HER-2-Positive Tumors: A Continuously Evolving Field in Cancer Research.

Almost 25 years ago, trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), was licensed for the treatment of patients with metastatic HER2-positive breast cancer in the United States of America (USA) [...].

Global cervical cancer research: A scientometric density equalizing mapping and socioeconomic analysis.

Cervical cancer has caused substantial morbidity and mortality for millions of women over the past decades. While enormous progress has been made in diagnosis, prevention and therapy, the disease is still fatal for many women-especially in low-income countries. Since no detailed studies are available on the worldwide research landscape, we here investigated the global scientific output related to this cancer type by an established protocol. The "New Quality and Quantity Indices in Science" platform assessed all relevant cervical cancer research published in the Web of Science since 1900. A detailed analysis was conducted including country-specific research productivity, indicators for scientific quality, and relation of research activity to socioeconomic and epidemiologic figures. Visualization of data was generated by the use of density equalizing map projections. Our approach identified 22,185 articles specifically related to cervical cancer. From a global viewpoint, the United States of America was the dominating country in absolute numbers, being followed by China and Japan. By contrast, the European countries Sweden, Austria, and Norway were positioned first when the research activity was related to the population number. When the scientific productivity was related to annual cervical cancer cases, Scandinavian countries (Finland #1, Sweden #4, Norway #5, Denmark #7), the Alpine countries Austria (#2) and Switzerland (#6), and the Netherlands (#3) were leading the field. Density equalizing mapping visualized that large parts of Africa and South America were almost invisible regarding the global participation in cervical cancer research. Our data documented that worldwide cervical cancer research activity is continuously increasing but is imbalanced from a global viewpoint. Also, the study indicated that global and public health aspects should be strengthened in cervical carcinoma research in order to empower more countries to take part in international research activities.

Endometrial cancer: mapping the global landscape of research.

BACKGROUND: From a global viewpoint, endometrial cancer belongs to the most common female cancers. Despite the heavy burden of diseases and numerous unanswered questions, no detailed pictures of the global structure of endometrial cancer research are available so far. Therefore, this malignancy was reviewed using the New Quality and Quantity Indices in Science (NewQIS) protocol. METHODS: Using NewQIS, we identified endometrial carcinoma related research published in the Web of Science from 1900-2015 (P1) and from 2016-2020 (P2). Item analysis was performed with regard to research activity. Also, semi-qualitative aspects and socio-economic benchmarks were visualized using density equalizing mapping. RESULTS: In total, 9,141 from 1900-2015 and 4,593 from 2016-2020 endometrial cancer related studies were identified with the USA having the largest numbers of publications, citations, institutions, as well as the highest country-specific h-Index concerning endometrial cancer research in both periods. In contrast to other fields of cancer research, the two East Asian countries Japan and China followed concerning total research activities until 2015. From 2016 until 2020, China was found in short distance to the USA and was ranked second. In the socio-economic analysis, European countries were in prominent positions. Greece published 579.83 endometrial carcinoma-related articles per billion US-$ GDP, Finland (527.29), Sweden (494.65), Israel (493.75), and Norway (367.85) followed in the ranking. Density equalizing mapping visualized that large parts of Africa, Asia and South America with a high burden of disease played almost no visible role in the endometrial cancer research activities. CONCLUSIONS: Endometrial cancer research activity is continuously increasing from a global viewpoint. However, the majority of original articles is published by authors based in high-income countries. Together with the finding that the research field of public health does only play a minimal role, our study points to the necessity that global health aspects should be introduced to endometrial cancer research.

Molecular Subtype Conversion between Primary and Metastatic Breast Cancer Corresponding to the Dynamics of Apoptotic and Intact Circulating Tumor Cells.

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis.

