Staging of head and neck squamous cell carcinoma using the MET oncogene product as marker of tumor cells in lymph node metastases.

In head and neck squamous cell carcinomas (HNSCC), metastasis to cervical lymph nodes is a major determinant of patient outcome. To detect metastases, we used the MET oncogene as marker, which encodes the receptor for hepatocyte growth factor/scatter factor, mediating epithelial cell motility and invasiveness. The MET gene is expressed in epithelia and over-expressed in carcinomas of specific histotypes, but not in lymphatic tissue. A total of 151 lymph nodes from 20 squamous cell carcinomas were studied with both in-depth histology and end-point and real-time quantitative RT-PCR. MET-encoded sequences were found in 61 of 151 nodes (40%), of which 24 (16%) were found metastatic by in-depth histopathology. Parallel routine histopathologic analysis of 654 lymph nodes from the same cases identified 36 metastases (5%). Real-time quantitative RT-PCR was used to measure MET gene-specific mRNA in normal tissues, primary tumors and lymphatic metastases and showed a 2-8-fold increased expression in tumor cells which metastasize. RT-PCR for 3 cytokeratins expressed in HNSCC (K4, K10 and K13) proved to be less sensitive in detecting occult lymphatic metastases. Western blot analysis demonstrated the presence of the full-size MET receptor in primary tumors and lymph node metastases; immunohistochemistry showed receptor localization in tumor cells. Altogether, these data demonstrate that the MET gene product is a valuable marker with which to detect occult tumor cells in lymph nodes, thanks to its high expression in metastatic cells. After RT-PCR analysis we were able to attribute a more advanced stage to 10 out of 20 HNSCC cases, including 5 cases classified as tumor-free after routine histopathology.

Development of a cross-thesaurus with Internet-based refinement supported by UMLS.

Combinatorial terminological systems are appearing, to solve the issues related to flexibility and precision of representation requested by modern healthcare information systems and in particular by messaging standards. The development of a robust system of descriptors ('cross-thesaurus') is a crucial activity in the production of combinatorial terminological systems. We developed a tool (I-BROWSE) to produce a cross-thesaurus by analysing existing terminological corpora. To facilitate the work of experts and to produce re-usable results, our application interacts via the Internet with the UMLS Knowledge Sources Server. We applied our tool on 6372 dissections on surgical procedures produced in the project GALEN-IN-USE, as a part of the internal Quality Assurance Program. Support from UMLS seems mostly promising about descriptors on , , and . Additional assistance can be given to domain experts on less frequent descriptors on pervasive modifiers. We plan to apply our tool also to production of terminological standards in CEN, as a part of a world-wide process of gradual convergence and transformation of coding systems into second-generation systems and terminological services.

Standards to support development of terminological systems for healthcare telematics.

The Technical Committee on "Medical Informatics" of the European Committee for Standardization (CEN/TC251) is supporting developers of terminological systems in healthcare by a series of standards. The dream of "universal" coding system was abandoned in favor of a coherent family of terminologies, diversified according to tasks; two ideas were introduced: (1) the "categorical structure", i.e. a model of semantic categories and their relations within a subject field and (2) the "cross-thesaurus", i.e. a system of descriptors to build a systematic representation (called here "dissection") for each terminological phrase, coherent across diverse terminologies on a given subject field. The goal is to assure coexistence and interoperability (and reciprocal support for development and maintenance) to three generations of systems: (1) traditional paper-based systems (first generation); (2) compositional systems built according to a categorical structure and a cross-thesaurus (second generation) and (3) formal models (third generation). Various scenarios are presented, on the exploitation of computer-based terminological systems. The idea of "operational meaning" of terminological phrases within administrative and organizational contexts and the idea of "task-oriented details" are also introduced, to justify and exploit design constraints on terminological systems.

Building cross-thesauri with the support of UMLS.

The absence of a robust system of descriptors (cross-thesaurus) hampers the development of combinatorial terminological systems. We developed a tool (I-BROWSE) to produce a cross-thesaurus by analyzing terminological corpora. To facilitate the work of experts and to produce re-usable results, our application interacts via the Internet with the UMLS Knowledge Sources Server. We applied our tool on 2999 dissections on surgical procedures produced in the project GALEN-IN-USE, as a part of the internal Quality Assurance program. Support from UMLS seems mostly promising about descriptors on , , and . Additional assistance can be given to domain experts on less frequent descriptors on pervasive modifiers. We plan to apply our tool also to production of terminological standards in CEN, as a part of a worldwide process of gradual convergence and transformation of coding systems into second-generation systems and terminological services.

