calcium gluconate constitutes a more effective and reliable stimulus for CT secretion from MTC cells than the use of either agent alone, and appears the most useful single screening test for the detection of occult MTC.

Malignant melanoma and pregnancy.

Confusion exists concerning the influence of pregnancy on survival in patients with malignant melanoma. To evaluate this problem a retrospective computer‐aided study was performed of women in the child‐bearing years treated for Stage I cutaneous melanoma at the Duke University Comprehensive Cancer Center. Fifty‐eight women were identified who had melanoma arise during pregnancy (Group 1) and 43 patients were noted who became pregnant within 5 years of diagnosis of their melanoma (Group 2). Appropriate control groups matched for the clinical variables of age, primary site, and stage of disease and the pathologic variables of Clarks Level, tumor thickness, ulceration, and histologic type were selected from the cohort of 2938 melanoma patients seen at Duke. Actuarial survivals for Group 1 and 2 patients did not differ from their respective controls, although the small number of deaths in each group resulted in wide confidence intervals. When actuarial disease‐free intervals were plotted, there was a significant difference beween women who had melanoma develop during pregnancy when compared to their controls (P = 0.04). In a multivariate regression analysis, after adjustment for the influence of the more significant prognostic factors for Stage 1 melanoma, including Clarks Level, ulceration, and tumor thickness, the effect of pregnancy on disease‐free interval became more apparent (P = 0.02). No difference in actuarial disease‐free interval was noted in the melanoma patients who elected to become pregnant within 5 years of diagnosis (P = 0.31). A multivariate regression analysis confirmed this finding. These data indicate that although an intercurrent melanoma during pregnancy has a worse prognosis than the control groups, once a woman has been diagnosed as having a cutaneous melanoma, a subsequent pregnancy has no effect on recurrence rate or survival. Cancer 55:1340‐1344, 1985.

Prognostic factors in metastatic and hormonally unresponsive carcinoma of the prostate.

Eighty‐eight patients with hormone‐resistant Stage IV prostate cancer were treated with a five‐drug chemotherapy program. Patient demographic data, prior therapy, symptoms, extent of disease, and laboratory studies were analyzed statistically to evaluate the association of these parameters with survival from the onset of chemotherapy. Factors associated with short survival included age >65, severe bone pain, poor performance status, presence of soft tissue metastases, anemia, elevation of serum LDH, SGOT, alkaline and acid phosphatases, and prolactin, and hypoalbuminemia. Race, stage at initial diagnosis, prior radiation therapy, prior orchiectomy, and elevation of CEA had no prognostic association. We suggest that clinical trials of new therapies of hormone‐resistant prostate cancer take into account the presence of these prognostic factors in the analysis of the results of therapeutic programs. Cancer 44:763‐775, 1979.

Prognosis of patients with stage D1 prostatic adenocarcinoma.

Of 44 patients with clinically localized prostatic adenocarcinoma and regional lymphatic metastases proved by staging pelvic lymphadenectomy 11 were treated by radical prostatectomy, 20 received extended field radiation and 13 were assigned to delayed hormonal therapy. The median survival for the entire group was 39.5 months. None of the 3 treatments appeared superior in prolonging survival. Furthermore, no enhancement of disease control could be demonstrated in either treatment group. Patients with prostatic adenocarcinoma and positive nodes appear to have equivalent adverse biological potential and should be candidates for treatments designed to produce systemic effect.

Clinicopathologic correlations in the oligodendroglioma

To determine the prognostic significance of histologic variables in oligodendroglial neoplasms, the presence and degree of 15 such variables were correlated with postoperative survival rates in 71 patients. By univariate analysis, prognostically significant factors, in order of decreasing importance, were mitoses (log), necrosis, nuclear cytologic atypia, vascular hypertrophy, and vascular proliferation. When studied by stepwise regression, necrosis and the number of mitoses contained all of the prognostically useful information. When each of the five variables significant by univariate analysis was tested in the Cox model by adding a variable to the model containing the other four, necrosis was found to be the only independently significant variable. There were significant positive pairwise correlations between each of the five significant histologic variables except for cytologic atypia with necrosis. The only histologic variable with a significant association with older age was the number of mitoses. These results suggest that necrosis and, to a lesser extent, the mitotic count are features that, in the appropriate setting, can be used to identify the “anaplastic” oligodendroglioma.

Association Between Cutaneous Occlusive Vascular Disease, Cigarette Smoking, and Skin Slough after Rhytidectomy

This prospective study attempted to determine if nonreversible occlusive vascular changes in the skin contribute to skin slough after rhytidectomy. The dermal microvasculature from 83 consecutive rhytidectomies was evaluated for intimal proliferation and/or hyalin sclerosis. Occlusive vascular disease increased progressively with age in all patients, but smokers and ex-smokers had significantly greater involvement than nonsmokers at any given age (p=0.03). Severe occlusive vascular disease and skin slough were associated (p=0.02), and there was a strong trend toward an association between active smoking and skin slough (p=0.06). Among smokers, there was a significant relationship between skin slough and failure to abstain from smoking postoperatively (p=0.006). We conclude that with aging, nonreversible occlusive changes develop in the dermal microvasculature. These changes appear to be accelerated by cigarette smoking. Our data, however, show that these nonreversible occlusive vascular changes by themselves do not completely account for the occurrence of skin slough after rhytidectomy.

