Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer.

The generation of antitumour immunity depends on the nature of dendritic cell (DC)-tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy.

Monitoring dendritic cells in clinical practice using a new whole blood single-platform TruCOUNT assay.

Dendritic cells (DC) from distinct DC subsets are essential contributors to normal human immune responses. Despite this, reliable assays that enable DC to be counted precisely have been slow to evolve. We have now developed a new single-platform flow cytometric assay based on TruCOUNT beads and the whole blood "Lyse/No-Wash" protocol that allows precise counting of the CD14(-) blood DC subsets: CD11c(+)CD16(-) DC, CD11c(+)CD16(+) DC, CD123(hi) DC, CD1c(+) DC and BDCA-3(+) DC. This assay requires 50 microl of whole blood; does not rely on a hematology blood analyser for the absolute DC counts; allows DC counting in EDTA samples 24 h after collection; and is suitable for cord blood and peripheral blood. The data is highly reproducible with intra-assay and inter-assay coefficients of variation less than 3% and 11%, respectively. This assay does not produce the DC-T lymphocyte conjugates that result in DC counting abnormalities in conventional gradient-density separation procedures. Using the TruCOUNT assay, we established that absolute blood DC counts reduce with age in healthy individuals. In preliminary studies, we found a significantly lower absolute blood CD11c(+)CD16(+) DC count in stage III/IV versus stage I/II breast carcinoma patients and a lower absolute blood CD123(hi) DC count in multiple myeloma patients, compared to age-matched controls. These data indicate that scientific progress in DC counting technology will lead to the global standardization of DC counting and allow clinically meaningful data to be obtained.

Surgical and physical stress increases circulating blood dendritic cell counts independently of monocyte counts.

Dendritic cells (DCs) are specialized antigen-presenting cells that have the unique ability to initiate a primary immune response. The effect of physiologic stress on circulating blood DCs has thus far not been studied. In this study, we applied a recently developed method of counting blood DCs to test the hypothesis that significant stress to the body such as surgery and exercise might induce measurable changes in the DC numbers, subsets, phenotype, and function. Twenty-six patients scheduled for elective laparoscopic cholecystectomy, 4 for elective hysterectomy, 56 controls, and 5 volunteers who underwent a stress exercise test were enrolled in the study. Absolute DC counts increased acutely (71.7% +/- 11% [SEM], P =.0001) in response to the stress of surgery and dropped below preoperative levels (-25% +/- 14% [SEM], P =.05) on days 2-3. The perioperative DC subset balance remained constant. Interestingly, DC counts changed independently of monocyte counts. Exercise also induced a rise in DC counts but coincidentally with monocyte counts. Surprisingly, no phenotypic or functional activation of DCs was seen in either stress situations in vivo. DCs are rapidly mobilized into the circulation in response to surgical and exercise stress, which may serve to prepare the host's immune defenses against trauma. The independent regulation of the DC and monocyte counts reinforces the distinction between these 2 cell populations.

Is parathyroid hormone-related protein a sensitive serum marker in advanced breast cancer?

BACKGROUND: To compare already used serum markers in advanced breast cancer, namely erythrocyte sedimentation rate (ESR), carcino-embryonic antigen (CEA), and polymorphic epithelial mucins (e.g. CA15-3) with a newer potential marker: parathyroid hormone related protein (PTHrP). METHODS: A study group of 33 patients of proven advanced breast cancer was compared with 11 patients with benign breast lumps who were undergoing surgery, and eight patients with humoral hypercalcaemia of malignancy of non-breast origin. ESR, CA15-3, CEA, PTHrP, parathormone (PTH), liver and renal function were measured using commercially available kits. Using given reference ranges, results were classified into normal versus abnormal, and univariate statistical comparisons were made using Fisher's exact test. For multivariate analysis, absolute serum levels were used, and multivariate logistic regression models were employed. RESULTS: By univariate analysis, only CA15-3 (P = 0.007), and CEA (P = 0.004), were significant markers of metastatic disease. By multivariate analysis the only independently significant serum marker was CA15-3 (P = 0.043). PTHrP was neither a sensitive (22%) nor specific (90.1%) serum marker when compared to CEA or CA15-3. ESR was the most sensitive single serum marker (93%). An incidental finding of elevations of serum parathormone was found in as many patients as in the study group as there were elevations of PTHrP. CONCLUSIONS: PTHrP would not have revealed any patients with metastatic disease that would not have been predicted by any existing tumour markers including CA15-3, CEA and ESR. The finding of elevated PTH in as many patients as PTHrP indicates the possible need for a study inclusive of other polypeptide hormones as markers in advanced breast cancer.

