Richard L. Kradin

1 alpha,25-dihydroxyvitamin D3 induces maturation of the human monocyte cell line U937, and, in association with a factor from human T lymphocytes, augments production of the monokine, mononuclear cell factor.

The monocyte factor, interleukin 1, or other factors homologous with interleukin 1, modulates functions of a variety of cells, including T and B lymphocytes, synovial cells, and chondrocytes. We have reported that a human monocyte cell line, U937, produces interleukin 1 when incubated with a soluble factor from lectin-stimulated T lymphocytes. We have also shown that U937 cells have a specific cytosolic receptor for 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25[OH]2D3). We now report that 1 alpha,25(OH)2D3(10(-11)-10(-10) M) induces maturational changes in the U937 cells similar to those produced by conditioned medium from lectin-stimulated T lymphocytes (increase in Fc receptors and OKM1 binding and decrease in proliferation), but does not induce monokine production as measured by mononuclear cell factor activity. 1 alpha,25(OH)2D3 is 200-300-fold more effective than 25-hydroxyvitamin D3, which is consistent with the known biological potency of these vitamin D3 metabolites. 1 alpha,25(OH)2D3 and the lymphokine together markedly augment maturational effects and, in addition, augment monokine production. The specificity of the interaction is further demonstrated by the lack of augmentation of monokine production with 1 beta,25-dihydroxyvitamin D3 in the presence of lymphokine. These interactions of a classical hormone and the hormonelike product(s) of the immune system with U937 cells serve as a model for human monocyte/macrophage differentiation and suggest a role for these interactions in some aspects of inflammation.

Benign lymphoid disorders of the lung, with a theory regarding their development

The authors review the clinical, radiographic, and pathologic features of the benign pulmonary lymphoid disorders. The essential role of immunopathologic techniques in distinguishing pulmonary lymphoid hyperplasias from malignant lymphoma is stressed. A theory regarding the development of pulmonary lymphoid hyperplasia is proposed as a basis for understanding these disorders. The authors suggest that lymphoid hyperplasia is a basic inflammatory response of the lung.

Tumor-derived interleukin-2-dependent lymphocytes in adoptive immunotherapy of lung cancer

SummaryA trial of adoptive immunotherapy was performed in which long-term cultured, interleukin-2 (IL2)-dependent T-lymphocytes were administered to patients with metastatic adenocarcinoma of the lung. Lymphocytes were isolated from explants of cancer tissues that were cultured in medium with recombinant IL-2. These T-cells expressed surface markers of activation, and killed a broad panel of tumor targets. Intravenously injected 111indium-labeled T-cell blasts distributed primarily to lungs, liver, and spleen. Despite a paucity of infused lymphocytes detected by external imaging at sites of tumor, five of seven patients showed reduction of their cancers. However, in no case was greater than 50% reduction of total tumor burden achieved. Evidence of increased delayed cutaneous hypersensitivity to protein antigens was observed in three patients following therapy. We conclude that long-term cultured tumor-derived T-cells can be transferred safely into humans and that these cells may be capable of enhancing immune responses and mediating tumor reduction in vivo.

Functional characterization of T lymphocytes propagated from human lung carcinomas.

Tissue fragments from biopsies of six patients with malignant tumors of the lung were cultured in interleukin 2 (IL-2). Cultures of proliferating lymphocytes were isolated from all cases. Tumor cell lines (small cell carcinoma and adenocarcinoma) were established in parallel cultures from two of these patients. Lymphocytes that proliferated in vitro were virtually all mature T lymphocytes (greater than 95% T3+, T11+). The T8+ subset accounted for an average of 70% while T4+ cells averaged 20% of the cells in culture. HNK-1 antigen was presented on 23% of cells. Seventy-four percent of cells expressed Ia (HLA-DR) antigens. B cells did not proliferate under these conditions. In all cases the cells lysed K562 targets and were active in lectin-mediated cytolysis against human lymphoblasts. All cultures produced lymphokines (IL-2 and IFN-gamma) when stimulated with PHA. Lymphocytes grown from a tissue specimen with adenocarcinoma were capable of killing autologous tumor cells in vitro. Specific cytotoxicity has been maintained by these cultured lymphocytes for greater than 6 months. IL-2 activated peripheral blood cells in this case showed little specific cytotoxicity for autologous tumor cells. Lymphocytes from another specimen of adenocarcinoma also lysed this tumor, but cells from the other four specimens did not. Lymphocytes propagated from the specimen of small cell undifferentiated cancer did not lyse autologous tumor cells. These data show that primary lung tumors contain activated T cells which will respond to IL-2 in vitro. These tumor-infiltrating lymphocytes have demonstrable function, which can include cytolytic activity against autologous lung tumor.

