Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research.

OBJECTIVES: Palliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes. METHODS: This was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients ≥18 enrolled in a PC programme. RESULTS: 30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21-97); median Karnofsky score 70 (10-100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and χ2 tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001). CONCLUSIONS: There is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01362816.

Preferences for place of death if faced with advanced cancer: a population survey in England, Flanders, Germany, Italy, the Netherlands, Portugal and Spain.

BACKGROUND: Cancer end-of-life care (EoLC) policies assume people want to die at home. We aimed to examine variations in preferences for place of death cross-nationally. METHODS: A telephone survey of a random sample of individuals aged ≥16 in England, Flanders, Germany, Italy, the Netherlands, Portugal and Spain. We determined where people would prefer to die if they had a serious illness such as advanced cancer, facilitating circumstances, personal values and experiences of illness, death and dying. RESULTS: Of 9344 participants, between 51% (95% CI: 48% to 54%) in Portugal and 84% (95% CI: 82% to 86%) in the Netherlands would prefer to die at home. Cross-national analysis found there to be an influence of circumstances and values but not of experiences of illness, death and dying. Four factors were associated with a preference for home death in more than one country: younger age up to 70+ (Germany, the Netherlands, Portugal, Spain), increased importance of dying in the preferred place (England, Germany, Portugal, Spain), prioritizing keeping a positive attitude (Germany, Spain) and wanting to involve family in decisions if incapable (Flanders, Portugal). CONCLUSIONS: At least two-thirds of people prefer a home death in all but one country studied. The strong association with personal values suggests keeping home care at the heart of cancer EoLC.

First Report of Amylostereum areolatum in Pines in the United States.

The wood decay fungus Amylostereum areolatum (Fr.) Boidin, native to Eurasia and North Africa (4), is the mycosymbiont of several siricid woodwasps including Sirex noctilio Fabricius, a major pest of pines in New Zealand, Australia, South America, and South Africa where it has been introduced. Adult females of S. noctilio are effective vectors of arthrospores (hyphal fragments) of the fungus, stored internally within mycangia in the abdomen, which are injected with the eggs and a phytotoxic mucus into the outer sapwood of coniferous tree hosts during oviposition. The toxin is translocated upward into the foliage causing needle wilting, necrosis, and crown dieback. The fungus decays the wood (white rot) and provides food for hatching larvae that form borer galleries. Extensive damage to the host via wood decay, galleries, and toxin effects cause mortality in heavily infested trees. S. noctilio adults have been intercepted from several locations in North America prior to 2003, but there has been no evidence of an established population in any native forests until recently. In September 2004, a single adult female was collected from a funnel-trap at the edge of a forest stand in Fulton, NY (Oswego County) and identified in February 2005 (3). A local survey in May 2005 revealed red pines and Scotch pines infested with siricid larvae on the SUNY Oswego campus and in Rice Creek Nature Preserve, 3 km from campus. All larvae from infested trees were identified as S. noctilio using the DNA barcode method (2). Bole sections of infested red pines were sent to the USDA-ARS quarantine facility in Stoneville, MS. Wood samples, taken from areas of incipient decay adjacent to larval galleries, were plated onto 4.5% potato dextrose agar. Fungal colonies in pure cultures arising from wood pieces were appressed and exhibited microscopic characters typical of A. areolatum. Molecular confirmation of identifications for nine isolates was achieved by PCR amplification and sequencing of the rDNA internal transcribed spacer (ITS) region using ITS1 and ITS4 universal primer pairs. BLAST program analyses of these sequences compared against the NCBI GenBank database revealed the isolates were identical (GenBank Accession No. FJ040860) and had 98.8 to 99.8% sequence homology with five A. areolatum GenBank sequences (AF454428, AY781245, AF218389, EU249343, and EU249344) from Germany, Sweden, Japan, and Canada. To our knowledge, this represents the first confirmed isolation of A. areolatum from a native pine stand in the United States and confirms the first incidence of infections of North American pines, 16 months prior to isolations in Ontario (1). This insect vector-decay fungus complex, native to Eurasia, has a very high-risk rating and threatens many pine (Pinus) species in North America, particularly southern U.S. species that have been severely attacked and killed where introduced in the Southern Hemisphere. The lack of complete sequence homology between New York and Ontario, Canada strains of A. areolatum suggests that these recent incidences probably resulted from multiple woodwasp introductions rather than from vector (S. noctilio female) movement after one introduction. References: (1) M. J. Bergeron et al. Plant Dis. 92:1138, 2008. (2) P. D. N. Hebert et al. Proc. R. Soc. Lond. B 270:313, 2003. (3) E. R. Hoebeke et al. Newsl. Mich. Entomol. Soc. 50:24, 2005. (4) J. P. Spradbery and A. A. Kirk. Bull. Entomol. Res. 68:341, 1978.