Von Willebrand factor (VWF) serves as a nidus for platelet aggregation and thrombosis. We hypothesize that VWF fibers contribute to the development of venous thromboembolism (VTE) and to metastasis formation. Here, we show that vascular and lymphatic endothelial cells (ECs) express VWF in vitro and release VWF fibers after activation by tumor cell supernatants. In contrast, an ex vivo analysis of primary mouse tumors revealed the presence of VWF fibers in the blood microvasculature but not in lymphatic vessels. Unlike the anticoagulant Fondaparinux, an inhibitor of thrombin generation, the low-molecular-weight heparin (LMWH) Tinzaparin inhibited VWF fiber formation and vessel occlusion in tumor vessels by blocking thrombin-induced EC activation and vascular endothelial growth factor-A (VEGF-A)-mediated VWF release. Intradermal tumor cell inoculation in VWF- and ADAMTS13-deficient mice did not alter lymph node metastases compared with wild type animals. Interestingly, multiple tumor-free distal organs exhibited hallmarks of malignancy-related VTE, including luminal VWF fibers, platelet-rich thrombi and vessel occlusions. Furthermore, ADAMTS13 deficiency, characterized by prolonged intraluminal VWF network lifetimes, resulted in a severely increased number of metastatic foci in an experimental model of hematogenous lung seeding. Treatment with Tinzaparin inhibited tumor-induced release of VWF multimers, impeded platelet aggregation and decreased lung metastasis. Thus, our data strongly suggest a critical role of luminal VWF fibers in determining the occurrence of thrombosis and cancer metastasis. Moreover, the findings highlight LMWHs as therapeutic strategy to treat thrombotic complications while executing anti-metastatic activities.

Lack of difference in acute nephrotoxicity of intravenous bisphosphonates zoledronic acid and ibandronate in women with breast cancer and bone metastases.

BACKGROUND: More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents. PATIENTS AND METHODS: The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and ß2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group. RESULTS: We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group. CONCLUSION: Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.

Growth-modulatory effects of heparin and VEGF165 on the choriocarcinoma cell-line JEG-3 and its expression of heparanase.

BACKGROUND: Expression of heparanase (HPSE) in tumor cells is strongly associated with invasion, metastasis and angiogenesis. It also plays a key role during pregnancy, in processes of implantation as well as placentation. Vascular endothelial growth factor (VEGF) and heparin are known to alter HPSE expression, with heparin given prophylactically to women with a history of placenta-mediated complications in subsequent pregnancies. MATERIALS AND METHODS: We examined the growth-modulatory effects of different concentrations of heparin and VEGF on the choriocarcinoma cell-line JEG-3 and the expression of heparanase under VEGF and heparin by proliferation assays, PCR, and western blot. RESULTS: Proliferation of JEG-3 cells was induced by heparin in a dose-dependent manner, whereas highly concentrated VEGF led to a decreased cell proliferation. Both agents did not influence the HPSE-expression. CONCLUSION: The presumed pregnancy-protecting effects of heparin may partially be due to an increase of trophoblast proliferation and not via regulation of HPSE expression.

Hybrid approach of retractor-based and conventional laparoscopy enabling minimally invasive hysterectomy in a morbidly obese patient: case report and review of the literature.

Minimally invasive hysterectomy in obese patients may be limited by laparoscopic sight on the one hand and by intraoperative complications related to reduced ventilation due to pneumoperitoneum on the other. Retractor-based laparoscopy offers an operative technique reducing anesthesia risks. We report the case of laparoscopic hysterectomy in an obese patient of short stature. Laparoscopic supracervical hysterectomy was performed by a hybrid approach of a retractor system exerting its effects on lifting the abdominal wall through gravity and conventional laparoscopy, thus bypassing the adverse effects of pneumoperitoneum on ventilation.

Therapeutic drugs in the treatment of symptomatic uterine fibroids.

INTRODUCTION: The therapy of symptomatic uterine fibroids is based on surgery in the majority of cases. Conservative medical treatment in cases of contraindication against operative treatment, bleeding control or preoperative down-sizing of the fibroids is classically based on sex steroid depletion by gonadotropin-releasing hormone (GnRH) agonist administration for a prolonged period. However, this approach is associated with often severe climacteric side effects and fibroids quickly relapse after treatment cessation. Furthermore, the achievement of menstrual bleeding control has been tried by administration of combined oral contraceptives, progestins or the levonorgestrel-releasing intrauterine device. These approaches, however, are not associated with a significant reduction in fibroid volume. AREAS COVERED: With the introduction of Ulipristal acetate (UPA), a new selective progesterone receptor modulator (SPRM) is now licensed for the preoperative treatment of fibroids. The administration should be limited to 3 months. UPA induces amenorrhea within a relatively short term of - on average - 7 days and may thus reduce fibroid-induced anemia. Furthermore, a significant reduction of the fibroid volume persisting after cessation of the treatment could be demonstrated for UPA. Herein, a review of the current therapeutic options for conservative and preoperative medical fibroid treatment is given and the clinical utility of UPA is outlined. EXPERT OPINION: In contrast to precedent myoma medication, volume reduction of the fibroids persists several months after cessation of UPA-administration. UPA optimizes operative conditions and thus the postoperative outcome by reducing anemia and down-sizing of fibroids.

