Radiation therapy and immunotherapy-a potential combination in cancer treatment.

Background: Radiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells. Methods: The aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response. Results: Up-to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here. Conclusions: The possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.

Chemotherapy may eradicate ductal carcinoma in situ (DCIS) but not the associated microcalcifications.

INTRODUCTION: We studied the effect of neoadjuvant chemotherapy (NAC) ± trastuzumab on the ductal carcinoma in situ (DCIS) component in patients with locally advanced breast cancer who achieved pathological complete response (pCR). METHODS: The diagnostic biopsies of 92 consecutive breast cancer patients that were treated with neoadjuvant chemotherapy (NAC) ± trastuzumab were evaluated for the presence of DCIS. Upon completion of NAC, the surgical specimens were evaluated for complete eradication of both the invasive and non-invasive cancer in the breast. The pretreatment mammograms were evaluated for the presence of microcalcifications and compared to the mammograms that were obtained upon completion of therapy prior to surgery. RESULTS: Thirty of 92 patients (33%) had a substantial component of DCIS in the pretreatment biopsy. Thirty nine patients (42%) achieved pCR: 22 (56%) following NAC + trastuzumab, 17 (32%) following chemotherapy only. Ten of 30 patients (33%) with DCIS component achieved pCR: 4 received chemotherapy only, in 6 trastuzumab was added. Multiple microcalcifications on the pretreatment mammograms were observed in 3 of 10 patients with DCIS who achieved pCR. No reduction in the area of calcifications was observed following NAC. CONCLUSIONS: DCIS may be completely eradicated by NAC ± trastuzumab. However, associated microcalcifications probably persist. Patients with locally advanced breast cancer with substantial DCIS may still opt for NAC and breast conservation as the DCIS component may respond and even completely disappear following NAC. Residual widespread microcalcifications after NAC do not necessarily indicate residual cancer. Larger studies are needed to direct the surgical management of these patients.

Involvement of HNF-1 in the regulation of phosphoenolpyruvate carboxykinase gene expression in the kidney.

The cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK) gene is differentially expressed in several tissues. A specific set of regulatory elements in the promoter are responsible for the control of PEPCK gene transcription and, in turn, determine its distinct metabolic role in each tissue. DNase I footprinting analysis of the PEPCK promoter, using nuclear proteins from tissues which express the gene for PEPCK, and transient expression assays in renal cell lines have demonstrated that the HNF-1 recognition motif (P2) in the PEPCK promoter characterizes kidney-specific expression. This site is required also for the response to acidosis. Since the P2 site is not involved in the expression of the PEPCK gene in the liver, we propose that its critical role in the kidney stems from a combination of abundance of HNF-1 together with low concentrations of members of the C/EBP family in this tissue.

Congenital myopathy with oculo-facial abnormalities (Marden-Walker syndrome).

Marden-Walker syndrome present in the neonatal period is characterized by oculo-facial abnormalities, congenital myopathy, and contractures. A newborn infant with a similar pattern of anomalies is reported, and further evidence for autosomal recessive inheritance as well as new neuropathological findings are included.

Experimental streptococcal meningo-encephalitis in cultured fish.

In 1984 a disease of fish appeared in Israel which spread rapidly in cultured fishponds. The disease affected tilapia (Oreochromis aura x Oreochromis nilotica hybrids) and trout (Oncorhynchus mykiss). Common carp (Cyprinus carpus), although reared in community with tilapia were not susceptible to the disease. Various species of ornamental cyprinids and cichlids were also affected. Morbidity was high and mortality ranged between 50% (in trout) and 30% (in tilapia). Clinical and pathological findings indicated that the tilapia and trout suffered from meningitis and menigo-encephalitis. Two new streptococcal species, Streptococcus shiloi and Streptococcus difficile were isolated from diseased fish. The disease was reproduced experimentally in both trout and tilapia with the two streptococcal species. The LD50s of S. shiloi and S. difficile strains cultured in vitro (two to three passages on BHI medium) were 10(7)-10(8) cfu. The virulence of these strains was increased (LD50:10(2)-10(5) cfu) after three passages in vivo (brain to brain passage in fish without culture on agar plates). Highly virulent strains did not differ from low virulent strains by any identifiable extrachromosomal elements.

The effect of short-term lipid infusion on liver function and biliary secretion in rats.