Long-term clinical outcome of immediate reconstruction after mastectomy.

Immediate reconstruction of a breast removed for treatment of carcinoma can be accomplished without altering the cancer-ablative surgical procedure. The theoretical possibility that reconstruction might compromise the cure rate has tempered enthusiasm for this approach. To test this issue, the relapse-free survival of 101 patients who underwent breast reconstruction in the immediate postmastectomy period was compared with that of 377 patients with breast cancer who underwent mastectomy without immediate reconstruction. This comparison was accomplished using multivariable statistical techniques to correct for baseline inequalities between the patient groups. After adjustment for the relevant prognostic factors, no significant difference remained between the two groups. We conclude that immediate reconstruction has no discernible adverse influence on the natural history of surgically treated breast carcinoma.

Breast cancer in the elderly. Current patterns of care.

To evaluate age‐related differences in the current patterns of presentation and clinical management of breast cancer patients, the authors reviewed 1795 patients referred to a university hospital for their initial treatment. No age‐related differences were found with respect to laterality and anatomic site. Age‐related differences were seen with respect to histology, with mucinous (colloid) carcinoma being relatively more common with increasing age and medullary and inflammatory carcinoma being more common among young patients. Patients over age 55 presented with more advanced extent of disease, but the proportion did not further increase above age 65. Patients age 75 and older were nearly twice as likely to have surgery as their sole treatment as patients under age 45. The difference in treatment was specifically associated with the differential use of adjuvant chemotherapy between age groups. Sixty percent of patients under 45 with regional node involvement received adjuvant chemotherapy compared with only 27% of those 65 and older. Despite their similar characteristics in regard to laterality, anatomic site, and histology, elderly patients are less frequently given adjuvant chemotherapy in stage II breast cancer.

Oligodendroglioma. An analysis of the value of radiation therapy.

The role of radiation therapy in the treatment of supratentorial oligodendrogliomas is controversial. To evaluate the role of radiation therapy, the Duke University Medical Center series was retrospectively analyzed. Clinical history, radiation dosages, and pathologic materials were reviewed. Seventy‐one patients were identified as having histologically proven oligodendroglioma. Analysis of the patient population demonstrated it to be similar in all major parameters to other populations previously reported in the literature. Multivariate statistical analysis of the demographic, clinical and radiographic variables of these patients showed that a poorer prognosis was associated with persons of increased age (P = 0.052) and black persons (P = 0.014), and in those with papilledema (P = 0.07), hemiparesis (P = 0.001), intellectual deficits (P = 0.0002), and necrosis (P = 0.041). All patients had a surgical procedure as first treatment while 18 and three patients, respectively, underwent a second and third surgical procedure. Thirty‐seven patients had a subsequent course of radiotherapy. Univariate and multivariate statistical analysis comparing the patients treated with surgery alone those treated with surgery plus radiotherapy revealed no significant population or prognostic differences between the groups. The median times until clinical deterioration were 39 versus 27 months, the median times until documented tumor recurrence were 27 versus 28 months and the median survival times were 4.5 versus 5.2 years, for nonirradiated versus irradiated patients. These data, from a large and rigidly evaluated population, demonstrated no statistically significant difference in the symptom‐free interval, time until tumor recurrence, or survival between the groups nor did radiation appear beneficial to any subgroup evaluated. The results suggest the need for a prospective clinical trial to evaluate the true role of radiation therapy in the treatment of this tumor.

Multivariate analysis of a personal series of 247 patients with liver metastases from colorectal cancer. II. Treatment by intrahepatic chemotherapy.

One hundred and seventeen patients with colorectal hepatic metastases had insertion of catheters for infusional chemotherapy. The two-year survival estimate of patients with less than 50% hepatic replacement and no other adverse factors was 37%. Nine of 39 patients in this group are alive at 24 months. The catheters were placed into the hepatic artery (HA), 23; into the portal venous system (PV), 18; into both HA and PV, 64; or into an accessory HA following ligation, 12. Fifty-nine patients had ligation of the common HA also. The 30-day postoperative mortality rate was 1.7% (2/117) and morbidity was 37.6%. The majority of complications were related to fever (61%, 27/44). Over the past 2 years, 87% of patients have been discharged within 10 days following surgery. Preoperative CEA ranged from 0.5–12,150 ng/ml (median 165 ng/ml); 93% (78/84) had plasma CEA levels exceeding 5 ng/ml. All patients had careful intra-operative staging: per cent hepatic replacement (PHR) ranged from 5–95% (median 60%); portal, celiac, or periaortic lymph node metastases were observed in 31% (36/117). Initial intrahepatic chemotherapy programs consisted of either CAMF (9 patients), MAFL (60 patients), BFS (22 patients), continuous infusion FUDR (14 patients), or miscellaneous drugs (4 patients). Median survival time of 109 evaluable patients was 11.5 months. The effect of 20 variables on the observed survival time was analyzed using a multivariate proportional hazard model. Three variables were found to have influenced survival: PHR emerged as the most significant, p = 0.000001. Increased PHR was associated with decreased survival time. Lymph node metastases and prior chemotherapy were prognostic factors also, p = 0.0006 and p = 0.03, respectively. No patient with PHR greater than 80% lived more than 8 months. Utilization of these variables would appear to be necessary for accurate stratification and evaluation of future chemotherapy trials in patients with colorectal hepatic metastases.