Influence of acetic acid on a pap smear of dysplastic lesion.

BACKGROUND: Cervical cancer prevention is performed by taking Pap smears. The correct execution of the smear is crucial as an inadequate smear might result in underdiagnosis. The second means of cervical cancer prevention is visual inspection of the cervix uteri with acetic acid, while often both methods are combined. We investigated whether the application of acetic acid compromises the Pap smear. PATIENTS AND METHODS: A total of 100 patients with dysplasia were prospectively included; Pap smears were obtained before and after the application of acetic acid. RESULTS: We observed an alteration of the result of the Pap smear after acetic acid application in 41%. However, these alterations did not result in a dysplastic case being classed as a normal smear or vice versa. CONCLUSION: The application of acetic acid to the transformation zone of the cervix uteri may enhance changes of the Pap smear in dysplasia, however, the changes affect subgroups of dysplasia and thus do not change therapeutic management.

Intrauterine growth restriction and the innate immune system in preterm infants of ≤32 weeks gestation.

OBJECTIVE: Intrauterine growth restriction (IUGR) is a well-known cause of adverse neonatal outcomes. As it may have an impact on innate immune responses, we aimed to investigate several parameters of the innate immune response in preterm infants of ≤32 weeks gestation who were small for gestational age (SGA). METHODS: We compared clinical data of SGA (n = 20) and appropriate for gestational age (AGA; n = 124) newborns with a gestational age of ≤32 weeks. We investigated full blood counts at birth and on days 3 and 7 of life and cytokine immune responses in a human whole cord blood assay. RESULTS: SGA preterm infants had a higher risk of the combined outcome mortality or bronchopulmonary dysplasia. Numbers of white blood cells and neutrophils were diminished in SGA infants at birth and on day 3. At birth, platelet counts were also diminished while the number of nucleated red blood cells tended to be elevated in SGA infants. After stimulation of whole blood cell cultures with lipopolysaccharides, the concentrations of interleukin-6 and interleukin-10 were significantly lower in SGA preterm infants compared to AGA infants. CONCLUSIONS: SGA infants differ remarkably from AGA infants in full blood counts and in their ability to mount an immune response. Whether the quantitative deficiency in innate immunity plays a role for adverse outcomes needs to be investigated in larger future trials.

Cancer in pregnancy. Part I: basic diagnostic and therapeutic principles and treatment of gynecological malignancies.

PURPOSE: Cancer in pregnancy is a rare circumstance. However, the coincidence of pregnancy and malignancy is supposed to increase due to a general tendency of postponing childbearing to older age. To date, clinical guidelines are scarce and experience regarding therapeutic management is limited to case reports. METHODS: This review focuses on general diagnostic and therapeutic principles including systemic therapy for malignancies in pregnancy. RESULTS: In part I, we report on diagnosis and therapy of gynecological tumors. CONCLUSION: The diagnosis of gestational cancer faces both oncologist and obstetrician to the dilemma of applying appropriate diagnostic techniques and adequate local and systemic therapy to an expectant mother without harming the fetus.

Primary metastasized extraskeletal Ewing sarcoma of the vulva: report of a case and review of the literature.