A tagging system for section headings in a CEN standard on patient record.

CEN is developing a series of standards for transmission of patient records. We present here preliminary results to produce a standard on section headings in record systems. Each record system uses its own scheme of headings, depending on specialty, National regulations and tasks; users cannot accept a unique, standard scheme. Enumerating all possible headings in all National languages is not necessary for a safe and faithful transmission of records. The focus of CEN standard is shifting from the headings to a system of tags that can be tied to them. We want to convey just the crucial properties to assure correct data handling by receivers. Our tagging system is organized into 5 clusters: C0 Nature, i.e. tags to identify the nature of data; C1 Safety context, i.e. essential tags that convey the main context of data; C2 Interpretation, i.e. tags about interpretation of data in the original context by the original user; C3 Intention, i.e. additional tags to make explicit the links that reveal sender's intentions and goals; C4 Organization, i.e. further tags to show the organization of the original record. Although tags were conceived for messages, they should be present in local systems since data generation. In fact, tags can be used to organize data within a record and allow for multiple views, without imposing a unique, fixed structure to the record.

Detection of MET oncogene/hepatocyte growth factor receptor in lymph node metastases from head and neck squamous cell carcinomas.

The c-MET oncogene encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), which is known to stimulate the invasive growth of epithelial cells cultured in vitro. The Met/HGF receptor is a heterodimeric transmembrane tyrosine kinase, which is a prototype for a new family of growth factor receptors. The c-MET oncogene is expressed in several types of epithelial tissue including keratinocytes and is over-expressed in a number of human carcinomas. Studies on various carcinoma cell lines have shown that over-expression and structural alteration of the receptor result in its activation and confer tumorigenesis. We have studied Met/HGF receptor expression in tissue specimens from 34 patients with head and neck squamous cell carcinomas (HNSCC) and in 17 regional lymph node metastases. Western blot analysis was employed, using monoclonal antibodies directed against either the intracellular or extracellular domain of the receptor. Each sample was compared to its normal counterpart. The receptor did not show any major structural alterations in HNSCC tissues, but its expression was increased from 2- to 50-fold in about 70% of tumors. Immunohistochemistry then showed that the same antibodies stained only a few cells in the basal layer of normal squamous epithelium but intensely marked tumor cells. In the lymph node metastases of Met-positive tumors, receptor expression was maintained and sometimes increased with respect to primary tumors. Immunohistochemical analysis of the metastatic lymph nodes showed that cells were negative in the normal lymphatic tissue and strongly stained in tumor cells. Over-expression of the Met/HGF receptor was found at all tumor stages but was more significant in those associated with enlarged or multiple (N2-N3) lymph node metastases. These data show that expression of the Met/HGF receptor may be involved in the progression of HNSCC towards a metastatic phenotype and may be a useful marker of head and neck tumor cell spread to regional lymph nodes.

Conceptual schemata for terminology: a continuum from headings to values in patient records and messages.

We developed a technique of reverse engineering to extract a conceptual schema--also called "categorial structure" in the European standard CEN ENV 12264 (MoSe)--from a set of terminological phrases. The technique was originally applied to coding systems, ie. to large value sets. We applied this technique to subsets of two new terminological resources for message standards: headings of patient record from Clinical LOINC and names of "Context Groups" for structured reporting from SNOMED DICOM Microglossary (SDM). Both sources provide context-independent names for message fields and domains of admitted values. Therefore conceptual schemata on the potential content for a field are compatible with the ones on names of the fields themselves. Both kinds of schemata can be compared and integrated with conceptual schemata for the information system that manages the patient record. This continuity in the schemata allows the coupling of applications with different organization of data, and will facilitate mapping from an application to standard messages and viceversa. Moreover, the simplified representation produced according the MoSe approach is easy to understand by healthcare operators, allowing their progressive involvement in cooperative efforts of design, discussion and validation of the schemata.