Pain assessment tools in palliative care: an urgent need for consensus.

At present, there is no universally accepted cancer pain assessment tool for use in palliative care (PC). The European Palliative Care Research Collaborative (EPCRC), therefore, aims to develop an international consensus-based computerised pain assessment tool. As part of this process, we have performed (1) a literature review on pain assessment tools for use in the PC and (2) an international expert survey to gain information on the relevant dimensions for pain assessment in PC. 230 publications were identified, only six met the inclusion criteria. Three further articles were identified through manual searching, totalling 11 different pain assessment tools. Nine tools were multidimensional. Pain intensity was assessed in seven, using various numerical/verbal rating scales (NRS/VRS); five tools focused on pain management. Three publications did not identify the rationale for the need to develop a new tool, and the selection procedure for items/dimensions was not described in six tools. Patient and/or professional expert groups were involved in the development of five tools and only two tools were extensively validated or cross-culturally tested. Thirty-two experts (71%) completed the expert survey and identified 'intensity', 'temporal pattern', 'relief/exacerbation', 'pain quality' and 'location' as the five most relevant dimensions. Most preferred assessment of 'pain intensity' was by NRS rather than VRS. Time windows extending 24 h were regarded as less relevant. Development of PC pain assessment tools seems to be a continuous process, which does not adhere to systematic guidelines, thus does not contribute to a universally accepted tool. No tool contained all relevant dimensions as defined by the experts. Many tools focused on particular dimensions, suggesting that specific research interests may drive the tool development process. Extensive literature reviews, expert and patient input and clinical studies are a needed approach in the development of a new consensus-based pain assessment tool.

The Nordic Specialist Course in Palliative Medicine: evaluation and experiences from the first course 2003-2005.

BACKGROUND AND AIMS: Palliative medicine is not recognized as a medical specialty in any of the five Nordic countries, but there is a great need for physicians with specialty qualifications to serve on an increasing number of palliative care services. The Associations for Palliative Medicine in the five countries agreed to develop a common Nordic course on a specialty level. RESULTS: A theoretical training course in six modules in two years was developed, based on the British palliative medicine curriculum and including a limited research project and a written exam. Twenty-two out of 30 students completed the first course as scheduled in 2005, and five more have obtained their course diploma later. The evaluation from the students showed very satisfactory personal experiences and subjective learning outcomes, and a positive influence on the overall development of palliative care in the respective countries. CONCLUSION: The Nordic Specialist Course in Palliative Medicine has proved a successful Nordic collaboration and may form the basis for a full specialist training programme.

Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Sialorrhea is a frequent problem in ALS patients with bulbar symptoms, because of progressive weakness of oral, lingual and pharyngeal muscles. This prospective study aimed to investigate the putative effect of palliative single-dose radiotherapy on problematic sialorrhea in patients with ALS. Twenty patients with ALS and problematic drooling were included; 14 were given radiotherapy with a single fraction of 7.5 Grey (Gy). Five patients were treated with botulinum toxin A (BTX-A) injections (20 U) into the parotid glands; two of these were later given radiotherapy. Symptom assessment, clinical examination and measurements of salivary flow (ml/min) were performed before and after treatment (1-2 weeks, 3 months). Salivary secretion was significantly reduced after radiation treatment, with a mean reduction of 60% (1 week) and 51% (2 weeks). Three months post-treatment, 21% reduction of the salivary secretion was observed compared with salivation before treatment. Mean salivary flow was not reduced after BTX-A treatment in five patients. No serious side-effects were observed with either of the two treatment modalities. Single-dose radiotherapy (7.5 Gy) significantly reduces sialorrhea and is an effective and safe palliative treatment in patients with ALS.

The amount of treatment versus quality of life in patients formerly treated for head and neck squamous cell carcinomas.

The aim of the present study was to investigate the association between the self-reported quality of life (QoL) versus the initial TNM stage and amount of primary and recurrent tumor therapy given in a population of formerly treated head and neck squamous cell carcinoma (HNSCC) patients. We determined QoL by the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ) C30/H&N35 by structured interview. One hundred and twenty-two patients less than 80 years old, who had been diagnosed with HNSCC in western Norway in the period from 1992 to1997, and who had survived until 2000, were identified. Of these patients, 106 were eligible to be included. Ninety-six of these patients agreed to be interviewed. For TNM stage as well as the type of therapy given (local surgery, neck dissection or radiation therapy), T stage predicted the general QoL scores. Both increased TNM stage and all given tumor therapy seemingly caused lower H&N symptom QoL scores. Of the various tumor treatments employed, neck radiation therapy and neck dissection were indicated to be the most closely associated with the H&N QoL scores. Having neck dissection performed seemingly caused impairment beyond what was explained by the initial TNM stage. In conclusion, tumor therapy to HNSCC should not be restricted due to general QoL considerations. Further study of how and when to perform neck treatment is suggested in order to avoid unnecessary reduced H&N QoL.

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy.

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin (P = 0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 (P = 0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations (P = 0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death (P = 0.001 and P = 0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Difference in patterns of Met expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue.

Met protein is a tyrosine kinase receptor for hepatocyte growth factor (HGF). c-Met has morphogenic, mitogenic, and motogenic properties and is overexpressed in many solid tumors. We studied c-met mRNA and protein expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue. The c-met mRNA was detected in all biopsies by reverse transcriptase-polymerase chain reaction and by hybridization of complex cDNA probes to a c-met-specific DNA fragment in a dot blot array. Immunohistochemistry on fresh frozen biopsies showed Met protein localized along the basal cell membrane of normal thyrocytes in 32 of 35 nonneoplastic thyroid tissue specimens, sometimes associated with weak cytoplasmic reactivity but without apical cell membrane staining. In papillary carcinomas an increased Met protein expression was seen, comprising a cytoplasmic (33 of 49) and apical cell membrane (24 of 49) immunoreactivity, whereas only 1 of 49 biopsies showed basal cell membrane staining. A 145-kDa Met-specific band was detected by Western immunoblotting on protein extracts from papillary carcinomas. The tight junction protein zona occludens-1 (ZO-1), studied by immunohistochemistry, was weakly expressed along the apical cell membrane in 10 nonneoplastic biopsies. In contrast, increased and cytoplasmic/apical membranous ZO-1 immunostaining was seen in 11 of 15 papillary carcinomas. Nuclear ZO-1 staining was present in a few papillary carcinomas with partial dedifferentiation. The concomitant overexpression and subcellular redistribution of Met and ZO-1 proteins indicate a change in cell polarity in papillary carcinomas compared to nonneoplastic thyroid tissue. These observations may reflect an important feature of the tumorigenesis of papillary thyroid carcinomas. No significant association was found between semiquantitative immunohistochemical assessment of Met protein and clinical parameters in papillary carcinoma patients.