This study was undertaken to determine the effect of various lipid emulsions on the hepato-biliary system in rats. Rats were randomly divided into six groups and infused continuously for 48 hr with either long-chain triglycerides (LCT), medium-chain triglycerides (MCT) or a mixture of MCT and LCT. One group infused with physiological saline solution served as controls. Throughout this period the rats received a fat free diet ad libitum. During the last hour of lipid infusion bile was collected for determination of bile flow and composition. Subsequently, the rats were sacrificed and the morphology and lipid content of the liver determined. Only LCT lipid emulsions induced morphological changes and increased liver cholesterol content. In two rats infused with radiolabeled LCT, no labeled cholesterol was found in the liver, indicating that the excess hepatic cholesterol level may originate from enhanced cholesterol mobilization to the liver. Biliary cholesterol and phospholipid concentrations in LCT-treated rats were also elevated, as was the lithogenic index, whereas the other emulsions had no such effects. None of the emulsions affected the plasma liver function tests or bile flow. We therefore conclude that the lithogenicity of the bile in rats is directly related to the lipid components of the total parenteral nutrition and the type of triglyceride infused.

Structural and functional evaluation of modifications in the composite skin graft: cryopreserved dermis and cultured keratinocytes.

Structural and functional aspects of modifications in the composite skin graft consisting of cultured keratinocytes and cryopreserved dermis were determined. Cryopreserved human cadaveric dermis separated from skin by short and mild trypsinization was compared with dermis obtained by prolonged incubation in medium and with fresh dermis obtained by the same methods. All types of dermis were shown to retain normal ultrastructure and topographic organization, as detected by scanning and transmission electron microscope and immunofluorescence analysis. However, in fresh skin, the layers were more firmly attached, mechanical separation was more difficult, and residual epidermis often remained attached to the dermis. Keratinocytes attached better, began replication earlier, and generally reached higher cell numbers when cultured on trypsinized dermis than on medium-treated dermis. The performance of several modifications in the reconstitution and grafting procedures of the composite skin graft after transplantation to athymic mice was examined. Cultured epidermis combined onto trypsinized or medium-treated whole and meshed dermis, dermis pregrafted and allowed to take before transplanting epidermis on top, and keratinocytes grown into multiple epithelia on top of trypsinized meshed or whole dermis prior to grafting. The best grafting results were obtained with an "instant" reconstituted skin model: multiple epithelia grown in vitro combined immediately before grafting onto meshed trypsinized dermis. The transplantation results of this modification were significantly better than those of all the other modifications, including initial growth of keratinocytes into multiple epithelia on top of trypsinized dermis prior to grafting.

Exaggerated placental site erroneously diagnosed as non-metastatic trophoblastic disease. A case report.

BACKGROUND: Exaggerated placental site (EPS) is classified as a non-neoplastic trophoblastic lesion, and histologically it consists of endometrial and myometrial invasion of intermediate trophoblasts and syncytiotrophoblasts and it differs morphologically from placental site trophoblastic tumors and placental nodules. The purpose of this report is to increase physicians' awareness of this lesion. CASE: A 48-year-old woman with post-molar rising betahCG titers and a clinical diagnosis of non-metastatic trophoblastic disease underwent hysterectomy. Final histopathology showed exaggerated placental site--a lesion often unfamiliar to clinicians. CONCLUSION: It is suggested that operative hysteroscopy may be useful in the diagnosis and management of EPS.

Separation of rare cell subpopulations with the aid of biotin-labelled ligands.

A universal method for selection of surface marker-positive cells is described. The cells, admixed with an excess of surface marker-negative cells, are first labelled with a specific biotinylated ligand and then isolated with the aid of monoclonal, anti-biotin coated beads. The method enables selection and isolation of cells with a frequency as low as 10(-4). The ligand can be an antigen (for selection of infrequent antibody-producing cells), an antibody (for selection of surface antigen-positive cells) or other molecules (for selection of specific receptor-positive cells).

Primary Burkitt's lymphoma of the appendix.

Appendicitis is a very rare presenting symptom of abdominal Burkitt's lymphoma. Only four cases have previously been identified in the literature, all of them males. This is the first reported case of a female as well as the youngest and is representative of the therapeutic considerations in this unusual manifestation of the disease.

Suckling stimulation test for neonatal tremor.

