A randomized controlled trial comparing surgical excisional biopsies using CO2 laser, Er:YAG laser and scalpel.

This randomized controlled trial (RCT) (ClinicalTrials.gov ID: NCT03001791) compared excisional biopsies of fibrous hyperplasia performed using a CO2 laser (140Hz, 400µs, 33mJ), Er:YAG laser (35Hz, 297µs, 200mJ, air-water cooling), or scalpel (15c blade). Clinical parameters recorded were duration of the intervention, intraoperative bleeding, need for electrocauterization and/or suturing, postoperative side effects, complications, pain, and intake of analgesics. Histopathological linear measurements of the thermal damage zone were performed on the laser biopsies. Results showed that the duration of the intervention was significantly shorter for both lasers compared to the scalpel (P<0.001). Intraoperative bleeding occurred less frequently with the CO2 laser (P<0.001). Additional electrocautery was used in 92% of Er:YAG laser interventions (P<0.001). Postsurgical complications, pain, and the intake of analgesics did not differ between the groups. The measured thermal damage zones differed significantly between the CO2 laser (median of 72.6µm) and Er:YAG laser (30.9µm) (P<0.001). This RCT showed that CO2 laser, Er:YAG laser, and scalpel are all adequate for excisional biopsies of small lesions in the oral mucosa. While patient postoperative morbidity is similar, the ideal instrument can be selected according to the surgical advantages preferred for the individual situation.

PRO_10--a new tissue-based prognostic multigene marker in patients with early estrogen receptor-positive breast cancer.

BACKGROUND/AIMS: Clinicopathological and molecular factors determine the prognosis of breast cancer. PRO_10 is a prognostic score based on quantitative RT-PCR of 10 proliferation-associated genes obtained from formalin-fixed, paraffin-embedded breast cancer tissues. We revalidated PRO_10 in patients treated in a non-trial setting. METHODS: The charts of 315 patients with postmenopausal estrogen receptor (ER)-positive breast cancer between 1996 and 2004 were reviewed. Forty-eight cases relapsed within 5 years of diagnosis; they were paired with controls by matching the N and T stage, histological grade, percent ER-positive cells, human epidermal growth factor receptor 2, age, adjuvant chemo- and endocrine therapy. The score was tested by conditional logistic regression. RESULTS: Despite strict matching, PRO_10 remained prognostic for recurrence in the whole group (odds ratio, OR = 4.7, p = 0.005) and in subgroups of grade 2 (OR = 5.5, p = 0.009) and N0 cancers (OR = 15, p = 0.002). Five-year recurrence-free survival was 29% in patients with high and 67% in patients with low scores (p = 0.002). PRO_10 was prognostic for overall survival (5-year overall survival 71 vs. 91%). CONCLUSION: PRO_10 is an independent prognostic marker in postmenopausal ER-positive breast cancer. It is based on formalin-fixed, paraffin-embedded tissue and could be integrated easily into the routine diagnostic workflow.

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients.

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). CONCLUSIONS: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.

[Laparoscopy in the management of endometrial cancer]. / Place de la laparoscopie dans le traitement du cancer de l'endomètre.

Recent advance in laparoscopy have changed the surgical approach of endometrial cancer patients. The Swissendos Center, Fribourg, in collaboration with AGO (Groupe de travail pour la gynécologie oncologique) and AGE (groupe de travail pour la gynécologie endoscopique) have established a consensus based on the available evidence for the use of laparoscopy in the management of patients with endometrial cancer The main objective was to define Swiss clinical practice guidelines appropriate to the country and consistent with the needs of the physicians.

A mixed epithelial and stromal tumor of the kidney in a ringtail lemur (Lemur catta).

Primary renal tumors are rare neoplasms in nonhuman primates. This report describes a mixed epithelial and stromal tumor of the kidney (MESTK) in a 14.5-year-old female ringtail lemur. The well-demarcated, solid, and cystic mass was located in the pelvis of the left kidney and consisted histologically of both epithelial and mesenchymal components. The mesenchymal cells were arranged in fascicles around cysts lined by a well-differentiated epithelium. Neither the mesenchymal nor the epithelial parts showed significant nuclear atypia or mitotic figures. To our knowledge, only 1 similar case, classified as adenoleiomyofibromatous hamartoma, has been reported in a ringtail lemur. In humans this tumor affects predominantly perimenopausal women and can express estrogen and progesterone receptors. However, neither estrogen nor progesterone receptors could be identified by immunohistochemistry in the tumor of the present ringtail lemur. Therefore, a hormonal mechanism could not be demonstrated in this case.

