CA 19-9 in pancreatic cancer.

CA 19-9 has achieved a defined role in the diagnosis, prognosis, and monitoring of patients with pancreatic cancer. For diagnosis, a reference value above 200 u/mL in a nonjaundiced patient with a confirming CT scan has a very high predictive value. For prognosis, a low preoperative value and a normal value after resection predict a good outcome. Similarly, CA 19-9 levels have been used successfully in monitoring the response to neoadjuvant therapy.

Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease.

A prospective, blinded study of CA19-9 in 2,467 patients having abdominal surgery yielded 356 patients with pancreatic, gallbladder, and biliary disease who submitted coded preoperative serum specimens. In this group, there were 84 patients with pancreatic cancer and 24 patients with gallbladder-biliary cancer; the remainder had benign lesions. The recorded imaging data and marker results were merged with the patients' demographic, clinical, and surgical data and tissue diagnoses for analysis. Receiver operator character calculation suggested that a reference value of 100 U/ml for CA19-9 was appropriate rather than the 37-40 U/ml value most frequently employed and yielded a specificity of 97% in the 467 operated patients with a sensitivity of 8.3% for all nonpancreatic-biliary cancers and 62% overall for these lesions. In the more diagnostically challenging nonicteric patients, CA19-9 sensitivity was 55%, specificity was > 99%, positive predictive value (PPV) was 97%, and negative predictive value (NPV) was 88%. When CA19-9 results were combined with those from endoscopic retrograde cholangiopancreatography, ultrasound (US), or computed tomography (CT), the PPV, and especially the NPV were increased. The addition of carcinoembryonic antigen results did not affect overall results. The addition of CA19-9 results to ambiguous or indeterminant imaging interpretation clearly improved the combined specificity, sensitivity, and PPV, but the change was less impressive, albeit positive, for NPV. The combination of CA19-9 and CT (or US) is a reasonable, cost-effective, noninvasive approach to establishing the diagnosis of pancreatic, cholangitic, or biliary cancer in nonicteric patients. Although no single procedure or combination of procedures was found to detect early, small lesions, CA19-9 is clearly a clinically useful adjunct to imaging in nonjaundiced patients suspected of having these malignancies.

Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) predisposes to the development of cholangiocarcinoma, a usually fatal complication that is difficult to diagnose. Serum concentrations of CA 19-9, a tumor-associated antigen, are frequently increased in patients with only cholangiocarcinoma. The aim of this study was to assess the value of an increased serum CA 19-9 level for the diagnosis of cholangiocarcinoma in patients with preexisting PSC. We analyzed serum samples from 9 patients with PSC and superimposed cholangiocarcinoma and from 28 patients with only PSC. Serum concentrations of CA 19-9 were measured in a blinded manner with use of an immunoradiometric assay. The serum CA 19-9 concentrations were increased in 8 of 9 patients (89%) with PSC and cholangiocarcinoma (mean +/- SE, 391 +/- 86 U/ml; range, 4 to 677), whereas they were increased in only 4 of 28 patients (14%) with only PSC (mean +/- SE, 61 +/- 16 U/ml; range, 2 to 370). The sensitivity of a CA 19-9 value greater than 100 U/ml for cholangiocarcinoma in PSC was 89%, and the specificity was 86%. The measurement of serum concentrations of CA 19-9 is a promising test for detecting cholangiocarcinoma in patients with PSC.

Evidence for the elevation of serum carcinoembryonic antigen and tumor-associated glycoprotein-72 levels in patients administered interferons.

Sera were collected from 111 patients diagnosed with adenocarcinoma or nonadenocarcinoma malignancies who received different schedules of interferon (IFN)-gamma or IFN-beta ser alone or in combination. Serum carcinoembryonic antigen (CEA) and tumor-associated glycoprotein-72 (TAG-72) antigen levels were measured to determine whether interferon could enhance the tumor shedding and, thereby, the serum level of either tumor antigen. Less than 10% of the sera samples from patients diagnosed with nonadenocarcinoma malignancies (e.g., hairy cell leukemia, melanoma) had positive titers of TAG-72 or CEA, and interferon neither increased nor resulted in the appearance of either tumor antigen in those sera. In contrast, 59.2% and 75.4% of the patients with adenocarcinoma had positive serum levels of TAG-72 and CEA, respectively, prior to interferon. IFN-gamma and IFN-beta ser alone or in combination significantly increased serum TAG-72 or CEA in approximately 65% of those patients. The results suggest that interferon administration to patients with adenocarcinoma can result in increased serum levels of selected tumor-associated antigens used in the diagnosis of malignancy. These preliminary findings may be important in the development of new strategies to obtain more sensitive tumor antigen serum assays for the diagnosis and monitoring for disease progression of adenocarcinoma.

