HER2-Positive Early Breast Cancer: Time for Ultimate De-Escalation?

De-escalation is currently taking place in both the surgical and systemic treatment of breast cancer. The introduction of trastuzumab, the first monoclonal antibody against the HER2 receptor, over 20 years ago was a milestone in the treatment of HER2-positive breast cancer and marked the beginning of a new era in targeted tumor therapy. In the sense of de-escalation, omitting non-targeted cytotoxic chemotherapy altogether is often hailed as the ultimate goal of oncological research. Especially in cases of small, node-negative, HER2-positive early breast cancer, it remains a challenge for clinicians to establish the safest and most efficient treatment plan while considering the significant potential for toxic side effects associated with chemotherapy and HER2-targeted therapy, and the generally excellent prognosis. In this context, several ongoing studies are currently assessing chemotherapy-free regimens as part of strategies aimed at de-escalating therapy in the field of HER2-positive early breast cancer. Despite the promising early results of these studies, the combination of anti-HER2 treatment with a chemotherapy backbone remains the standard of care.

On the quest for hidden ovarian teratomas in therapy-refractory anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-NMDA-receptor (anti-NMDAR) encephalitis is often associated with ovarian teratoma (OT). The best management of anti-NMDAR encephalitis patients with normal imaging studies (pelvic ultrasound/MRI) but clinically high risk of OT (e.g., female, adult, black) is unclear. We report on the surprising diagnostic quest in a young black woman with anti-NMDAR encephalitis, in whom invasive procedures could finally disclose two OTs that were hidden from the initial non-invasive diagnostics. CASE REPORT: The patient presented with a one-week history of psychotic symptoms, developing oro-facial dyskinesia, seizures and coma, eventually requiring mechanical ventilation. NMDA-receptor antibodies were positive in serum and cerebrospinal fluid. Pelvic MRI and transabdominal ultrasound were normal. Exploratory laparoscopy was also unremarkable at first, but due to a suspicious echogenic mass (15 mm) in the right ovary on perioperative transvaginal ultrasound, an ovarian incision was performed which led to the detection of a first OT and its removal via ovarian-preserving cystectomy. Following a severe therapy-refractory clinical course despite aggressive immunotherapy and tumor removal, 6 months later bilateral oophorectomy was performed as ultima ratio, disclosing a second micro-OT (6 mm) in the left ovary. Unfortunately, the patient has not improved clinically yet. CONCLUSIONS: In therapy-refractory anti-NMDAR encephalitis with high risk of OT, small and bilateral OTs hidden from primary non-invasive diagnostics should be considered, which may trigger further invasive diagnostic procedures.

Paraneoplastic encephalomyeloradiculits with multiple autoantibodies against ITPR-1, GFAP and MOG: case report and literature review.

BACKGROUND: Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies. CASE PRESENTATION AND LITERATURE REVIEW: A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed. CONCLUSION: Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.

The use of intracytoplasmic sperm injection is associated with a shift in the secondary sex ratio.

RESEARCH QUESTION: What is the association between assisted reproductive technologies and human sex ratio as a proportion of male offspring at birth. DESIGN: A total of 59,628 singleton deliveries resulting from IVF, intracytoplasmic sperm injection (ICSI) and intrauterine insemination (IUI) or ovulation induction from 101 IVF clinics in Germany, that had been documented in a national German IVF registry, were analysed. Sex ratio after assisted reproductive technology was also compared with the sex ratio reported in the birth records of the German Federal Statistical Office. RESULTS: The sex ratio was 50.0% (95% CI 49.5% to 50.5%) for ICSI, 52.2% (95% CI 51.5% to 52.9%) for IVF, 52.2% (95% CI 50.9% to 53.5%) for IUI or ovulation induction and 51.3% in the national birth records, respectively. Significant differences existed across the three treatment groups (P = 6.86 × 10-7) as well as in pairwise comparisons between ICSI versus IVF (P = 6.88 × 10-7) and ICSI versus IUI or ovulation induction (P = 0.003). No difference existed between the groups IUI or ovulation induction versus IVF. Same results were also present after stratification by maternal age: IVF versus ICSI (P = 6.433 × 10-7), ICSI versus IUI or ovulation induction (P = 0.003), and IVF versus IUI or ovulation induction (non-significant). Compared with the national birth records, ICSI is associated with a lower sex ratio compared with the reference group (P < 0.001), whereas IVF is associated with a higher sex ratio (P = 0.015). CONCLUSIONS: The use of ICSI is associated with an equal proportion of sexes at birth, which is not the case for IVF, IUI or ovulation induction, or natural conception. This phenomenon is not influenced by maternal age.

