Nadja Dornhöfer

Lysyl oxidase is essential for hypoxia-induced metastasis

Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell or cell–matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

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.

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.

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.

Vulvovaginal reconstruction for neoplastic disease

Current treatment of neoplastic disease that involves the external female genitalia aims to achieve local disease control, but not to restore form and function of these organs. Despite a growing trend to reduce the extent of surgical resection, impaired quality of life after surgery due to severe sexual dysfunction and disturbed body image is common. We postulate that the integration of surgical techniques for vulvar and vaginal reconstruction into primary treatment would improve aesthetic and functional results and therefore quality of life. We systematically searched the literature for surgical procedures designed and validated for vulvovaginal reconstruction. Various skin flaps, both with random vascularisation and those based on vascular territories (ie, axial pattern, fasciocutaneous, musculocutaneous, and bowel flaps), can restore important parts of vulvovaginal form and function with acceptable morbidity at the donor and recipient sites. Appropriate vulvovaginal reconstruction cannot be achieved by doing a few standardised procedures; rather, it necessitates specialists who are familiar with general principles of reconstructive surgery to master many techniques to select the optimum procedure for the individual patient. Vulvovaginal reconstructive surgery has limitations, particularly achievement of functional restoration in irradiated tissue. Physicians who treat women with neoplastic disease of the external genitalia should be aware of the current state of vulvovaginal reconstructive surgery. Prospective controlled clinical trials are warranted to assess the effect of vulvovaginal reconstruction on morbidity and quality of life after treatment.

New insights into the biology of preeclampsia

Abstract Despite recent research progress, the biology of preeclampsia is still poorly understood and neither effective prediction nor causal therapy have yet emerged. Nevertheless, recent studies have documented new and exciting pathophysiological mechanisms for the origin and development of preeclampsia. These studies provide a more differentiated view on alterations of particular peptide systems with strong impact on angiogenesis and cardiovascular regulation in this pregnancy disorder. With the identification of the antiangiogenic factor soluble fms-like tyrosine kinase 1 and the agonistic autoantibody to the angiotensin II type 1 receptor, two factors have been described with a clear linkage to the development of the disease. This review focuses on the most recent and relevant insights into the biology of preeclampsia and develops hypotheses regarding possible links between the reported aspects of preeclampsia.

Obesity as an Obstetric Risk Factor: Does It Matter in a Perinatal Center?

Objectives: Obesity before and during pregnancy is associated with several obstetrics risk factors for both mother and fetus. The aim of this retrospective study was to analyze the influence of BMI before pregnancy on distinct perinatal parameters.

Ontogenetic anatomy of the distal vagina: Relevance for local tumor spread and implications for cancer surgery

OBJECTIVE We have suggested to base cancer surgery on ontogenetic anatomy and the compartment theory of tumor permeation in order to improve local tumor control and to lower treatment-related morbidity. Following the validation of this concept for the uterine cervix, proximal vagina and vulva, this study explores its applicability for the distal vagina. METHODS Serial transverse sections of female embryos and fetuses aged 8-17 weeks were assessed for the morphological changes in the region defined by the deep urogenital sinus-vaginal plate complex. Histopathological pattern analysis of local tumor spread was performed with carcinomas of the lower genital tract involving the distal vagina to test the compartment theory. RESULTS Ontogenetically, the female urethra, urethrovaginal septum, distal vagina and rectovaginal septum represent a morphogenetic unit derived from the deep urogenital sinus-vaginal plate complex. Herein, the posterior urethra, the urethrovaginal septum and the distal vagina form a distinct subcompartment differentiated from the dorsal wall of the urogenital sinus. From 150 consecutive patients with distal vaginectomy as part of their surgical treatment 26 carcinomas of the lower genital tract had infiltrated the distal vagina. All 22 tumors involving the ventral wall invaded the urethra/periurethral tissue. Of the five carcinomas involving the dorsal wall none invaded the rectum/mesorectum. CONCLUSION The pattern of local tumor permeation of lower genital tract cancer in the distal vagina can be consistently explained with ontogenetic anatomy and the compartment theory.