Human papillomavirus status in advanced cervical cancer: predictive and prognostic significance for curative radiation treatment.

Human papillomavirus (HPV) infection plays a major role in oncogenesis of squamous cell carcinoma of the cervix. This study was performed to investigate if HPV status and E2 gene integrity are prognostic parameters for clinical outcome and predictive for radiation response. Forty women with locally advanced cervical cancer treated with curative radiotherapy were analyzed for HPV infection and E2 gene integrity by multiplex polymerase chain reaction. Statistical analyses were performed for overall survival, disease-free survival (DFS), local progression-free survival, and treatment response (clinical complete remission). Twenty-eight (70%) of 40 carcinomas were HPV positive. The only significant factor for a better overall survival, DFS, and local progression-free survival was HPV positivity (P < 0.02, P= 0.02, and P < 0.05, log-rank, respectively). HPV-positive tumors had a significantly better clinical complete remission (67% vs 33%, P= 0.04, Fisher's exact test). An intact E2 gene region showed a trend for a better DFS (P= 0.1, log-rank). This study reveals HPV as an independent prognostic parameter for outcome and radiation response. Integration of the virus genome into host cell DNA might be a molecular target to determine the treatment response of HPV-positive cancers.

Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy.

Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, beta3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of beta3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of beta3-integrin. The impact of immunoreactivity for beta3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. beta3-integrin was expressed in 61% (50 of 82) of the patients. Kaplan-Meier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with beta3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. beta3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.

EGFR dependent expression of STAT3 (but not STAT1) in breast cancer.

STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Activation of c-Src and EGF receptor tyrosine kinases is associated with progression of breast cancer. Both these events lead to activation of STAT proteins, Src kinases activate STAT3 dependent transcription in mammary epithelial cells and EGF receptor activation can lead to activation of STATs 1 and 3. STAT3 activation has been demonstrated to have a role in oncogenesis and increasingly, activated STAT proteins are found to be activated in human cancer. In this study we describe detailed immunohistochemical analysis of nuclear and cytoplasmic STATs 1 and 3 expression in primary breast carcinomas and correlate this with EGFR, HER2, p53, ER, PR, p21/waf1, Bcl-XL and Ki-67 expression. We also compared expression between normal and tumor tissue. We report here a highly significant correlation between nuclear STAT3 expression and breast cancers compared to normal tissue. We also report a very strong correlation between nuclear STAT3 and EGFR expression in breast cancers. These data clearly demonstrate a strong association between STAT3 activation and breast tumorigenesis and strengthen the assertion that STAT3 activation may play an important role in the tumorigenic conversion of breast tissue mediated by tyrosine kinase signaling pathways.

Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours.

Prognosis of lung cancer is related to stage of disease at time of diagnosis. In this study we examine alterations of pathways governing the cell cycle, in particular pRb-cyclinD1-p16 alpha and p53-p14ARF, in a series of NSCLC (n=92) at different stages at diagnosis. Using immunohistochemistry, we assessed the expression of the retinoblastoma protein (pRb), cyclin D1, p16 alpha, p53 and p14ARF. Tumours in stage I-IIIA (resectable) were more likely to have alterations in the pRb-cyclinD1-p16 alpha pathway than tumours in advanced stage (IIIB-IV) (90% versus 63%, P=0.002). pRb and p14ARF were more frequently downregulated in resectable tumours (P< or =0.03), and cyclin D1, p16 alpha, and p53 were altered at a similar frequency in resectable and advanced tumours. In 12 patients, metastatic sites (5 lymph node, 3 bone, 2 brain and 2 gastrointestinal metastases) were available for comparison with the primary tumour: 19 altered protein expressions were found to be concordant, six additional alterations (in 4 patients) were found in the metastases only, especially in lymph node metastases (3 patients). Compared with normal protein expression, both pathway alterations were associated with a longer survival (P=0.02). In a multivariate analysis (Cox regression) this difference was not maintained after adjustment for age, stage and tumour differentiation. Cyclin D1 was the sole protein with independent prognostic value in resectable tumours: the relative risk of local relapse was 4.7 in tumours without cyclin D1 overexpression (P=0.02, Cox regression analysis). No protein studied had a predictive significance for response after chemotherapy in non-resectable tumours. These results demonstrate a strong correlation between stage and pathway alterations, cell cycle regulators being less likely altered in advanced NSCLC. Tumours with defects in these control pathways tend therefore to remain localised and to metastasize at a later phase in tumour development. This finding might be an explanation for distinct biological behaviour (e.g. chemotherapy response) of resectable versus advanced disease.

Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast.

BACKGROUND: Axl, a member of a family of receptor tyrosine kinases characterized by an extracellular domain resembling cell adhesion molecules and an intracellular conserved tyrosine kinase domain has been reported to induce cell proliferation and transformation. In mice, axl is expressed in the normal mammary gland and over-expressed in aggressive mammary tumors. PATIENTS AND METHODS: We have investigated the expression of axl immunohistochemically in 23 normal human breast samples and in 111 consecutive breast carcinomas. Expression of axl was correlated with tumour characteristics (lymph node involvement, stage, grade) and immunohistochemical expression of ER, PR, Ki-67 and c-erbB-2. RESULTS: In normal tissue, axl localizes to the membrane of breast epithelial cells. Axl protein shows membrane associated staining in high correlation (P = 0.004) with the expression of the estrogen receptor (ER). Axl expression was found in a subset of breast carcinomas and was also correlated with high significance (P < 0.0001) with the presence of ER. CONCLUSION: Our results suggest that axl may serve as a mediator of estrogen stimulation preventing the completion of the breast epithelial life cycle and that estrogen induced axl expression may give a survival signal to cancerous cells, preventing them from dying through apoptosis.

The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression.

Genes of the polycomb group function by silencing homeotic selector genes that regulate embryogenesis. In mice, downregulation of one of the polycomb genes, bmi-1, leads to neurological alterations and severe proliferative defects in lymphoid cells, whilst bmi-1 overexpression, together with upregulation of myc-1, induces lymphoma. An oncogenic function has been further supported in primary fibroblast studies where bmi-1 overexpression induces immortalization due to repression of p16/p19ARF, and where together with H-ras, it readily transforms MEFs. It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF). Tumours (48 resectable NSCLC (32 squamous, 9 adeno-, 2 large cell, 4 undifferentiated carcinomas and 1 carcinoid); stage I, 29, II, 7, III, 12; T1, 18, T2, 30; differentiation: G1 12, G2 19, G3 17) were studied by immunohistochemistry for protein expression and by comparative multiplex PCR for gene amplification analysis. In tumour-free, normal lung tissue from patients, weak - moderate bmi-1 staining was seen in some epithelial cells, lymphocytes, glandular cells and in fibroblasts, whereas blood, endothelial, chondrocytes, muscle cells and adipocytes did not exhibit any bmi-1 expression. In tumours, malignant cells were negative/weakly, moderately and strongly positive in 20, 22 and 6 cases, respectively. As assessed by multiplex PCR, bmi-1 gene amplification was not the reason for high-level bmi-1 expression. Tumours with moderate or strong bmi-1 expression were more likely to have low levels of p16 and p14ARF (P = 0.02). Similarly, tumours negative for both, p16 and p14ARF, exhibit moderate-strong bmi-1 staining. 58% of resectable NSCLC exhibit moderate-high levels of bmi-1 protein. The inverse correlation of bmi-1 and the INK4 locus proteins expression (p16/p14ARF) supports a possible role for bmi-1 misregulation in lung carcinogenesis.

Clear cell adenocarcinoma of the cervix associated with a rare genitourinary malformation.

BACKGROUND: Cervical adenocarcinoma and genitourinary malformations are relatively common disorders, yet their coexistence is rare. CASE: A 49-year-old woman developed clear cell adenocarcinoma in the atretic hemicervix of a communicating uterus type 7 and had ipsilateral renal agenesis. Compared with the unaffected right hemicervix, only the tumor-involved glands of the atretic left hemicervix contained ciliated tuboendometrial cells. Four and a half years after radical hysterectomy and pelvic radiation, she showed no evidence of recurrence. CONCLUSION: In contrast to current opinion, communicating uteri type 7 are associated with ipsilateral renal agenesis. Our histologic findings support the hypothesis that tuboendometrial cells are the cells of origin for cervical clear-cell adenocarcinoma.

Differential expression of p73 splice variants and protein in benign and malignant ovarian tumours.