Excisions of severe cervical dysplasia: Are there mandatory diameters of the cone that need to be considered?

OBJECTIVE: To achieve optimal depth for negative margin cones after loop electrosurgical excision procedures (LEEP) for cervical dysplasia. MATERIAL AND METHODS: Retrospective cohort analysis of LEEP cones of 201 patients with cervical dysplasia during a four-year period. Analysed cones were divided into two different groups: cones with negative margins without dysplasia, and cones with margins positive for dysplasia. In order to determine the cut-off value of the depth of the resected cones, receiver operating characteristic (ROC) analysis was performed. RESULTS: Negative margins were found in 71.0% (n=49) of all cones, whereas positive margins were reported in 29.0% (n=20). Negative margin cones were achieved in 100% with a cone depth of ≥20 mm. A resection depth between 10-19.9 mm led to 73.0% negative margin cones. Calculation of cone volume shows for 2.0 cm3, a sensitivity of 79% and a specificity of 64%. Statistical analysis using an ROC model showed p=0.002. CONCLUSION: Forth greatest safety of patients, cone depths from LEEPs for cervical dysplasia should be ≥20 mm to achieve negative margins.

C-Section Prevalence Among Obese Mothers and Neonatal Hypoglycemia: a Cohort Analysis of the Department of Gynecology and Obstetrics of the University of Lübeck.

INTRODUCTION: Data from the World Health Organization (WHO) demonstrates an increasing prevalence of obesity in Western countries. This study investigates the influence of obesity on the mode of delivery and the occurrence of hypoglycemia in newborns. MATERIALS AND METHODS: A retrospective analysis of all deliveries at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany was conducted over a period of eleven years with the primary outcome as non-elective C-sections and hypoglycemia of newborns from obese mothers. Patients were divided into six subgroups according to WHO weight classifications as follows: control group body mass index (BMI) 18.5 - 24.9 kg/m 2 , n = 7712; general obesity BMI ≥ 25 kg/m 2 , n = 4227; overweight BMI 25 - 29.9 kg/m 2 , n = 2628; obesity I° BMI 30 - 34.9 kg/m 2 , n = 1017; obesity II° BMI 35 - 39.9 kg/m 2 , n = 370; obesity III° BMI ≥ 40 kg/m 2 , n = 212. RESULTS: Analysis of the primary outcome shows an increased incidence of non-elective C-sections with an elevated BMI (general obesity vs. control group: 20.5 vs. 15.9%, p < 0.001; OR 1.3; 95% CI 1.2 - 1.4) and elevated rates of neonatal hypoglycemia in newborns of obese mothers (general obesity vs. control group: 0.6 vs. 0.3%, p < 0.05; OR 1.8; 95% CI 1.0 - 3.0). CONCLUSIONS: Obesity is an essential obstetric risk factor. Obese women face an increased risk of non-elective C-sections, and newborns of obese mothers suffer from elevated rates of hypoglycemia.

Do ART patients face higher C-section rates during their stage of delivery? A German monocenter experience.

PURPOSE: The mode of delivery depends on multiple parameters. After assisted reproductive technology (ART), previous studies have shown elevated C-section rates but few studies differentiated between elective and emergency operations and different protocols of cryopreservation. Because these studies did not use multiparity as exclusion criteria which reduces confounding with previous pregnancies, aim of this study is to compare mode of delivery of different techniques of ART using data of primiparae only [1, 2]. METHODS: Retrospective analysis of patient data treated at the university hospital of Luebeck in a period of 12 years. Patients were divided in different groups according to their way of conception: spontaneous conception and conception after ART. The group of ART was further divided into: (a) a group of fresh transferred embryos (IVF/ICSI), (b) vitrification and (c) slow freezing. Exclusion criteria were defined as: multiparity, delivery <24. + 0 p.m., incomplete data and treatment outside university of Luebeck. Main parameter of this study was mode of delivery which was divided into spontaneous delivery or C-section. C-sections were further differentiated into elective or emergency C-sections. RESULTS: The group of fresh transferred embryos and slow freezing showed higher risks for elective and emergency C-sections (elective C-sections odds ratio 2.0, CI 95% 1.6-2.6, emergency C-sections odds ratio 1.4, CI 95% 1.1-1.9). Moreover, all groups of ART show enhanced risk of significant perinatal bleeding. CONCLUSION: Patients after ART treatment suffer from higher C-section rates during their stage of delivery.

