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Biomedical subjects

Michael Höckel

Publications and source records attributed to Michael Höckel.

At least 19 recordsLinked to original sources
PubMed2006

Expression of erythropoietin and erythropoietin receptor in cervical cancer and relationship to survival, hypoxia, and apoptosis.

PURPOSE: Physiologically, hypoxia induces the expression of erythropoietin (Epo) in adult kidney cells. Epo, in turn, acts on the Epo receptor (EpoR) in RBC precursors to stimulate growth and prevent apoptosis. Because hypoxia plays a major role in the malignant progression of tumors and Epo and its receptors have also been detected in malignant tumors, we investigated the expression of Epo and EpoR and their relationship with hypoxia, proliferation, apoptosis, and clinicopathologic variables in cervical cancer. EXPERIMENTAL DESIGN: Intratumoral oxygen measurement and needle biopsies of the tumors were done in 48 patients with cervical cancer. The obtained tissue was analyzed by immunohistochemistry with antibodies against Epo, EpoR, and Ki-67 as well as by terminal deoxynucleotidyl transferase-mediated deoxyuracil triphosphate nick-end labeling assays. RESULTS: Epo and EpoR were expressed in 88% and 92% of samples, respectively. Cervical cancers with higher Epo expression showed a significantly reduced overall survival (3 years, 50.0% versus 80.6%; P = 0.0084). Epo and EpoR expression correlated significantly with apoptosis (r = 0.49, P = 0.001 and r = 0.36, P = 0.021). Furthermore, EpoR expression correlated significantly with tumor size (r = 0.32, P = 0.032) and was significantly associated with the presence of lymphovascular space involvement (P = 0.037). However, we observed no correlation between Epo or EpoR expression and intratumoral hypoxia, although in well-oxygenated tumors, EpoR localized significantly more often to the invasion front (P = 0.047). CONCLUSIONS: This study analyzes Epo/EpoR expression and their relationship with intratumoral pO(2) levels as well as with survival in patients with cervical cancer. The data suggest a critical role of the endogenous Epo/EpoR system in cervical cancer.

Adult↗
PubMed2006

Tumor hypoxia and expression of c-met in cervical cancer.

OBJECTIVES: Hypoxia enhances malignant progression by promoting the development of metastases and increasing invasiveness. One key regulator that controls growth, invasion and metastasis in cancer cells is the growth factor receptor c-met. The aim of this study, therefore, was to investigate the expression of the c-met protooncogene in cervical cancers in relation to intratumoral hypoxia levels and to clinico-pathological parameters. METHODS: 43 Patients with cervical cancer were subjected to intratumoral pO(2) measurement with the Eppendorf electrode and biopsies were taken. The tissue was subsequently analyzed by immunohistochemistry with an anti-c-met antibody. RESULTS: c-met was expressed in 72% of cervical cancers. There was a significantly stronger expression in poorly differentiated tumors (r=0.4, p=0.008). Furthermore, c-met expression was significantly associated with a spray-like pattern of invasion (p=0.008). However, there was no significant relationship between c-met expression and intratumoral hypoxia, pT stage, FIGO stage, lymphovascular space involvement, tumor size or overall survival. CONCLUSIONS: Although c-met has been shown to be hypoxia-induced in vitro, our results suggest that it is not the mediator of deleterious effects of hypoxia on clinical outcome in cervical cancer.

Adult↗
PubMed2006

Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis.

Pancreatic cancer is highly aggressive and refractory to most existing therapies. Past studies have shown that connective tissue growth factor (CTGF) expression is elevated in human pancreatic adenocarcinomas and some pancreatic cancer cell lines. To address whether and how CTGF influences tumor growth, we generated pancreatic tumor cell lines that overexpress different levels of human CTGF. The effect of CTGF overexpression on cell proliferation was measured in vitro in monolayer culture, suspension culture, or soft agar, and in vivo in tumor xenografts. Although there was no effect of CTGF expression on proliferation in two-dimensional cultures, anchorage-independent growth (AIG) was enhanced. The capacity of CTGF to enhance AIG in vitro was linked to enhanced pancreatic tumor growth in vivo when these cells were implanted s.c. in nude mice. Administration of a neutralizing CTGF-specific monoclonal antibody, FG-3019, had no effect on monolayer cell proliferation, but blocked AIG in soft agar. Consistent with this observation, anti-CTGF treatment of mice bearing established CTGF-expressing tumors abrogated CTGF-dependent tumor growth and inhibited lymph node metastases without any toxicity observed in normal tissue. Together, these studies implicate CTGF as a new target in pancreatic cancer and suggest that inhibition of CTGF with a human monoclonal antibody may control primary and metastatic tumor growth.