The p73 gene encodes a protein with substantial structural and functional similarities to the tumour-suppressor p53. Alternative splicing of p73 mRNA leads to expression of 6 known RNA species and proteins (alpha, beta, gamma, delta, epsilon, zeta). We analysed the expression of these splice variants in ovarian adenocarcinoma by RT-PCR followed by detection of amplicons with the Southern technique and by immunoblot in 32 malignant and benign epithelial ovarian tumour specimens and 3 ovarian adenocarcinoma cell lines (A2780, 2008, OVCAR-3). p73alpha mRNA was expressed in all 17 ovarian cancer specimens, and 14 of 17 expressed at least 3 splice variants. In contrast, a different expression pattern was present in the ovarian adenomas: p73alpha was detected in 6 of 12 benign tumours, and only 1 adenoma expressed 3 splice variants. p73 protein was expressed in 9 of 16 ovarian cancer specimens, in all cell lines and in 1 of 3 borderline tumours. In contrast, none of 9 ovarian adenomas expressed detectable amounts of p73 protein. Expression of p73 mRNA and protein was not correlated with FIGO stage and histological grade, but we observed a significant correlation with over-expression of p53 protein. In summary, epithelial ovarian cancers express a more complex p73 isoform pattern and higher levels of p73 mRNA and protein than ovarian adenomas.

Paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological complication in adults with extracerebral neoplasms. It is characterized by a diffuse cerebellar dysfunction, usually leading to severe neurological sequelae. In childhood, this complication is extremely rare. We report on PCD as primary manifestation of Hodgkin disease (HD) in a thirteen-year old boy. On magnetic resonance imaging, irreversible atrophy of the cerebellum developed within three months. Antibodies against Purkinje cells were detectable at diagnosis and normalised after successful treatment of the lymphoma. Cerebellar symptoms, however, only partially resolved. The necessity of a search for a malignant tumour is emphasised in the presence of an otherwise unexplained, subacutely developing, diffuse cerebellar dysfunction.

p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non-small cell lung cancer.

p21 (p21WAF1/CIP1) is involved in cell cycle regulation, as an inhibitor of cyclin dependent kinases (CDK2, CDK4 and CDK6). However, subsequent in vitro studies have suggested that p21 may influence this process by an additional mechanism, in particular through the regulation of cyclin D1 subcellular localisation. This study of primary resectable non-small cell lung cancer (NSCLC) was designed to examine p21 functions in association with the expression of cyclin D1 (including its subcellular localisation), p16INK4a and pRb. p21 expression was examined in 50 NSCLC (stage I-IIIA) and in several normal lung samples all of which had previously been studied for cyclin D1 (DNA, RT-PCR, immunostaining), p16INK4a (DNA, RT-PCR, immunostaining), and pRb (immunostaining). As assessed by immunoblotting and immunostaining, p21 was expressed at low levels in normal lung tissue with immunoreactivity seen in a small number of bronchial epithelial cells only. In NSCLC, p21 expression (> or =10% of positive cells) was observed in 42% (21/50) of cases. High p21 expression was associated with well differentiated tumours (p = 0.01) and cyclin D1 nuclear staining (p = 0.02). Furthermore, we found an inverse correlation with p16INK4a (p = 0.004) and a direct correlation with pRb expression (p = 0.02). Risk of relapse was associated with p16INK4a and p21 status with no relapse in patients with normal p16INK4a and p21. Our results confirm that a large number of NSCLC have a low level of p21 expression. The associations of p21 and nuclear cyclin D1, pRb, p16INK4a support the relevance of pathways linked to lung carcinogenesis that involve p21 but may act in addition to direct CDK inhibition.

Hormone-dependent nuclear localization of the tyrosine kinase iyk in the normal human breast epithelium and loss of expression during carcinogenesis.

iyk, a member of the frk family of non-receptor tyrosine kinases, was originally isolated from normal mouse mammary glands and is characterized by a nuclear localizing signal within the SH2 domain. We have investigated the expression and subcellular localization of iyk in the normal human breast and in malignant breast diseases. Immuno-histochemical analyses revealed that in normal tissue iyk localizes to both cytoplasmic and nuclear compartments of breast epithelial cells. The subcellular distribution was dependent on the hormonal state, being mostly cytoplasmic during the follicular, proliferative phase of the menstrual cycle, whereas frequent nuclear staining was observed in the resting stages during the luteal phase and, most prominently, after menopause. Strikingly, invasive carcinomas, irrespective of tumor type or hormonal status of the patient, exhibited almost complete loss of iyk expression in both the cytoplasm and the nucleus. In contrast, in situ breast carcinomas from post-menopausal patients showed a clear reduction of the nuclear iyk localization while retaining cytoplasmic staining. Our results indicate that iyk expression is gradually lost during carcinogenesis; thus, iyk may be classified as a tumor-suppressor gene.

