Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can
show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we
highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for
therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Nanoparticle therapeutics: an emerging treatment modality for cancer

A murine monoclonal antibody specific for calf intestinal alkaline phosphatase has been prepared and used in an unlabeled antibody bridge technique for labeling monoclonal antibodies. This procedure--the alkaline phosphatase monoclonal anti-alkaline phosphatase (APAAP) method--gives excellent immunocytochemical labeling of tissue sections and cell smears, comparable in clarity and intensity to that achieved with immunoperoxidase labeling. If the enzyme label is developed with a naphthol salt as a coupling agent and Fast Red or hexazotized new fuchsin as a capture agent, a vivid red reaction product is obtained which is very easily detected by the human eye. For this reason the APAAP technique was found particularly suitable for labeling cell smears (for both cytoplasmic and surface-membrane antigens) and for detecting low numbers of antigen-bearing cells in a specimen (e.g., carcinoma cells in a malignant effusion). It was found possible to enhance the intensity of the APAAP labeling reaction substantially by repeating the second and third incubation steps (i.e., the unlabelled "bridge" antibody and APAAP complexes). The APAAP technique was superior to immunoperoxidase labeling for staining tissues rich in endogenous peroxidase, and could be used in conjunction with immunoperoxidase methods for double immunoenzymatic staining. The method was also applicable to the detection of antigenic molecules following their electrophoretic transfer from SDS-polyacrylamide gels to nitrocellulose sheets ("immunoblotting").

Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes).

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma study group

Background DNA fragments that appeared to belong to an unidentified human herpesvirus were recently found in more than 90 percent of Kaposi's sarcoma lesions associated with the acquired immunodeficiency syndrome (AIDS). These fragments were also found in 6 of 39 tissue samples without Kaposi's sarcoma, including 3 malignant lymphomas, from patients with AIDS, but not in samples from patients without AIDS. Methods We examined the DNA of 193 lymphomas from 42 patients with AIDS and 151 patients who did not have AIDS. We searched the DNA for sequences of Kaposi's sarcoma–associated herpesvirus (KSHV) by Southern blot hybridization, the polymerase chain reaction (PCR), or both. The PCR products in the positive samples were sequenced and compared with the KSHV sequences in Kaposi's sarcoma tissues from patients with AIDS. Results KSHV sequences were identified in eight lymphomas in patients infected with the human immunodeficiency virus. All eight, and only these eight, were body-cavity–based lymphomas — that...

Kaposi's Sarcoma–Associated Herpesvirus-Like DNA Sequences in AIDS-Related Body-Cavity–Based Lymphomas

Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.

A total of 67 samples from normal and pathological thyroid glands were stained (as formalin fixed paraffin sections) with a panel of monoclonal antibodies directed against intermediate filament proteins. The study confirmed previous reports of cytokeratin and vimentin coexpression in primary thyroid carcinomas, but coexpression was also detected in normal thyroid and in a range of benign conditions including follicular adenomas, Hashimoto9s thyroiditis, and diffuse hyperplasia (thyrotoxicosis). Prekeratin expression was found (using antibodies recognising higher molecular weight cytokeratins) predominantly in areas of squamous change, independent of the underlying thyroid pathology. This study does not therefore support previous findings that prekeratin expression provides a reliable means of distinguishing follicular pattern papillary carcinoma from follicular carcinoma with its poorer prognosis or that it helps distinguish benign from malignant papillary lesions. No evidence of desmin or neurofilament expression was seen, and in particular, neurofilaments could not be detected in any of the cases of medullary carcinoma studied.

https://jcp.bmj.com/content/jclinpath/40/2/136.full.pdf

Expression of intermediate filament proteins in normal and diseased thyroid glands.

Fifty-four human lung tumours have been immunostained with a large panel of monoclonal antibodies including reagents against cytokeratins, prekeratins, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA) and neural antigens. These results have been compared with the histological types of tumour using the current WHO classification scheme. The most striking finding of this study was the considerable overlap of antigenic profile between different histological types of tumour. This suggests that there may be a greater underlying similarity between different histological categories of lung tumour than has hitherto been assumed. Secondly it was evident that immunostaining highlighted areas of different morphology within many tumours emphasizing the heterogeneous differentiation patterns seen in lung cancers. The present study supports the viewpoint that lung tumours arise from a common stem cell and that these neoplasms represent a single tumour with a tendency to differentiate along one or more pathways.

Human lung tumours: a correlation of antigenic profile with histological type.

Three methods, the enumeration of large non-cleaved cells (LNCC), the enumeration of nucleolar organizer regions (AgNORs), and the estimation of the percentage of Ki67-positive cells, have been compared on a series of 36 follicular lymphomas for their utility in subclassification. All three methods produced similar subdivisions to those obtained using the histological classification of the Working Formulation for clinical usage. Twenty cases have been followed clinically to assess any relationship between these parameters and short-term (less than 4 years) survival. Each technique showed a trend towards identifying patients with a poor short-term prognosis with no one method being superior to any other. Unless larger series with longer follow-up suggest otherwise, there is no indication to use either the AgNOR or Ki67 methods which offer no advantage over the simple and inexpensive Working Formulation or Berard's LNCC counting.

The utility of Ki67 immunostaining, nuclear organizer region counting, and morphology in the assessment of follicular lymphomas

Aims : To investigate whether an antibody against an intracellular epitope can detect CD19 in routine biopsy specimens and thus to document in detail its expression in human lymphomas.

Method and results : A polyclonal antibody to the C terminus of CD19 was used to immunostain paraffin-embedded samples of normal and neoplastic lymphoid tissues. CD19 was widely expressed in normal B cells and in extramedullary plasma cells. It was found in most B-cell neoplasms, but expression in follicular lymphoma was weak (33/69) or negative (four cases). Similarly, CD19 expression in diffuse large B-cell lymphomas was weak (28/56) or negative (eight cases). In T-cell-rich B-cell lymphomas, CD19 was also weak (4/10) or negative (three cases). CD19 was often absent in post-transplant B lymphoproliferative disease, classical Hodgkin's disease and plasma cell neoplasms. An unexpected finding was the frequent absence of CD19 in the neoplastic cells in lymphocyte predominant Hodgkin's disease.

Conclusions : CD19 can now be detected in routine biopsy specimens. In contrast to the classical pan-B marker CD20, CD19 is not always strongly expressed in B-cell neoplasms. Furthermore, the lymphocytic and histiocytic (L&H) cells of lymphocyte predominant Hodgkin's disease (which express most B-cell-associated markers) commonly lack CD19.

Loss of CD19 expression in B-cell neoplasms.

CD30 positive anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin's lymphoma associated with a specific chromosome translocation between chromosomes 2 and 5 Recent molecular characterization of the translocation breakpoint has identified a gene fusion between NPM (nucleophosmin) and ALK (anaplastic lymphoma kinase) Using a DNA hybridization technique, the NPM rearrangement was found among 5/5 ALCL samples We have developed a PCT methodology which has enabled the detection of the NPM-ALK rearrangements amongst seven t(2;5)(p23;q35) ALCL cases based on a long-range PCR of genomic DNA The rapidity and robustness of this method may have diagnostic applications for ALCL

D Y Mason

Papers

Expression of intermediate filament proteins in normal and diseased thyroid glands.

Human lung tumours: a correlation of antigenic profile with histological type.

The utility of Ki67 immunostaining, nuclear organizer region counting, and morphology in the assessment of follicular lymphomas

Loss of CD19 expression in B-cell neoplasms.

Detection of NPM-ALK DNA rearrangement in CD30 positive anaplastic large cell lymphoma