Expression and alternative splicing of c-ret RNA in papillary thyroid carcinomas.

Somatic rearrangements of the ret receptor tyrosine kinase have been consistently reported in papillary thyroid carcinomas (PTC). It is unclear whether the expression of wild-type c-ret may also be implicated in thyroid tumorigenesis. We studied ret mRNA expression in PTC from Norwegian patients. Using RT-PCR, wild-type ret mRNA was detected in all of 22 PTC and in a PTC cell line. c-ret mRNA was clearly overexpressed in PTC as compared to non-neoplastic thyroid tissue. Hybridization using ret exon DNA dot blot arrays and complex cDNA probes confirmed expression of ret RNA in thyroid biopsies. In accordance with the RNA data, Western immunoblotting showed evidence of wild-type Ret protein in PTC. Rearrangements generating the ret/PTC oncogenes co-existed with c-ret mRNA in PTC. Multiple alternative ret splicing variants were detected in PTC. Four novel ret splicing events were found in the region encoding the extracellular domain. The open reading frames of these transcripts were all in-frame with the Ret tyrosine kinase domain. In the central ret mRNA region encoding the cysteine-rich, transmembrane, and main tyrosine kinase domains, no evidence of alternative splicing was detected. Two alternative splice events were detected in the ret mRNA encoding the C-terminal part of Ret protein harboring tyrosine residues important for Ret signaling, excluding exon 19, or retaining intron 19, respectively. Ribonuclease protection assays confirmed the presence of ret alternative splicing events in thyroid biopsies. We conclude that in addition to ret/PTC rearrangements, wild-type c-ret mRNA and alternatively spliced ret transcripts are present in PTC. Transcriptional up-regulation and post-transcriptional mechanisms of c-ret RNA processing may contribute to differences in expression of Ret protein observed in PTC compared to non-neoplastic thyroid tissue.

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer.

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.

Expression of heregulins and associations with the ErbB family of tyrosine kinase receptors in papillary thyroid carcinomas.

Heregulin (Hrg) growth factors are natural ligands for ErbB3 and ErbB4. Because these receptors are involved in papillary thyroid carcinomas, we studied expression of Hrgs in fresh-frozen thyroid tissue and analyzed for possible coexpressions among the 4 members of the ErbB family of growth factor receptors and Hrgs in papillary carcinomas. Immunohistochemistry for the Hrg precursor isoform (134 biopsies from 101 patients) showed nuclear immunostaining in 83% of papillary carcinomas but not in normal thyroid tissue. Cytoplasmic immunopositivity for the Hrg precursor isoform was moderate or strong in 78% of papillary carcinoma specimens and weak in 13% of normal thyroid tissue samples. Western blot for the Hrg precursor isoform showed the expected protein band of approximately 70 kDa in papillary carcinomas, but not in non-neoplastic thyroid biopsies. Whereas weak cytoplasmic immunostaining for the mature Hrg alpha, beta1, and beta3, was present in 48, 38, and 51% of papillary carcinomas, respectively, normal thyroid tissue samples were negative. Hrg mRNA was present in both tumor and nontumor tissue, with evidence of increased mRNA expression in 5 of 12 papillary carcinomas. RT-PCR of hrg mRNA, with subsequent DNA sequencing, confirmed the presence of hrg alpha, beta1, beta2, and beta3 mRNA in papillary carcinomas. In 55 papillary carcinomas, increased cytoplasmic immunostaining of the ErbB2 and ErbB3 receptors was significantly associated with each other and with cytoplasmic epidermal growth factor receptor (EGFR) immunoreactivity, indicating a common regulatory mechanism. Cytoplasmic staining for Hrg beta3 was significantly associated with ErbB3 immunostaining, indicating this receptor as the cognate one. The overexpression and nuclear localization of the Hrg precursor isoform were not associated with the expression of ErbB-receptors. This may reflect an unknown mechanism of action, possibly independent of the ErbB receptor system.