PURPOSE: Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are closely related malignant neoplasms, usually affecting the skeletal system. Extraosseous ES/PNETs are uncommon, with occasional reports of tumors affecting the genitourinary tract. Only few cases of primary vulvar Ewing's sarcoma/PNET have previously been reported. METHODS: We present a patient with primary vulvar Ewing's sarcoma with pulmonary metastasis who presented at the Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Campus Luebeck. RESULTS: The present report is the third case of a primary vulvar Ewing's sarcoma and the first constellation with pulmonary metastasis at diagnosis in the current literature. We present the diagnostic and therapeutic management including surgery, chemotherapy and radiation. CONCLUSION: The treatment of the Ewing's sarcomas and PNETs requires a multidisciplinary systemic approach. Despite its rarity, the differential diagnosis of vulvar sarcoma must be considered in young women.

Cancer in pregnancy. Part II: treatment options of breast and other non-gynecological malignancies.

PURPOSE: In case of non-gynecological solid tumors and hematological malignancies diagnosed during pregnancy, individual diagnostic and treatment options must be established by an interdisciplinary team. METHODS: In part II of the present review we report on diagnostic and therapeutic principles in distinct entities of solid and hematological malignancies. RESULTS: On the basis of a review of the current literature, clinical guidelines and algorithms have been established for diagnosis and therapy of maternal cancer during pregnancy. CONCLUSIONS: The prognosis of the malignancy and the patient's informed consent must be taken into consideration when the well-being of the expectant mother is weighed against the well-being of the unborn child in case of maternal cancer during pregnancy.

Spontaneous uterine rupture at the 21st week of gestation caused by placenta percreta.

PURPOSE: To describe the management of a ruptured uterus caused by placenta percreta in the 21st week of gestation. METHODS: We present a case report of a 33-year-old patient with a ruptured uterus in the 21st week of gestation who presented at the Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Campus Luebeck. Therapeutic management was performed by laparoscopy, and consecutive laparotomy and hysterectomy. RESULTS: A 33-year-old patient presented with severe abdominal pain in the 21st week of gestation at the department of abdominal surgery. A laparoscopy was performed to exclude appendicitis. There was about one liter of blood in the peritoneal cavity and a small, bleeding lesion in the fundus uteri was found which was coagulated. The blood was evacuated and the patient returned to department of gynecology. One hour after the first operation, the patient developed signs of hypovolemic shock and ultrasound showed absent fetal heart beat. An immediate laparotomy was performed and a ruptured uterus was detected. The fetus was removed and a hysterectomy performed. Pathology results showed a placenta percreta. After a few days in hospital and transfusion of 4 liters of blood the patient was discharged in a healthy condition. CONCLUSIONS: In a pregnant woman with severe abdominal pain even in the 21st week of gestation a placenta percreta has to be considered as a differential diagnosis. If there is no evidence of other causes, laparoscopy may help to confirm the diagnosis and hysterectomy is a life saving intervention.

Current diagnostic modalities and clinical pitfalls in malignant secondary breast tumours.

Breast cancer is the most common malignancy in women with increasing incidence. The occurrence of metastatic disease to the breast in both females and males is relatively rare, constituting 0.5-6% of all breast malignancies. The therapy of secondary breast cancer is usually completely different from that of primary malignant lesions. Thus, early confirmation of secondary involvement is crucial to direct appropriate and to avoid potentially harmful treatment. The main focus remains to include secondary breast involvement in the differential diagnosis of breast tumours. In recent years, a number of new or improved imaging modalities have been introduced in the diagnosis of breast neoplasm. Current diagnostic concepts of metastatic neoplasm to the breast, including latest imaging modalities and their possible future applications, are presented in this review with special emphasis on possible pitfalls.

Does acetic acid influence the non-dysplastic Pap smear?

OBJECTIVE: Acetic acid tests are commonly performed for colposcopic evaluation of the cervix. However, it is unclear whether the acetic acid influences normal Papanicolaou (Pap) smear results. METHODS: Patients were routinely seen in our outpatient department between April and May 2009. Two Pap smears were performed in 50 patients. One smear was done before, the other after the acetic acid test. The smears were evaluated by an experienced cytologist. He did not know whether the smear was done with or without acetic acid. RESULTS: In a normal smear, there was no influence of acetic acid on the cytologic result. In two patients, a smear of Pap III [Bethesda, atypical squamous cells of undetermined significance (ASCUS)] was seen before acetic acid test. This changed to Pap IIID [Bethesda, low-grade squamous epithelial lesions (LSIL)] after acetic acid test. CONCLUSIONS: The acetic acid test does not seem to alter the result of the non-dysplastic smear. In contrast to this, a dysplastic smear seems to be influenced by the acetic acid. This should be evaluated in a further investigation.