New Developments in the Surgical Therapy of Cervical Carcinoma

For almost a century abdominal radical hysterectomy has been the standard surgical treatment of early‐stage macroscopic carcinoma of the uterine cervix. The excessive parametrial resection of the original procedures of Wertheim, Okabayashi, and Meigs has later been “tailored” to tumor extent. Systematic pelvic and eventually periaortic lymph node dissection is performed to identify and treat regional disease. Adjuvant (chemo)radiation therapy is liberally added to improve locoregional tumor control when histopathological risk factors are present. The therapeutic index of the current surgical treatment, particularly if combined with radiation, appears to be inferior to that of primary chemoradiation as an oncologically equivalent therapeutic alternative. Several avenues of new conceptual and technical developments have been used since the 1990s with the goal of improving the therapeutic index. These are: surgical staging, including sentinel node biopsy and nodal debulking; minimal access and recently robotic radical hysterectomy; fertility‐preserving surgery; nerve‐sparing radical hysterectomy; total mesometrial resection based on developmentally defined surgical anatomy; and supraradical hysterectomy. The superiority of these new developments over the standard treatment remains to be demonstrated by controlled prospective trials. Multimodality therapy including surgery for locally advanced disease represents another area of clinical research. Both neoadjuvant chemotherapy followed by radical surgery, with or without adjuvant radiation, and completion surgery after (chemo)radiation are feasible and have to be compared to primary chemoradiation as the new nonsurgical treatment standard. Surgical treatment of postirradiation persisting or recurrent cervical carcinoma has been traditionally limited to pelvic exenteration for central disease. Applying the principle of developmentally derived anatomical compartments increases R0 resectability. The laterally extended endopelvic resection allows even the extirpation of a subset of visceral pelvic side wall tumors with clear margins. Many questions regarding the indication for these “ultraradical” operations, the surgery of irradiated tissues, and the optimal reconstructive procedures are still open and demand multi‐institutional controlled trials to be answered.

Treatment of early endometrial carcinoma: is less more?

Endometrial carcinoma is the most common gynaeco logical cancer in developed countries, with an annual inci dence of more than 20 women in 100 000. Postmenopausal women are predominantly aff ected, and the disease can have a slow natural course of progres sion; 70% of tumours are diagnosed at stage I when confi ned to the uterine corpus. Consequently, 5-year disease-specifi c survival is high at 80% overall. Stage I endometrial carcinoma constitutes a range of tumours with 5-year survival ranging from over 95% to less than 50%, related to histopathological risk factors. Most patients die from distant metastases, but pelvic disease is found in 45–65% of relapsing patients who did not receive adjuvant therapy. Isolated vaginal recurrence is the dominant type of pelvic relapse. The mainstay of surgical treatment for early-stage endo metrial cancer, including stage I and stage IIA (additional endocervical gland involvement), is total hysterectomy with bilateral salpingo-oophorectomy (THBSO). To improve locoregional tumour control, THBSO can be supple mented with lymph-node dissection, adjuvant external beam radiotherapy (EBRT), and vaginal brachy therapy. Pelvic and periaortic lymphadenectomy is done as surgical staging, although a therapeutic eff ect has been assumed. The presence of lymph-node metastases is regarded as an indication for adjuvant pelvic EBRT. If nodal status is unknown, histopathological features of the primary tumour, such as histological type, grade, and depth of myometrial invasion predicting an increased risk of extrauterine disease, are used as surrogates. Additional therapies increase treatment-related mor bidity, which can be aggravated by comorbidities associated with older age and obesity in many patients. These therapies are widely applied and recommended in practice guidelines, although current evidence is insuffi cient to prove a benefi t in survival or quality of life. Two large randomised studies published in The Lancet today should aff ect current clinical practice and direct future research. The ASTEC surgical trial randomised just over 1400 women with endometrial carcinoma, preoperatively thought to be confi ned to the uterine corpus, to systematic pelvic lymph-node dissection, defi ned as removal of the iliac and obturator nodes, or not, in addition to standard THBSO. Irrespective of lymph-node status, patients whose hysterectomy specimens showed intermediate-risk and highrisk features entered the ASTEC radiotherapy trial, being randomised to pelvic EBRT or not. The ASTEC data were combined with those from the Canadian EN.5 study which had a similar design (except it was not linked to another trial that randomised for lymphnode dissection), yielding just over 900 women. Moreover, a meta-analysis of fi ndings from ASTEC/ EN.5 and two previously published trials (PORTEC 1 and GOG 99) was done, including a total of more than 2000 patients. The important fi ndings from these studies are that in early-stage intermediate-risk and high-risk endometrial carcinoma, pelvic lymph-node dissection improved neither pelvic control nor overall survival; pelvic EBRT reduced pelvic recurrences but did not increase survival. In addition to higher treatment costs, both pelvic lymph-node dissection and EBRT were associated with about 50% more moderate and severe complications and late sequelae. The authors conclude that neither pelvic lymph-node dissection nor EBRT can be recommended in addition to