Enhanced expression of EGF receptor and low frequency of ras mutations in X-ray-induced rat thyroid tumours.

Radiation is recognized as a carcinogenic factor for the thyroid gland. In this experimental study, oncogene expression was investigated in radiation-induced rat thyroid tumours. Forty 3-month-old Wistar rats received X-ray-irradiation to the neck region; 40 animals were untreated controls. After 14 months, thyroid tumours had developed in 25 of the 29 irradiated animals still alive; 76% of these tumours were considered malignant. No tumours developed in controls. Mutations of codons 12-13 and 59-63 of H-, K- and N-ras were analysed by PCR-SSCP (single-strand conformation polymorphism analysis) and sequencing of DNA from thyroid tissue. SSCP indicated a ras mutation frequency of 8%, but only one K-ras codon 12 (Gly-Cys) mutation was confirmed by sequencing. Protooncogene expression was analysed by mRNA slot blot hybridization analysis and immunohistochemistry. K-ras mRNA expression and EGF receptor mRNA and protein expression were significantly increased in the irradiated animals compared with controls, and in tumours versus nontumour tissue. This study of radiation-induced rat thyroid tumours demonstrates that ras expression may be subject to changes apart from activating mutations. Increased expression of EGF receptor in the tumours parallels the situation in human thyroid cancer.

[Diagnostic molecular biology in solid tumors--thyroid gland]. / Diagnostisk molekylaerbiologi ved solide svulster--thyreoidea.

Thyroid cancer is not a common disease. It includes tumour types of great diversity in clinical course and molecular basis. Mutations of TSH-receptor, rearrangements of ret proto-oncogene, and altered expression of other tyrosine kinase growth factor receptors are characteristics of the follicular neoplasias and papillary carcinomas, while undifferentiated tumours harbour p53 mutations. Knowledge acquired to date has led to an increased understanding of thyroid growth and tumour development, but it has had no significant impact on diagnostic and treatment measures. On the other hand, the C-cell derived medullary carcinomas include familial cases where identification of germ-line ret mutations provides the basis for prophylactic thyroidectomy in affected individuals.

Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas.

c-erbB-3 and c-erbB-4 protein expression was analyzed using immunohistochemistry in 138 fresh-frozen thyroid tissue samples from 106 patients, including 56 cases of papillary thyroid carcinoma. Increased expression of c-erbB-3 and c-erbB-4 proteins was observed in papillary carcinomas compared to nonneoplastic thyroid tissue. No amplifications of the c-erbB-3 and c-erbB-4 genes were detected. Coexisting overexpression of epidermal growth factor receptor, c-erbB-2, c-erbB-3, and c-erbB-4 was demonstrated in 36 (64%) of 56 papillary thyroid carcinomas. These findings suggest a common regulatory mechanism for the type I (epidermal growth factor receptor-related) receptors in papillary thyroid carcinomas and provide numerous possibilities for functional receptor interactions.

Cytoplasmic localization of EGF receptor in papillary thyroid carcinomas: association with the 150-kDa receptor form.

We have previously reported that papillary thyroid carcinomas show an increased expression of EGFR mRNA and protein, compared to non-tumorous thyroid tissue. EGFR immunoreactivity was localized to the cytoplasm as well as to the membrane in papillary carcinomas. To further study EGFR protein expression in human thyroid tissue, we performed immunohistochemistry and Western blots of 64 different thyroid tissue samples from 36 patients, including 23 patients with papillary carcinomas. Two receptor forms were identified in human thyroid tissue, a 170-kDa and a 150-kDa form. The 150-kDa receptor form was more pronounced in papillary carcinomas, while the 170-kDa receptor was the dominant form in non-malignant thyroid tissues. Predominance of the 150-kDa EGFR in the tumour samples was associated with strong cytoplasmic EGFR staining. EGFR gene structure, protein synthesis and maturation were found to be normal. Immunoprecipitation and Western-blot analysis of EGFR from the human thyroid SGHTL-34 cells after increased ligand concentration showed a decreased amount of the mature 170-kDa receptor and a relative increase in the 150-kDa receptor. We have previously demonstrated the presence of a TGF-alpha-EGFR autocrine loop in papillary thyroid carcinomas, and this may explain increased receptor turnover and accumulation of a cytoplasmic degradation product.