Antibiotics as biological response modifiers.

This review suggests that infections are potent immunomodulators by causing significant alterations in one or more mediators of homeostasis and that an effective antibiosis may be a potent immunomodulator, albeit indirectly. When large numbers of microorganisms are killed, their enzymes and toxins are rapidly released and activate the immune system. The septic syndrome and the potentially progressive states of septic shock, acute respiratory distress syndrome and multiple organ system failure illustrate the biological response modulating (BRM) activity of both infection and antibiotic. Enhancement of phagocytosis and intracellular killing would be a useful immunomodulatory activity for antibiotics. Equally useful would be the capacity of the antibiotic to bind or inactivate bacterial lipopolysaccharide (LPS) to diminish monocyte release of tumour-necrosing factor (TNF) at a rate equal to or faster than the killing effect of the antibiotic on bacteria. For other types of immune deficiencies, such as are observed in HIV-positive patients with secondary bacterial, fungal and viral infections, modulation of viral receptors including HIV-R on CD4 lymphocytes accompanied by their up-regulation, enhancement of interferon (IFN) and natural killer (NK) function and inhibition of CD8 suppressor activity would be important activities. The classic example of polymyxin as an immunomodulating, albeit toxic, antibiotic offers a rational and definitive basis for the concept. In-vitro data on cefodizime, a third generation cephalosporin that achieves good tissue levels, are presented and show the ability of the intact antibiotic, as well as its immunomodulating side-chain, to down-regulate TNF and interleukin 1 (IL-1) released from human monocytes by lectin-activated lymphocytes, LPS and IFN.

Temporary elevation of CA 125 after abdominal surgical treatment for benign disease and cancer.

Analyses of preoperative and one to seven day postoperative determinations of CA 19-9, carcinoembryonic antigen (CEA) and CA 125 levels in 873 patients indicate that postoperative CA 19-9 and CEA serum levels were within the expected technical variance of the preoperative assay values in patients who were considered to have negative findings (below the reference value) from these tests preoperatively. If the test results were preoperatively positive in patients with cancer, they decreased postoperatively to or below normal reference values, unless the operation was palliative and significant tumor removal was not possible. For patients with a preoperative positive CA 125 level (greater than 35 units per mililiter), the postoperative serum levels were comparable with the CEA and CA 19-9 result. However, when the preoperative CA 125 level was within normal limits, 62 per cent of the patients had postoperative elevations, often to levels of less than 35 units per milliliter. Sequential postoperative determinations of CA 125 in 21 patients revealed that maximum levels of CA 125 were seen about two to four hours after the operation and that elevations persisted for as long as three months. Inferential evidence suggests that postoperative increases in serum CA 125 occur from incision and healing of the peritoneum and omentum by de novo synthesis of this antigen rather than shedding from tissues. Patients with CA 125 negative results and with carcinoma of the ovary having postoperative increases of this antigen within two months of the operation may pose a difficult problem in interpretations, and such patients require further investigation.

Comparison of portal and peripheral blood levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens in patients with colorectal and pancreatic cancer.

Synchronous serum specimens from the systemic and portal circulations of 43 patients with gastrointestinal cancer were assayed for levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens. The number of patients having a mean ratio of portal to systemic levels greater than 1 and the observed quantity of tumor-associated antigens were significant for carcinoembryonic antigen and CA 125 only in patients with colorectal cancer. No correlations were noted with the surgical stage of disease or with high or low (normal) levels of the three tumor-associated antigens. These findings suggest that peripheral concentrations of these antigens are in equilibrium with shedding from tumors and that hepatic clearance of a single pass does not significantly alter peripheral concentrations.

T-lymphocyte subsets in patients with idiopathic dilated cardiomyopathy.

T-cell subsets were measured in the peripheral blood of 33 patients with heart failure from idiopathic dilated cardiomyopathy, 22 patients with heart failure from other causes, and 33 normal controls. Mean T-suppressor cell percentage was 30% in normals, 21% in patients with idiopathic dilated cardiomyopathy whose duration of symptoms was less than 1 year (P = 0.0005), and 26% in those with symptoms for greater than 1 year (P = 0.05). Similarly, percentage of T-suppressor cells in the group with heart failure from causes other than idiopathic dilated cardiomyopathy was significantly lower (23%; P = 0.005) in those with short duration of symptoms. When both heart failure groups were combined those with symptoms for less than 1 year had significantly lower T-suppressor frequencies (22%) than those with symptoms for more than 1 year (P = 0.015). Multivariate analysis identified duration of symptoms and age as the only independent predictors of T-suppressor cell frequencies. Decreased percentage of T-suppressor cells in patients with idiopathic dilated cardiomyopathy may be an epiphenomenon related to duration of heart failure. This should be taken into account in assigning an etiologic mechanism for T-suppressor cells in idiopathic dilated cardiomyopathy.

Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: discrimination of benign from malignant disease.

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.

An initial analysis of preoperative serum CA 125 levels in patients with early stage ovarian carcinoma.

Preoperative serum CA 125 levels were determined for 36 patients with Stage I and II ovarian carcinoma. Levels ranged from 9 to 1962 U/ml with a mean of 216 U/ml. In Stage I patients, CA 125 levels averaged 133 U/ml and in Stage II patients 382 U/ml. Nine of 24 Stage I (38%) and 9 of 12 Stage II patients (75%) had CA 125 levels in excess of 65 U/ml in a population somewhat overrepresented in mucinous tumors. Patients with non-mucinous neoplasms had CA 125 elevations more often--in 75% of the cases--than those with mucinous tumors. A larger study will be required to more precisely estimate the fraction of early stage patients with elevated preoperative serum CA 125 levels; however, this investigation demonstrates an assay sensitivity minimally adequate to initiate a pilot evaluation of serum CA 125 levels in a population at risk for ovarian carcinoma.

Repeatedly relapsing disseminated histoplasmosis: clinical observations during long-term follow-up.

We report three patients (followed up for 13, 9, and 12 years) who had multiple episodes of disseminated histoplasmosis. Clinically, all three patients had high yields of positive cultures and all developed corticoadrenal insufficiency; all survived the recurrent relapses. One patient had unilateral progressive panophthalmitis, with ocular cultures positive for Histoplasma capsulatum. These relapses occurred despite conventional treatment with large doses of amphotericin B. Prolonged remissions were associated with using small doses of this drug. One patient had a long-term remission while taking ketoconazole daily for more than four years. These patients did not have conditions associated with immunosuppression. Lymphocyte proliferation to mitogens and, in one patient, to histoplasmin, was markedly reduced at the time of relapse and when tested preceding a relapse. All three patients showed a reversal to normal lymphocyte proliferation at the time of the longest last remission.

CA 125 in gynecologic practice.

Serum CA 125 levels were determined in 64 women with benign ovarian lesions, 92 women with uterine fundal lesions, and six patients who had negative second-look laparotomy for epithelial ovarian carcinoma. Of those with benign lesions, 13 of 31 patients with endometriosis had levels greater than 35 U/ml. Six of 34 patients with endometrial carcinoma had elevated levels before the primary operation, and six of 15 patients with recurrent endometrial carcinoma had elevated levels. The six ovarian cancer patients had had negative findings at second look 7 to 40 months before recurrence. Where close serial levels were available, the level became elevated 2 to 5 months before clinically apparent recurrent disease was noted.

Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study.

Twenty patients with disseminated favorable histology non-Hodgkin's lymphomas (16 patients) or chronic lymphocytic leukemia (four patients) who had not received previous chemotherapy were treated with recombinant leukocyte A interferon (IFL-rA) (Hoffmann-La Roche, Nutley, NJ). Treatment was administered in a moderate dose (12 X 10(6) U/m2) by intramuscular (IM) injection three times weekly for 8 weeks, followed by weekly maintenance therapy for an additional 16 weeks in patients responding to therapy. Five patients with stable disease at 8 weeks received four additional weeks of three-times-weekly treatment at an escalated dose (25 X 10(6) U/m2). Interferon was tolerated without severe toxicity by most patients, although treatment was discontinued prematurely due to side effects in four patients. Objective tumor responses (one complete response [CR] and six partial responses [PRs]) were seen in seven of 16 patients with lymphoma (44%). One of four patients with chronic lymphocytic leukemia also experienced a PR. Median time-to-progression from initiation of therapy among responding patients was 26 + weeks (range, 7 + to 84 + weeks). This study has demonstrated single agent antitumor activity of IFL-rA given in a tolerable outpatient dosage regimen in patients with advanced favorable histology non-Hodgkin's lymphomas, and serves as a basis for further trials of IFL-rA combined with chemotherapy as initial therapy for such patients in the future.

Treatment of varicella-zoster pneumonia with transfer factor.