Animals↗
PubMed2006

Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: reality or wishful thinking?

BACKGROUND: Tumor hypoxia is considered to be relevant for several aspects of tumor pathophysiology, for acquired treatment resistance, and tumor progression (e. g., in cancers of the uterine cervix). Therefore, there is a demand for simple and universally applicable methods allowing the estimation of oxygenation status in patient material obtained during pretherapeutic diagnostic procedures (biopsies) or surgical treatment. Protein members of the transcriptional response to hypoxia expressed in tumor tissue, e. g., hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter-1 (GLUT-1) and carbonic anhydrase IX (CA IX) are currently being discussed as "endogenous hypoxia markers". MATERIAL AND METHODS: The (hypothetic) suitability of different markers for the assessment of the oxygenation status is reviewed on the basis of current knowledge. RESULTS: Data from studies investigating the suitability of different markers are conflicting. Although a robust induction of HIF-1alpha, GLUT-1 and CA IX by hypoxia has been demonstrated in vitro, this reaction is modulated both by confounding factors of the tumor microenvironment and intrinsic traits of malignant cells in vivo. CONCLUSION: On the basis of the available data, the suitability of "endogenous hypoxia markers" for the estimation of the oxygenation status of advanced cervix cancers seems questionable.

Biomarkers↗
PubMed2006

Impact of hemoglobin levels on tumor oxygenation: the higher, the better?

BACKGROUND AND PURPOSE: Tumor hypoxia has been linked to tumor progression, the development of treatment resistance, and thus poor prognosis. Since anemia is a major factor causing tumor hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation status has been examined. PATIENTS AND METHODS: Published data on the relationship between pretreatment cHb values and tumor oxygenation (in terms of median pO(2) values, hypoxic fractions) have been summarized. Pretreatment O(2) tension measurements were performed in histologically proven experimental tumors, human breast cancers, squamous cell carcinomas of the head and neck, and cancers of the uterine cervix and of the vulva. In order to allow for a comparison between solid tumors and normal tissues, pO(2) measurements were also performed in healthy tissue in anemic and nonanemic patients. cHb was determined at the time of the pO(2) measurements. RESULTS: Based on current information from experimental and clinical studies there is increasing evidence that anemia is associated with a detrimental tumor oxygenation status. Increasing cHb values are correlated with significantly higher pO(2) values and lower hypoxic fractions. Maximum tumor oxygenation in squamous cell carcinomas is observed at normal (gender-specific) cHb values (approximately 14 g/dl in women and approximately 15 g/dl in men). Above this "optimal" Hb range, the oxygenation status tends to worsen again. In anemic patients, tumor oxygenation is compromised due to a decreased O(2) transport capacity of the blood. At the upper edge of the Hb scale, a substantial increase in the blood's viscous resistance to flow in "chaotic" tumor microvessels is thought to be mainly responsible for the observed restriction of O(2) supply. CONCLUSION: Review of relevant clinical data suggests that a maximum oxygenation status in solid tumors is to be expected in the range 12 g/dl < cHb < 14 g/dl for women and 13 g/dl < cHb < 15 g/dl for men. Considering the "optimal" cHb range with regard to tumor oxygenation, the concept of "the higher, the better" is therefore no longer valid. This finding has potentially far-reaching implications in the clinical setting (e. g., inappropriate erythropoietin treatment of nonanemic tumor patients).

Adult↗
PubMed2006

Juxtatumoral desmoplastic stromal reaction is associated with high tumor cell dissociation in squamous cell carcinomas of the uterine cervix.