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts.

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1-4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC. Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model.

Expression of apoptosis regulatory proteins of the Bcl-2 family and p53 in primary resected non-small-cell lung cancer.

Proteins of the Bcl-2 family as well as p53 are important regulators of apoptosis. Alterations in the expression of these proteins can contribute to the formation of cancer, as well as influence tumour response to chemo- and radiotherapy. We used antibodies specific for the human Bcl-2, Mcl-1, Bax, Bak and p53 proteins to examine the expression of these apoptosis-regulating genes in 49 archival specimens of patients with radically resected non-small-cell lung cancer (NSCLC). Tumour cells containing immunostaining for the antiapoptotic proteins Bcl-2 and Mcl-1 were present in 31% and 58% of the cases evaluated, respectively, whereas immunopositivity for the proapoptotic proteins Bax and Bak was found in 47% and 58% of the samples. p53 immunopositivity was detected in 61% of the samples. The expression of Bcl-2 and p53 and the expression of Mcl-1 and Bax showed a positive association (P = 0.02 and P = 0.06 respectively), whereas the expression of Bax was inversely related to p53 (P = 0.008). The expression of Bcl-2 had a negative influence on relapse-free survival in this population of primary resected NSCLC patients (P = 0.02). The expression of p53 and Bcl-2 was significantly associated with metastasis-free survival (P < 0.01). Only patients with p53-positive tumours developed metastases during the follow-up period. Our results establish the frequent expression of the Bcl-2 family proteins Bcl-2, Mcl-1, Bax and Bak in NSCLC. It can be expected that Bcl-2 family members have no straightforward impact on clinical outcome in this disease because their interactions in the regulation of apoptosis are complex.

Lymphadenectomy in high risk endometrial carcinoma stage I and II: no more morbidity and no need for external pelvic radiation.

The objectives of this retrospective study were to analyze the morbidity of surgical staging and to evaluate the omission of external radiotherapy in high-risk patients with stage I and II endometrial carcinoma when the lymph nodes were negative. From 1988 to 1996, 63 of 117 patients underwent a pelvic and periaortic lymphadenectomy. The decision to perform lymphadenectomy was influenced by patient general health. Patients with lymphadenectomy had a better physical status (P < 0.0001). Lymphadenectomy increased mean operative time (P < 0.0001) and blood loss (P < 0.01), but there was no increase in postoperative complications. At a median follow-up of 54 months, there was one cuff recurrence in 56 patients. Nineteen high-risk patients without external pelvic radiation had the same disease-free survival rate as 37 low-risk patients (P = 0.1). In the group without lymphadenectomy, the disease-free survival for 18 high-risk patients and 32 low-risk patients was similar (P = 0.21). Surgical staging in properly selected patients does not increase postoperative complications and brachytherapy without external radiotherapy is associated with excellent disease-free survival when the lymph nodes are negative.

mTHPC Polymer Conjugates: The In Vivo Photodynamic Activity of Four Candidate Compounds.

The in vivo photodynamic activities of four poly(ethylene glycol) (PEG) conjugates of the photosensitiser 5,10,15,20-tetrakis-(m-hydroxyphenyl)chlorin (mTHPC, temoporfin, Foscan(®)) were compared with that of mTHPC over a range of drug-light intervals using acute tumour necrosis and skeletal muscles swelling in a mouse model in order to ascertain the influence of linking group stability and PEG chain length on the photodynamic activity. The four compounds examined contained either PEG 2000 or PEG 5000 attached by carbonate or triazine linkages at the phenol hydroxyl groups of the mTHPC.All compounds tested caused tumour necrosis at drug-light intervals of between one and four days. mTHPC produced tumour necrosis of over 5 mm at drug-light intervals of 1 and 2 days with limited muscle damage at early drug-light intervals. The relatively labile carbonate-linked conjugates gave tumour necrosis similar to mTHPC but produced severe muscle and systemic phototoxicity on irradiation at 4-24 h after injection. The more stable triazine-linked conjugates produced no significant muscle damage at any of the drug-light intervals tested, but gave only limited tumour necrosis under the conditions tested. PEG chain length had relatively little effect on the patterns of bioactivity.It is concluded that both classes of mTHPC PEG conjugates may be suitable for photodynamic therapy if the problems of stability and early photosensitivity in the case of the carbonates and reduced potency in the case of the triazines can be overcome through improved formulations and PDT treatment regimens.