Non-Hodgkin's lymphoma of the thyroid: is more than biopsy necessary?

Whereas excisional surgery and radiotherapy have resulted in a favorable outcome when non-Hodgkin's lymphoma of the thyroid (NHLT) is confined to the thyroid gland, controversy persists over the potential advantage of aggressive debulking in favor of diagnostic biopsy alone when disease cannot be completely resected. Our aims in this study were to delineate the present role of surgery in NHLT in pre-operative staging, the impact of the extent of resection on achieving complete remission and cause-specific survival, and patterns of failure. All 62 patients who underwent primary surgery for NHLT at the Mayo Clinic between 1965 and 1989 were analyzed. By postoperative staging, 50 patients were stage IE or IIE. Overall survival was 53% and 46% at 5 and 10 years; 80% for stage IE confined to the thyroid, 58% for stage IE-extrathyroid, 50% for stage IIE, and 36% for stages IIIE and IVE. Complete remission was achieved in 88% of patients who underwent diagnostic biopsy plus adjuvant therapy alone compared to 85% for patients in whom debulking plus adjuvant therapy was used. There was no difference in cause-specific survival in these two groups or in cause-specific survival in two subgroups who achieved complete remission. Relapse after complete remission occurred in 12 (26%) of 46 patients, only 2 of whom survived long-term after salvage therapy. The role of surgery in NHLT is diminishing and advances that will increase complete remission and relapse-free survival will not likely involve more aggressive surgical resections.

Late anastomotic recurrence after radical resection of carcinoma of the ampulla of Vater: case report.

Although 5-year survival after radical resection for ampullary carcinoma has traditionally been regarded as a cure, recent reports have documented late recurrences from these tumors. This case report describes an anastomotic recurrence developing more than 5 years after a curative resection for ampullary carcinoma. This case report is unique in its location, unusually late development, and proposed mechanism of occurrence.

The spectrum of serous cystadenoma of the pancreas. Clinical, pathologic, and surgical aspects.

Serous cystadenoma of the pancreas is a rare lesion thought to be almost invariably benign. Since 1978, 211 cases have been reported in the literature. Some have been recognized by computed tomography (CT) when small and asymptomatic. The authors have reviewed their experience with 40 patients (median follow-up of 1.9 years, maximum of 22.2 years) from 1936 to 1991. One third (13) were asymptomatic, of whom eight (20%) were discovered intraoperatively. Of those 20 who had CT, an unequivocal preoperative diagnosis was reached in none. Needle biopsy proved accurate in two patients. Endoscopic retrograde cholangiopancreatography (ERCP) and biopsy were performed with diagnostic success on one occasion. Three patients presented acutely. The tumor was resected in 90%, with an operative mortality rate of 10%. Enucleation of the tumor without formal anatomic pancreatectomy necessitated reoperation for complications in four of eight patients. Survival after successful resection paralleled expected survival. Serous cystadenoma may be associated with von Hippel-Lindau syndrome. The current role for conservative management remains questionable because of our current inability to reliably differentiate many of these benign neoplasms from malignant cystic neoplasms of the pancreas.

Prognostic significance of calcitonin immunoreactivity, amyloid staining, and flow cytometric DNA measurements in medullary thyroid carcinoma.

The proven power of DNA ploidy to predict mortality risk in medullary thyroid carcinoma (MTC) may be weakened when analyzed in conjunction with calcitonin immunoreactivity (CI) and amyloid staining (AS) of tumors. In this study 12 prognostic variables, including DNA ploidy, CI, and AS, were studied in 65 patients with MTC (57 sporadic; mean age 51 years) treated during 1946 through 1970. Cause-specific mortality rates at 10 and 15 years were 15% and 26%, respectively. By univariate analysis, TNM stages III or IV (p less than 0.0001), tumor unresectability (p less than 0.0001), male sex (p = 0.019), negative AS (p = 0.032), and low CI (p = 0.033) were significant predictors of increased mortality rates. DNA ploidy (p = 0.058) and inheritance pattern (p = 0.25) were nonsignificant. By multivariate analysis, only TNM stage, tumor resectability, and AS were independently significant (p less than 0.005). A prognostic model was created, based on presence or absence of these independent risk factors, and four risk groups were defined, capable of predictably defining mortality rates in MTC (p less than 0.0001). The model requires validation in larger series and independent verification by others. However, we believe that a risk-group scheme for MTC based on AS, disease stage, and completeness of tumor resection may have wide applicability and prove relevant to clinicians treating this disease.