There are different types of tumoral growth patterns invading host tissue. During tumor infiltration, cancer cells not only destroy the pre-existing extracellular matrix, but usually induce new matrix formation by activating the peritumoral stromal cells; that is, desmoplastic stromal reaction (DSR) at the front of invasion (juxtatumoral stroma). This study evaluates the association between different types of invasion and DSR. Eighty-eight squamous cell carcinomas (Fédération Internationale de Gynécologie et d'Obstétrique [FIGO] stage IB to IV) were evaluated histologically for different patterns of invasion (PI) using a 3-level scoring system (pushing, finger-like, and spray-like). Desmoplastic stromal reaction was scored from none to weak, moderate, or strong. The pattern of invasion and DSR were compared with patients' age, FIGO stage, clinical tumor size, tumor grade, and the presence of lymphovascular space involvement. Finger-like PI was the most common (72.7%), followed by the spray-like PI (27.3%), whereas pushing PI was not seen. Of the tumors, 23.9% showed no DSR; 51.1%, weak; 14.8%, moderate; and 10.2%, strong DSR. Tumors with spray-like PI showed a significantly stronger desmoplastic reaction compared with the finger-like PI (P < .0001) and were significantly associated with poor tumor cell differentiation (P = .018). Moderate or strong DSR was associated with G2 and G3 carcinomas (P = .027). No correlation was seen neither for PI and DSR to lymphovascular space involvement, FIGO stage, and tumor size. The intensity of DSR, as understood in the context of a remodeling of the juxtatumoral stroma to the infiltrative tumor growth, might be indicative of a highly dissociative tumor growth and is correlated to poorly differentiated tumors.

Adult↗
PubMed2006

The status of cyclooxygenase-2 expression in ductal carcinoma in situ lesions and invasive breast cancer correlates to cyclooxygenase-2 expression in normal breast tissue.

OBJECTIVES: There is a paucity of data on cyclooxygenase (COX)-2 expression in normal breast tissue and on the changes in COX-2 expression from normal tissue via ductal carcinoma in situ (DCIS) lesions to invasive cancer. The aim of this study, therefore, was to investigate COX-2 protein expression in normal breast tissue, DCIS, and invasive breast cancer in samples from the same patients. METHODS: In 39 patients, we investigated and compared COX-2 expression in paired samples of invasive cancer and normal adjacent breast epithelium by immunohistochemistry with a monoclonal COX-2 antibody. Furthermore, in 29 of these cases, we also analyzed a concomitant DCIS lesion. RESULTS: Patients without COX-2 expression in normal breast tissue also do not express COX-2 in invasive breast cancer and in DCIS lesions, respectively. Conversely, COX-2 expression in normal breast tissue was an indicator for COX-2 expression in the paired breast tumors. There was no significant correlation between COX-2 expression and pathologic tumor stage, nodal status, hormone receptor status, tumor size, grading, and lymphovascular space involvement. CONCLUSIONS: This is the largest study to date investigating COX-2 in paired samples of breast tumors and normal adjacent breast tissue. Our data are consistent with the hypothesis that COX-2 overexpression is an early event in breast carcinogenesis.

Adult↗
PubMed2006

Pelvic exenteration for gynaecological tumours: achievements and unanswered questions.

Pelvic exenteration has been used for 60 years to treat cancers of the lower and middle female genital tract in radiated pelves. The mainstay for treatment success in terms of locoregional control and long-term survival is resection of the pelvic tumour with clear margins (R0). New ablative techniques based on developmentally derived surgical anatomy and laterally extended endopelvic resection have raised the number of R0 resections done, even for tumours that extend to the pelvic side wall, which were traditionally judged a contraindication for exenteration. Although mortality has fallen to less than 5%, treatment-related severe morbidity of pelvic exenteration still exceeds 50%, possibly because of compromised healing of irradiated tissue and use of complex reconstructive techniques. The benefits of exenteration for patients who have advanced primary disease or recurrent tumours after surgery, versus those who have chemoradiotherapy, are not proven by results of controlled trials, but can be assumed from retrospective data. Comparative findings are missing, and arguments are unconvincing to favour pelvic exenteration over less extensive treatments and best supportive care for palliation of cancer symptoms in most patients.

Female↗
PubMed2005

Clonal history of papillomavirus-induced dysplasia in the female lower genital tract.