Standardized technique of laparoscopic pelvic and para-aortic lymphadenectomy in gynecologic cancer optimizes the perioperative outcomes.

INTRODUCTION: The main objective of this study is to illustrate the effectiveness and the safety of standardized technique of laparoscopic lymphadenectomy (LNE), newly introduced in a University Hospital, in patients with gynecologic malignancy. MATERIALS AND METHODS: A cohort of 104 patients with gynaecologic malignancies (71 with endometrial and 33 with cervical cancer), who underwent laparoscopic pelvic with or without para-aortic LNE between September 2008 and March 2010, were analyzed. Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy (TLH & BSO) was the standard approach for patients with endometrial cancer (n = 71), while laparoscopic (nerve sparing) radical hysterectomy (n = 29), laparoscopic-assisted radical vaginal hysterectomy (n = 2) and radical trachelectomy was the treatment for patients with cervical cancer. All LNE were performed by a learning team under the supervision of an expert surgeon, familiar with the technique. RESULTS: The median number of pelvic lymph nodes yielded was 22 (range 16-34) and of para-aortic 14 (range 12-24). The mean operative time ± standard deviation for pelvic LNE for each side was 29 ± 17 and 64 ± 29 min for para-aortic LNE. The overall complication rate was 7.6% (n = 8). Two patients were reoperated laparoscopically, one because of postoperative hemorrhage and the other because of lymphocyst formation; laparoconversion was not necessary. DISCUSSION: Laparoscopic lymphadenectomy performed by a learning team with standardized technique is effective with adequate number of harvested nodes, in acceptable operative time and with low rate of perioperative complications.

Successful application of vacuum-assisted closure therapy for treatment of mastitis-associated chronic breast wounds.

INTRODUCTION: Although non-puerperal mastitis is rare and its cause is rather unclear, the number of patients diagnosed with this defect is increasing. In some cases, standard therapy fails and it progresses to a chronic disease. Vacuum-assisted closure (VAC) therapy has shown good results in healing complex wounds. PATIENTS AND METHODS: The goal of this study was to evaluate our experiences with VAC therapy and to answer the question whether or not should be accepted as an effective treatment in healing chronic wounds caused by non-puerperal mastitis. Retrospectively, we identified five patients with a non-puerperal mastitis chronic wound that was treated using VAC and report on their outcome. RESULTS: We reached both wound control and closure of the breast wounds in all patients. CONCLUSION: According to our findings, the VAC therapy can be considered when managing challenging breast wounds, particularly when other therapeutic options have failed. The role of VAC therapy as a primary therapeutic option has not yet been evaluated.

Hysteroscopic findings in women with two and with more than two first-trimester miscarriages are not significantly different.

The purpose of this study was to analyse hysteroscopic results in patients with recurrent miscarriages and to compare the frequency of uterine anomalies in women with a history of exactly two and with more than two consecutive miscarriages. A retrospective analysis of 206 patients undergoing hysteroscopy for repeated early pregnancy losses was performed at two university centres. Late miscarriages were excluded, terminations of pregnancy were not counted. Eighty-seven patients had suffered from exactly two early miscarriages and 119 from more than two. Both groups were comparable with respect to age at admission (32.95+/-4.46 versus 34.06+/-5.02 years) and at first miscarriage (30.43+/-4.24 versus 29.08+/-5.38 years). The prevalence of acquired (adhesions, polyps, fibroids) and congenital uterine anomalies (septate or bicornuate uterus, etc.) did not differ significantly (acquired: 28.7 versus 27.7%; congenital: 9.2 versus 16.8%). The rates of uterine anomalies did not differ significantly overall (36.8 versus 42.9%). In conclusion, uterine anomalies are frequently found in patients with two and with more than two early miscarriages. Due to the high rate of anomalies, their risk for adverse pregnancy outcome and a possible therapeutic approach, hysteroscopy might be a diagnostic option even after two early miscarriages.