Evidence against involvement of APC mutation in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is one of several tumours associated with familial adenomatous polyposis (FAP), an inherited tumour syndrome which appears to result from germ-line mutation of the APC tumour suppressor gene. Here we investigate the possibility that somatic mutation of APC might play a role in sporadic PTC. 16 cases of PTC together with matched normal tissue were examined by single-strand conformation polymorphism (SSCP) analysis, concentrating on the mutation cluster region (MCR) of the APC gene (codons 1286-1513). No evidence of mutation was observed in any sample. We conclude that APC mutation, at least in the MCR, is not a significant causal mechanism in sporadic PTC.

Academic health centers and health care reform.

There is increasing support for the proposition that academic health centers have a duty to accept broad responsibility for the health of their communities. The Health of the Public program has proposed that centers become directly involved in the social-political process as advocates for reform of the health care system. Such engagement raises important issues about the roles and responsibilities of centers and their faculties. To address these issues, the authors draw upon the available literature and their experiences in recent health care reform efforts in Minnesota and Vermont in which academic health center faculty participated. The authors discuss (1) the problematic balance between academic objectivity and social advocacy that faculty must attempt when they engage in the health care reform process; (2) the management of the sometimes divergent interests of academic health centers, some of their faculty, and society (including giving faculty permission to engage in reform efforts and developing a tacit understanding that distinguishes faculty positions on reform issues from the center's position on such issues); and (3) the challenge for centers to develop infrastructure support for health reform activities. The authors maintain that academic health centers' participation in the process of health care reform helps them fulfill the trust of the public that they are obligated to and ultimately depend on.

Demonstration of a TGF-alpha-EGF-receptor autocrine loop and c-myc protein over-expression in papillary thyroid carcinomas.

Autocrine growth stimulation has been identified in several types of human cancer. In the present study we wanted to establish whether autocrine stimulation of the epidermal-growth-factor receptor (EGF-r) by its ligand, transforming growth factor alpha (TGF-alpha) occurs in thyroid neoplasia. We examined 190 fresh, frozen thyroid tissue samples from 70 patients by immunohistochemistry with antibodies to EGF-r, TGF-alpha, c-erbB-2 and c-myc. EGF-r expression was detected in 17 out of 19 papillary carcinomas, TGF-alpha expression in 10, and c-erbB-2 expression in 15. No papillary carcinoma expressed TGF-alpha without also expressing EGF-r. Concomitant expression of EGF-r, TGF-alpha and c-erbB-2 was seen in 7 papillary carcinomas. No EGF-r, TGF-alpha or c-erbB-2 immunopositivity was found in normal-appearing thyroid tissue (25 cases), whereas a few of the non-neoplastic lesions (colloid goitres and diffuse hyperplasias) expressed either EGF-r or TGF-alpha. c-myc expression was detectable in all tissue samples, and expression was invariably nuclear. Increased expression was observed in 10 out of 19 papillary carcinomas, and 8 of these also co-expressed EGF-r and TGF-alpha. In situ hybridization confirmed the presence of TGF-alpha mRNA in tumour epithelium of TGF-alpha-immunopositive samples. The concomitant expression of EGF-r, TGF-alpha and TGF-alpha mRNA gives evidence for a TGF-alpha-EGF-r autocrine loop in thyroid papillary carcinomas. The increased c-myc expression may reflect the proliferative advantage of these tumours.