BACKGROUND: Dysplastic lesions of the vagina or the vulva often occur in women who have a previous history of cervical dysplasia. Most lesions in the female lower genital tract are induced by infections with high-risk oncogenic human papillomaviruses (HR-HPVs), including HPV16 and HPV18. HR-HPV genomes frequently integrate into host cell chromosomes at random sites. We analyzed viral integration sites in multiple metachronous lesions of the lower genital tract from women previously treated for HR-HPV-positive cervical dysplasia or cancer to determine whether the metachronous lesions emerged from a single common preexisting dysplastic cell clone or as consequence of independent HR-HPV infection events in the female lower genital tract. METHODS: From among 1500 patients with anogenital lesions, seven patients with high-grade vaginal or vulvar lesions and with a previous history of cervical disease (five with prior high-grade cervical dysplasia and two with a history of cervical cancer) were included in this study. Integration sites of HPV16 or HPV18 in vaginal or vulvar lesions were mapped by an adaptor ligation polymerase chain reaction (PCR) method. The sequence information was used to design an integrate-specific PCR assay that was applied to DNA extracted from archival paraffin-embedded material derived from biopsy samples of cervical lesions. RESULTS: Identical HPV DNA integration loci were found in vaginal or vulvar and cervical samples of all lesions available for four of the five patients with a prior history of high-grade cervical dysplasia and for both patients with a history of cervical cancer. CONCLUSIONS: These data indicate that high-grade dysplastic lesions in the female lower genital tract may emerge primarily as monoclonal lesions from a transformed cell population derived from the uterine cervix.

Adult↗
PubMed2005

Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix.

PURPOSE: Carbonic anhydrase IX (CA IX) can be induced by hypoxia in vitro and shows an immunohistochemical expression pattern that is predominantly found in perinecrotic tumor areas and correlates with exogenous markers of hypoxia, such as pimonidazole. CA IX might therefore serve as an endogenous marker of tumor hypoxia, although comparisons of CA IX immunostaining with direct oxygenation measurements using pO2 microsensors have thus far yielded contradictory results. EXPERIMENTAL DESIGN: Because tumor heterogeneity may be among the factors responsible for the discrepancy between the two methods, CA IX expression in tissue samples originating from oxygen microelectrode tracks of locally advanced cervical cancers was assessed in this study. Seventy-seven biopsy specimens were analyzed immunohistochemically using an anti-CA IX rabbit polyclonal antibody and semiquantitative scoring. RESULTS: CA IX expression showed no correlation with the oxygenation variables median pO2 and hypoxic fraction 2.5, 5, or 10. Cases with higher International Federation of Gynecology and Obstetrics stages (IIb-IVa) exhibited stronger expression of CA IX (P = 0.035) and CA IX expression tended to be more prevalent in node-positive patients (P = 0.051). CONCLUSIONS: These data indicate that CA IX cannot be recommended as a substitute for oxygen microelectrode measurements. That the expression of CA IX does not correlate with the oxygenation status may be due to the degree to which other factors, such as nutrient (e.g., glucose) deficiency or the action of oncogenic mutations, can modulate the in vivo expression of this protein, rendering a strict association with tumor hypoxia too unreliable for clinical use.

Antigens, Neoplasm↗
PubMed2005

Association between the mesenchymal compartment of uterovaginal organogenesis and local tumour spread in stage IB-IIB cervical carcinoma: a prospective study.

BACKGROUND: Macroscopic, microscopic, and occult local tumour spread might be restricted to a permissive territory related to the morphogenesis of the tissue or organ from which the tumour originates. We aimed to define such a morphogenetic unit in Müllerian development, and to assess the role of total mesometrial resection in the treatment of patients with stage IB-IIB cervical carcinoma. METHODS: We analysed uterovaginal development in serial sections of female human embryos and fetuses, and defined the distal Müllerian morphogenetic unit from the Müllerian mesenchyme. We assessed prospectively the histopathological and clinical findings from patients who underwent total mesometrial resection-modified surgery for stage IB-IIB cervical carcinoma that aims to remove the uterus, proximal vagina, and extracervical mesenchyme within the borders of the distal Müllerian morphogenetic unit. FINDINGS: The spatial extension of the Müllerian mesenchyme, its vascularisation, and its innervation during early uterovaginal organogenesis determine a tissue territory that can be followed during fetal development and identified in women as a morphogenetic unit. 105 of 106 patients who had total mesometrial resection, 63 of whom were classed as high risk, had microscopically tumour-free resection margins (ie, R0). 48 (96%) of 50 patients had pelvic recurrence-free survival at 3 years (95% CI 92-100) without adjuvant radiotherapy. INTERPRETATION: Radical en-bloc resection of a topographically defined anatomical territory derived from common precursor tissue leads to local tumour control, preservation of autonomic nerves, and a reduced need for adjuvant radiotherapy.

Adult↗
PubMed2005

The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection.