Introducing a new scoring system for pap smear in the detection of high-grade squamous intraepithelial lesions in pregnancy (The Luebeck Score).

PURPOSE: To construct a scoring system for pap smears to objectify cytological appraisal and to enhance the accuracy and comparability of pap smear interpretation in pregnancy. MATERIALS AND METHODS: For development of a scoring system for cell appraisal of pap smears the style of the Modified Masood's Scoring Index for appraisal of cells from fine needle aspirations of breast lesions was used. Cohort analysis of n = 54 dysplastic pap smears for polymorphology of cells, anisonucleosis, structure of the nucleus, signs of tissue destruction, nucleus/plasma relation and signs of tumordiathesis. Each criteria was classified into three stages: The first with little evidence for dysplasia (one point), second stage with sporadic evidence (two points) or third stage with frequent evidence (three points). To further evaluate if pregnancy associated cells changes interfere with this scoring system we compared the results of pregnant and non-pregnant women. Histological result was used as an indicator of correctness of the score. RESULTS: Statistical analysis showed a good correlation of the scoring system with histological results. Especially in pregnancy statistical analysis shows promising results (sensitivity 86.67 %, Specificity 100 %, receiver operating characteristic analysis p ≤ 0.05). CONCLUSION: The Luebeck Score seems to be a useful approach for appraisal of pap smears in pregnancy. Further studies containing high numbers of cases are needed for further evaluation of potential benefits of the scoring system compared to conventional evaluation of pap smears.

Method comparison between Munich II and III nomenclature for Pap smear samples.

OBJECTIVE: Munich Nomenclature III for cervical smear evaluation also known as Papanicolaou (Pap) smear was launched in Germany in July 2014, and it is the only used system in Germany. The study aims at a method comparison between the previously used nomenclature Munich II and the currently used Munich III. MATERIAL AND METHODS: A method comparison was performed by analyzing 117 Pap smear samples (pss) in the cytological laboratory of the department of Obstetrics and Gynecology of Luebeck University between January and March 2014. The samples were evaluated twice using both nomenclatures (Munich II and Munich III). RESULTS: One out of the 117 pss showed a loss of cellular material. According to Munich III, this Pap smear should be linked to group 0. Concerning Pap I, Munich II showed 0/117 pss (0%) and Munich III showed 55/117 pss (47%) cases (p<0.001). Pap II results were seen less frequently in Munich III than in Munich II (47% vs 93%, p<0.001). Pap IVa, IVb, and V stay similar in both nomenclatures [IVa: 1/117 pss (0.85%), IVb: 0/117 pss (0%) and V: 1/117 pss (0.85%)]. CONCLUSION: Patients at risk are clearly separated by Munich III from those with no evidence of pathology. The former clusters have been extended by distinctly defined subgroups, resulting in a more precise way to differentiate cytological findings. Differentiating between Pap IIID 1 and IIID 2 clearly separates mild and moderate dysplasia [cervical intraepithelial neoplasia (CIN) 1 (CIN 1) and CIN 2)].

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.

Epidemiology of aeromedical evacuation: an analysis of 504 cases.

BACKGROUND: Increasing air travel has resulted in a significant increase in aeromedical evacuation (AE) over the past decade. However, there are limited epidemiological data available on the diagnosis, costs, and transport characteristics of AE cases. METHODS: Cases of AE by a relief organization (Workers' Samaritan Federation Germany) were analyzed based on the following criteria: age, sex, and diagnosis of the patient, ventilation mode, days of illness before transport, type of transport, flight routes, flying time, flight distance, type of aircraft, type and distance of connecting transport from the destination airport to the final hospital, total cost per repatriation, cost per flight-minute, and cost per flight-kilometer of each transport type. RESULTS: A total of 504 patients (273 males, 231 females, aged 42 d-96 y, median 66 y) were included in the study. The top three diagnoses for adults were fracture of the femoral neck (n = 74, 15%), stroke (n = 69, 14%), and myocardial infarction (n = 39, 8%). Transport was carried out with an air ambulance (n = 391, 78%, 73.67 €/min), a scheduled aircraft with regular seating (n = 62, 12%, 17.57 €/min), a stretcher in a scheduled aircraft (n = 48, 10%, 35.28 €/min), or a patient transport compartment installed on board a scheduled aircraft (n = 3, < 1%). CONCLUSIONS: As the demand for AE is likely to increase in the future, the cost-effectiveness and selection of the appropriate form of air transportation, while assuring the right medical response, will be of increasing importance. Patients are likely to benefit from further epidemiological assessments like those presented in this study.