FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer

Background

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Oligoclonal populations of T and B cells in a case of angioimmunoblastic T-cell lymphoma predominantly infiltrated by T cells of the VB5.1 family.

AIMS: Immunohistological and molecular characterisation of a case of peripheral T-cell lymphoma (PTCL) of angioimmunoblastic T-cell lymphoma (AILD) type. METHODS: Frozen and paraffin wax sections of the diagnostic lymph node were stained with a panel of T- and B-cell lineage monoclonal antibodies. DNA was isolated from the paraffin wax embedded biopsy material for T-cell receptor (TCR) and immunoglobulin (Ig) PCR amplification, and resultant PCR products were cloned and sequenced. RESULTS: Immunohistological analysis of the presenting lymph node was consistent with an extensive infiltrate of pleomorphic CD3+CD8+ lymphocytes. Most (>80%) of these infiltrating CD3+ cells were also positive for the TCR VB5.1 gene family product, and were shown to be oligoclonal by TCRB PCR amplification and sequencing. Three oligoclones of B cells were also demonstrable by PCR amplification with Ig heavy chain primers and sequencing, a finding at variance with the diagnosis of AILD. CONCLUSIONS: These data demonstrate the complexity and heterogeneity of PTCL which require extensive histological examination and molecular characterisation.     

Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the CADASIL locus. The fully developed CADASIL phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of CADASIL. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of CADASIL. Two other members had migraine with and without aura as a presenting clinical symptom of CADASIL. This disorder has been shown by linkage analysis to map to the CADASIL locus at chromosome 19. The phenotype at presentation of CADASIL in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.     

Lymphocytotoxins in infectious mononucleosis: a non-cytotoxic effect on their cytotoxicity in vitro

The lymphocytotoxic activity (LCA) of sera from patients with infectious mononucleosis (IM) was tested against lymphocytes under various experimental conditions. Firstly, lymphocytes from 11 healthy donors were preincubated with pools of normal human sera (NHS) or IM sera at 37°C and then tested for (a) reactivity with the same IM sera in a standard lymphocytotoxin assay at 15°C; (b) rosetting with various sheep erythrocyte (E) preparations (E, EA and EAC) and (c) stimulation by non-specific activators (phytohaemagglutinin, pokeweed mitogen and concanavalin A). These experiments showed that preincubation of normal cells with IM sera caused significant reduction in subsequent lymphocyte killing at 15°C (P<0·01) compared to unincubated cells or those preincubated with pooled NHS. There was no change in the binding of E, EA and EAC or mitogen stimulation following incubation. Culture of preincubated lymphocytes in lymphocytotoxin-free medium for 24 hr did not restore LCA at 15°C. Secondly, a pool of normal lymphocytes was incorporated into media containing either 2,4-dinitrophenol or sodium azide and tested for LCA against 11 acute IM sera and two NHS at both 15 and 37°C. No significant change in cell killing was observed at 15°C in the presence of these inhibitors, but there was a significant return of LCA at 37°C. Finally, normal lymphocytes and cells from two patients with IM were cultured at 37°C in lymphocytotoxin-free medium to determine the role of down-regulation of lymphocyte surface receptors in reducing autolymphocytotoxicity during the acute phase of the illness. There was no change in cell killing by IM sera after culture for 24 hr. These experiments show that lymphocytotoxic sera from patients with infectious mononucleosis interact with normal lymphocytes at 37°C without causing cell killing. This interaction caused a change in surface-binding characteristics that was not reversed by culture in ligand-free medium for 24 hr. Studies using metabolic inhibitors suggested that the failed lymphocytotoxicity at 37°C resulted, at least in part, from lymphocyte metabolism, although this did not inhibit the reaction between cytotoxic material and the lymphocyte surface.     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Enhanced MYCN expression and lsochromosome 17q in pineoblastoma cell lines

We have established two cell lines, PER-452 and PER-453, from an 8-month-old girl with an extensive pineoblastoma. Characterization of these lines revealed that the proto-oncogenes MYC and MYCN were not amplified, but both cell lines showed MYCN expression comparable to a cell line with 200-fold MYCN amplification. Both cell lines contained an i( 17q). These results support the concept that pineoblastomas belong to a larger group of primitive neuroectodermal tumors of the central nervous system. These two cell lines provide a unique opportunity to investigate the molecular genetic mechanisms underlying these neoplasms further. Genes Chrom Cancer 9:129-135 (1994).© 1994 Wiley-Liss, Inc.