After surgical resection with microscopically clear margins, solid malignant tumors recur locally in up to 50%. Although the effect of a local tumor recurrence on the overall survival may be low in common cancers such as carcinoma of the breast or prostate, the affected patients suffer from exacerbated fear and the burden of the secondary treatment. With some tumor entities such as carcinoma of the uterine cervix or carcinoma of the head and neck, a local recurrence indicates incurability in the majority of cases. The pathomechanisms of local tumor spread and relapse formation are still unclear and comparatively little research has been devoted to their elucidation. Through the analysis of clinical and molecular data, we propose the concept of two pathogenetically and prognostically different local relapse types (i) in situ recurrences that arise in the residual organ/organ system not involved in the surgery for the primary tumor and (ii) scar recurrences that develop at the site of previous tumor resection. Whereas field cancerization, the monoclonal or multiclonal displacement of normal epithelium by a genetically altered but microscopically undistinguishable homologue, may explain the origin of in situ recurrences, most scar recurrences are regarded as the result of the interaction of minimal residual microscopically occult cancer with the surgical wound environment inside a developmentally defined tissue or organ compartment. The therapeutic implications derived from these concepts and areas of future research aimed to reduce local relapses are discussed in this perspective.

Humans↗
PubMed2005

Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers.

PURPOSE: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated. EXPERIMENTAL DESIGN: The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tracks from locally advanced cervical cancers in 47 patients using immunohistochemistry. RESULTS: No correlation was found between the expression of GLUT-1 and oxygenation variables (median pO2, HF 2.5 and HF 5). Expression of GLUT-1 was found greater in larger tumors (P = 0.0001) and to exhibit a linear increase with Federation Internationale de Gynecologie et d' Obstetrique stage (P = 0.002). Overall survival (P = 0.004) and recurrence-free survival (P = 0.007) were significantly shorter for patients with expression of GLUT-1. In the subgroup of patients treated with surgery, this effect on prognosis was not independent when pT stage or pN stage were included in a multivariate Cox proportional hazards model. CONCLUSIONS: The suitability of GLUT-1 as an endogenous marker of tumor hypoxia seems questionable. The association with prognosis may partially depend on confounding factors.

Female↗
PubMed2005

A misdiagnosed case of caesarean scar pregnancy.

CASE REPORT: We report a case of an ectopic pregnancy in a caesarean section scar, which was initially misdiagnosed despite using ultrasound. For the first time, a strongly vascularised pelvic tumour developed while the titre of serum human chorionic gonadotrophin decreased after a curettage abortion for an unwanted pregnancy. OUTCOME: Due to uncontrollable haemorrhage, an emergency hysterectomy had to be performed 8 weeks later.

Adult↗
PubMed2005

Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion.

Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers. Hypoxia results from an imbalance between the supply and consumption of oxygen (O2). Major pathogenetic mechanisms for the emergence of hypoxia are (i) structural and functional abnormalities in the tumor microvasculature, (ii) an adverse diffusion geometry, and (iii) tumor-related and therapy-induced anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histology and grade. Hypoxia is intensified in anemic patients, especially in tumor (areas) with low perfusion rates. Tumor hypoxia is a therapeutic problem since it makes solid tumors resistant to sparsely ionizing radiation, some forms of chemotherapy, and photodynamic therapy. However, besides more direct mechanisms involved in the development of therapeutic resistance, there are, in addition, indirect machineries that can cause barriers to therapies. These include hypoxia-mediated alterations in gene expression, proteomic and genomic changes, and clonal selection. These in turn can drive subsequent events that are known to further increase resistance to therapy in addition to critically affecting long-term prognosis.

Anemia↗
PubMed2005

Expression of Apaf-1 in cervical cancer correlates with lymph node metastasis but not with intratumoral hypoxia.

OBJECTIVES: The aim of this study was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers. Moreover, we studied its correlation to intratumoral pO(2) and to clinico-pathological parameters. METHODS: 86 patients with cervical cancer were subjected to intratumoral pO(2) measurement with the Eppendorf electrode. From these patients, cervical cancer tissue was used for immunohistochemistry with an anti-Apaf-1 antibody. RESULTS: Apaf-1 is expressed in cervical cancer. Cervical cancers with strong or moderate Apaf-1 expression had significantly less lymph node metastases at time of surgery than tumors with weak or negative Apaf-1 expression (P = 0.022). There was no significant correlation between Apaf-1 expression and intratumoral pO(2), pT stage, FIGO stage, lymphovascular space involvement, and grade. CONCLUSIONS: Loss of Apaf-1 expression may represent a marker of aggressive tumor behavior since it correlates significantly with the occurrence of lymph node metastasis in cervical cancer.

Adult↗