A 29-year-old woman with a long history of immunoreactive disease--thrombocytopenic purpura, bullous pemphigoid, nephropathy, and hemolytic anemia--contracted generalized herpes zoster and varicella pneumonia. Respiratory failure requiring assisted respiration accompanied progressive chest findings. She recovered rapidly simultaneous with the administration of transfer factor from a healing herpes zoster patient. We believe that this therapy should be attempted in similar desperate circumstances.

Effect of bacterial immunization on experimental reflux nephropathy.

This study was designed to test the hypothesis that young animals with vesicoureteral reflux might be more vulnerable to renal parenchymal infection by bacteria to which they had not been previously exposed. Forty-four crossbred male piglets had surgical induction of vesicoureteral reflux at 2 weeks of age and introduction of urinary tract infection at 6 weeks. They were sacrificed at 12 weeks of age. Between the ages of 2 and 6 weeks, 22 piglets received subcutaneous injections of formalin-killed Escherichia coli in incomplete Freund's adjuvant as described. The remaining 22 piglets received incomplete Freund's adjuvant and vehicle alone. The antibody responses to antigenic challenge were weak to moderate. Immunized animals tended to have less renal scarring and better renal tubular uptake of dimercaptosuccinic acid, in addition to significantly lower serum creatinine values (p less than 0.001) and less mesangial cell proliferation in glomeruli (p = 0.05). We conclude that previous exposure to a specific bacterial strain and bacterial immunization have at least a mild protective effect on the development of reflux nephropathy.

Initial clinical evaluation of an immunoradiometric assay for CA 19-9 using the NCI serum bank.

More than 1,600 coded sera obtained from blood donors and the NCI/Mayo Clinic Serum Bank were analyzed with an improved immunoradiometric assay for the carbohydrate antigenic determinant, CA 19-9. Results indicated that CA 19-9 is elevated in a large fraction of sera (67%) from patients with advanced adenocarcinomas of the upper gastrointestinal (GI) tract, including those with pancreatic, hepatobiliary and gastric carcinomas. Several of these sera had CA 19-9 exceeding 300,000 U/ml. A smaller fraction (18%) of patients with carcinomas of the large bowel had elevated serum CA 19-9 levels, the majority among patients with metastatic disease. In contrast, none of the healthy donors from the serum bank and only 4 of 1,023 of the blood donor specimens (0.4%) had CA 19-9 levels greater than or equal to 40 U/ml. Three of 235 sera (1.3%) from benign disease patients had levels of CA 19-9 in excess of 40 U/ml. These data suggest that the improved CA 19-9 immunoradiometric assay may have clinical utility as a diagnostic adjunct for adenocarcinoma of the upper GI tract and that the assay also may have some value in monitoring patients with advancing colorectal carcinoma, particularly in combination with CEA determinations. Rigorous prospective clinical trials will be necessary to verify these hypotheses.

Establishment and characterization of a human non-secretory plasmacytoid cell line and its hybridization with human B cells.

A human non-secretory plasmacytoid cell line has been established for 6 years in more than 170 passages. Over 300 passages have been made from several early and late passages. The cell line is karyotypically normal, easily grown and has the characteristic features of a non-secretory plasmablast. Its characteristics suggest its use for hybridization by new methods as well as a study of its secretory defect. HPRT-negative phenotypic mutants can be derived from this line and a single polyploid clone has also been isolated. Hybridization with the HPRT+ and HPRT- lines X human B cells is described.

A prospective controlled evaluation of combined pelvic radiotherapy and methanol extraction residue of BCG (MER) for locally unresectable or recurrent rectal carcinoma.

Forty-four patients with unresectable primary, residual, or recurrent colorectal carcinoma confined to the pelvis were randomized to treatment with split course megavoltage radiotherapy alone (5,000 rad given over 7 weeks) or in combination with the intradermal administration of the methanol extraction residue of BCG (MER) over an eight-month period. No improvement was observed in frequency of symptomatic palliation, interval to progression, or survival among patients receiving MER. Furthermore, there was no evidence of enhanced immunological status in patients receiving MER as compared to those receiving radiation alone. Although temporary pain relief was seen in 94% of patients with pretreatment pelvic or perineal pain, 37 patients (84%) have experienced subsequent progressive malignant disease. Regional recurrences within the radiotherapy port were observed in 28 of 31 patients who were evaluable for analysis of pattern of sites of initial progression. Eleven of the 28 patients with local failure also had distant metastasis at the time of tumor progression. There was no discernible clinical value associated with MER treatment in combination with radiotherapy as employed in this study. The high frequency of pelvic recurrence following radiotherapy at the dose and schedule we employed highlights the need for more effective treatment strategies for this group of patients.