A cooperative methodology to build conceptual models in medicine.

We designed a methodology to perform distribute activities on conceptual modelling among cooperating centers. Our methodology assigns responsibilities and tasks and regulates interactions preserving coherence; it passes through the construction of unambiguous paraphrases to make explicit the context within the original sources, and through their compositional representation in an intermediate language. The process is intrinsically iterative, with continuous feedbacks and refinements, alternating analytic view on details and synthetic view on regularities and structures. Our methodology is based on requirements and experience made in the first GALEN project, and was applied in the GALEN-IN-USE project to coordinate modelling activities of three teams of surgeons in Rome with activities of other partners, during the production of an extensive model of surgical procedures.

A second generation of terminological systems is coming.

Diverse achievements by recent computer-based terminological systems are outlining a new generation of systems (i.e. a "second generation"). We collected the relevant features of various advanced terminological systems and we systematized these features into four components of a unique framework. We review a set of systems according to our framework, and we discuss how standardization activities can support the evolution of computer-based terminological systems towards a complete set of new performances.

Pantaloon vein graft technique in tibial revascularization with arteriovenous fistula for limb salvage.

Graft patency and limb salvage in 91 successive patients operated upon between April 1989 and April 1994 with a human umbilical vein graft combined with an adjunctive arteriovenous fistula at the distal anastomosis of the prosthetic graft in a single limb were evaluated. All the patients operated on were in the 'limb salvage' category. On discharge from hospital 91% of the revascularized limbs were salvaged. Secondary cumulative patency at 57 months was 57.3% with a 61.5% limb salvage rate. This technique, which has anatomical and haemodynamic advantages, results in improved graft patency and foot salvage rates in patients with critical leg ischaemia and poor distal run-off when autologous saphenous vein is absent or cannot be used.

An ontological perspective on surgical procedures.

We studied terminological phrases on surgical procedures-from coding systems, controlled vocabularies, textbooks, and medical records-by an ontological point of view. A surgical procedure can be accurately described only by a set of sentences, in textbooks or surgical reports; a terminological phrase is just a short synthesis of that description. We outline three points of view actually used to construct a phrase, based on i) relevant phases and variants; ii) focus on structures, functions and pathologies; iii) evolution of information and decisions during the process of care. For each of them we discuss potential principles and mechanisms, with the aim of deriving guidelines to generate homogeneous systematic names, to organize regularities in classifications and nomenclatures, to normalize expressions in formal languages.

Temporary regression of recurrent squamous cell carcinoma of the head and neck is achieved with a low but not with a high dose of recombinant interleukin 2 injected perilymphatically.

The efficacy of ten daily injections of 500 or 500,000 U of recombinant interleukin 2 (IL-2) day-1 given 1.5 cm from the insertion of the sternocleidomastoid muscle on the mastoid was evaluated in 31 patients with recurrent head and neck squamous cell carcinoma. No toxic effects were noted. One complete response (CR) and three partial responses (PRs) were observed in the 16 patients who received 500 U of IL-2, whereas the higher dose was not effective. The CR was recorded in one of the seven patients with a oropharyngeal recurrence. Partial responses were obtained in 1/5 patients with hypopharyngeal recurrences, in 1/5 patients with oral cavity recurrences and 1/7 patients with laryngeal recurrences. The duration of the responses was 3-5 months and additional courses of ten injections of IL-2 had no further effect.

[Spontaneous limited dissection of the external iliac artery. Case report after 14 year follow-up]. / Spontane limitierte Dissektion der A. iliaca externa. Fallbeschreibung nach 14 Jahren Beobachtungszeit.

The case of a limited dissection of the external iliac artery in a 31-year-old woman is described. The clinical symptomatology was that of an acute ischemia of the right lower extremity. Histology revealed the existence of a cystic Medionecrosis. With reference to the literature, the clinical and surgical aspects are discussed.

[Loco-regional treatment with low and high doses of interleukin-2 of head and neck squamous cell carcinoma recurrences]. / Trattamento loco-regionale con basse ed alte dosi di interleuchina-2 di recidive di carcinomi squamosi della testa e del collo.