Whole-Slide Imaging Digital Pathology as a Platform for Teleconsultation: A Pilot Study Using Paired Subspecialist Correlations

CONTEXT -Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. OBJECTIVE -To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. DESIGN -Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. RESULTS -Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. CONCLUSIONS -Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications.

Pulmonary blastoma with argyrophil cells and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal lung)

A tumor of the lung in a 35-year-old woman contained numerous complex, branching tubules resembling the developing fetal lung in its canalicular state. Some of the epithelial cells within the tubules were argyrophilic, and electron microscopy demonstrated the dense-core neurosecretory-type cytoplasmic granules. These characteristics support an endodermal origin for this neoplasm. Morphologically the tubules are similar to the epithelial component seen in pulmonary blastoma, but the tumor lacks the sarcomatous areas integral to the concept of blastoma. The designation pulmonary endodermal tumor resembling fetal lung may better describe this unusual neoplasm.

Sertraline Effects on Dyspnea in Patients With Obstructive Airways Disease

Dyspnea can have a debilitating effect on psychosocial and physical functioning in patients with chronic obstructive airways disease. Previous research has suggested that treatment of concomitant mood or anxiety symptoms can improve dyspnea and exercise intolerance among patients with respiratory disease. The authors report here on a case series of 7 patients with obstructive airways disease who reported improvements in dyspnea after sertraline 25-100 mg/day was added to their medication regimens. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder. Subjective improvements in dyspnea may have been related to relief of mood or anxiety symptoms or to direct effects on central respiratory systems. Controlled studies are needed to clarify the potential antidyspneic effects of sertraline.

Phenotype of blood lymphocytes in PTSD suggests chronic immune activation

Patients with posttraumatic stress disorder (PTSD) have a past history of extremely stressful experience and often present with somatic complaints. Peripheral blood lymphocytes (PBL) of patients with PTSD associated with a history of childhood sexual abuse were examined for changes in immune phenotype. The ratio of CD45RO-positive to CD45RA-positive lymphocytes (CD45RO/CD45RA), an index of lymphocyte activation, was higher (P = 0.04) in the PTSD subjects than in the normal subjects. No differences were observed for the number of PBL or the representation of major T, B, or NK lymphocyte subsets. These findings suggest the presence of increased lymphocyte activation in the PBL of patients with PTSD.

Iatrogenic Trichuris suis infection in a patient with Crohn disease.

We report a case of biopsy-proven iatrogenic infection by the pig whipworm Trichuris suis in a patient with Crohn disease. The deliberate therapeutic ingestion of T suis ova has been adopted as an experimental approach to the treatment of Crohn disease in an effort to promote a switch from the T helper subtype 1 to T helper subtype 2 inflammatory phenotype in vivo. This report examines the morphology of the immature and adult T suis, the effects of this intervention on the immunophenotype of the bowel mucosa, and it also raises the possibility of persistent active infection in man.

A phase II trial of interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma.

PURPOSE A phase II trial that used a regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) was undertaken to evaluate the efficacy of this combination in the treatment of metastatic renal cell carcinoma. PATIENTS AND METHODS Thirty-four assessable patients were treated with one to two induction cycles of IL-2 administered by continuous intravenous (IV) infusion at a dose of 3 x 10(6) U/m2/d [corrected] for 4 days per week plus IFN-alpha administered by subcutaneous injection at a dose of 5 x 10(6) U/m2/d [corrected] for 4 days per week for 3 consecutive weeks. A maintenance regimen of IL-2 2 x 10(6) U/m2/d [corrected] given by continuous IV infusion for 5 days per week plus IFN-alpha subcutaneously at a dose of 6 x 10(6) U/m2/d [corrected] that was given 3 days per week for 3 weeks was administered for one to five cycles. Twenty-eight patients (82%) completed one to two induction cycles, and 14 patients (41%) received maintenance doses. RESULTS Major responses were achieved in four patients (12%), which included one complete response (CR) in a bone metastasis. Responses were observed in patients both with and without prior nephrectomy as well as in a primary tumor. Toxicity was moderately severe and included two treatment-related deaths. CONCLUSIONS In view of the minimal antitumor activity and associated toxicity, the combination of IL-2 and IFN-alpha in this trial cannot be recommended. The investigation of new cytokines and the identification of biologic prognostic factors for a response to immunologic therapy are essential.