The response of neonatal tremor to a suckling stimulation test was investigated in 102 healthy neonates born at full term. In 84 the tremor resolved immediately; none had hypocalcaemia and only one had mild hypoglycemia. Eighteen in whom the tremor continued had either hypocalcaemia (n = 13) or hypoglycaemia (n = 5).

Lymph node cell vaccination against the lupus syndrome of MRL/lpr/lpr mice.

Immunization with pathogenic lymphoid cells has been shown to induce resistance to disease in experimental animal models of cell mediated autoimmunity. In the present work we tested the effectiveness of this approach in a spontaneous murine autoimmune disease, the MRL/lpr/lpr (MRL/1) murine lupus model. We now report that the anti-DNA antibodies and glomerulonephritis of MRL/1 mice could be prevented by the adoptive transfer of spleen cells from MRL/+ mice that had been vaccinated with MRL/1 lymph node T lymphocytes, but not by direct vaccination of MRL/1 mice with their cells. These results indicate that the lupus of MRL/1 mice is susceptible to regulation by adoptive vaccination and that these autoimmune mice lack the ability to raise a suppressive response against their own pathogenic cells.

Intermediate filament protein profiles of human testicular non-seminomatous germ cell tumors: correlation of cytokeratin synthesis to cell differentiation.

The patterns of cytoskeletal differentiation were studied in 20 testicular non-seminomatous germ cell tumors by immunohistochemistry, using diverse monoclonal antibodies specific for different intermediate filament (IF) proteins and for desmoplakin. Immunofluorescence and immunoperoxidase methods on both formalin-fixed and frozen tissues were applied, in some cases together with a gel electrophoretic analysis of IF proteins. The tumors examined included embryonal carcinoma (EC), endodermal sinus tumor (EST), choriocarcinoma and teratoma. Nine of the tumors were composed of only one histological type, the others showed mixed components. Cytokeratins 8 and 18 were identified in all these neoplasms, but their immunostaining was weak in ECs. Cytokeratin 19 was absent or very scarce in ECs, but strongly expressed in ESTs, choriocarcinomas and teratomas, thus allowing the identification of small EST and choriocarcinoma elements in ECs even when they were morphologically not obvious. Occasionally, some cells in ECs and ESTs also stained for cytokeratins 4 and/or 17, indicating potential for epithelial stratification. The majority of the germ cell tumors showed varied amounts of vimentin, often in co-existence with cytokeratins. Neurofilaments were demonstrated in scattered tumor cells in a single case of EST. In the teratomas studied, each type of tissue component present showed the expected IF protein. However, in many germ cell tumors some stromal cells and blood vessels contained, in addition to vimentin and desmin, also cytokeratins 8 and 18. This heterogeneity of the cytoskeletal profile of germ cell tumors is indicative of the varied differentiation potential inherent in these neoplasms.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of intermediate filament expression in human testicular seminomas.

Testicular seminoma has in the past been considered to represent a germ cell tumor incapable of further differentiation. In recent years this view has been challenged on the basis of morphologic and chromosomal studies. Moreover, studies of intermediate filaments (IF) of seminoma cells have provided evidence of the capability of seminoma cells to differentiate in different directions. In the present study of the IF protein profile of 26 human testicular seminomas, using frozen as well as formalin-fixed, paraffin-embedded tissues, we report evidence of a heterogeneous differentiation potential inherent in these neoplasms. Thus, in 4 of the seminomas neither cytokeratins nor vimentin were detected; 3 showed vimentin positive cells but no cytokeratins; in 4 seminomas only cytokeratins were detected. In the remaining 15 cases both cytokeratins and vimentin were present, with occasional cells demonstrating coexpression of cytokeratin and vimentin. While the cytokeratins present were mostly of the "simple epithelial type", in 2 instances seminoma cells also contained cytokeratins 4 and 17, normally found in stratified and/or complex glandular epithelia. Furthermore, in 3 cases scattered tumor cells stained for desmin and in 2 other seminomas neurofilaments were identified. All of the cases showed variable positive staining for desmoplakins and desmoglein, indicative of the presence of desmosomes. It can therefore be concluded that, while some seminomas seem to be devoid of IFs, most of them show varied differentiation patterns usually with epithelial features but occasionally also with components commonly regarded as characteristic of myogenic or neurogenic differentiation. These observations may help to elucidate the relationship of seminomas to other germ cell tumors, and also contribute to our understanding of the histogenesis of these neoplasms.