The present study reports the effects of repeated administration of two different doses of recombinant (r) Interleukin-2 (IL-2) around tumor-draining lymph nodes in 22 patients with recurrent squamous cell carcinoma of the head and neck (HNSCC). Each patient was randomly assigned a dose of 500 or 500,000 IU/r-IL-2/day. Inoculation was made at a depth of 15 mm in the anterior margin of the sternocleidomastoid muscle at 15 mm from its insertion into the mastoid. The injections were made on the same side as the recurrent tumor when draining lymph nodes were still present and contralaterally when only contralateral lymph nodes were present. The 10 daily injection were followed by an interval without treatment until day 40. A further three courses of 10 injections were made at thirty-day intervals in the absence of a CR. There was no toxicity. One complete response (CR) and 2 partial responses (PR) were observed in the 11 patients who received 500 U of IL-2, whereas the higher dose was not effective. The CR was recorded in the 4 patients with an oropharyngeal recurrence. One PR was obtained in the 4 patients with hypopharyngeal recurrences and one in 3 with oral cavity recurrences. Clinical responses were nearly always preceded by improvement of the functional impairment caused by tumour infiltrations of the upper respiratory-digestive organs. The responses lasted 3-5 months and additional courses of 10 injections of IL-2 had no further effects.

Immunomodulation therapy for squamous cell carcinoma of the head and neck.

The role of the immune system in the pathogenesis and treatment of cancer is currently a popular area of research. An underlying fundamental concept of cancer immunology is the supposition that tumor cells express antigens differently than normal cells, both qualitatively and quantitatively. Understanding tumor-host interactions may suggest opportunities to modify these relationships to obtain antitumor effects. There is growing evidence that the immune system plays an important role in the pathogenesis of squamous cell carcinoma of the head and neck (SCCHN). Based on this evidence, trials studying the therapeutic efficacy of biologic response modifiers (BRMs) have been undertaken. These trials have had variable success, but continued efforts incorporating newer cytokines are underway.

[Local immunity following treatment with S-carboxymethylcysteine-lysine in tracheotomy patients]. / Immunità locale in seguito a trattamento con S-carbossimetilcisteina sale di lisina nei soggetti tracheotomizzati.

Pathological modification in secretory IgA values as well as in circadian rhythms were found in tracheotomized patients in both nasal and tracheo-bronchial secretions. The protective role of the mucosal immune system in addition to the frequency of severe infectious respiratory diseases in laryngectomized patients justifies the efforts of clinicians to prevent and treat such modifications. Mucoregulatory drugs have a peculiar role in these therapeutical attempts. Forty tracheotomized subjects with neoplastic disease were studied. Twenty received SCMC-Lys as a mucoregulatory drug. IgA 7S, 11S and albumin values in nasal and tracheo-bronchial secretions, were evaluated at surgery, 15 and then 40 days later. In accordance with clinical data, an improvement in local antibody production, damaged by tracheostomy, was found in the treated group. The influence of SCMS-Lys on SIgA production, whose evaluation was made by means of an original, highly selective and sensitive Immuno-IsoElectroFocusing procedure, seems to encourage the use of mucoregulatory drugs in laryngectomized patients.

Interleukin 2 receptors on squamous cell carcinomas of the head and neck. Characterization and functional role.

IL2Rs, in the presence of IL2, mediate activation and proliferation of human normal lymphocytes and modulate functional changes of some human leukocytic malignancies. IL2Rs have been demonstrated also on human neoplastic and fetal non-hematologic cells in vitro, although their functional role has not been described. We describe the presence of high affinity IL2Rs on squamous cell carcinoma of the head and neck (SCCHN) lines in vitro. Expression of 200 binding sites for IL2 with an affinity of 17 x 10(-12) was demonstrated by radiobinding experiments. When cytocentrifuged SCCHN cells were studied by immunoperoxidase staining, strong positive staining was repeatedly obtained using a monoclonal antibody to the p70 subunit of the IL2Rs. Experiments in vitro and in vivo, in a nude mouse model, showed a functional role for these receptors. In fact, low doses (8-500 U/ml) of IL2 were able to inhibit growth of 11 of the 16 SCCHN lines tested. Our observations may have broad implications for the immunotherapy of cancer in general, showing the complementary immunomodulatory and direct effects of IL2.