NGS-Guided Precision Oncology in Breast Cancer and Gynecological Tumors-A Retrospective Molecular Tumor Board Analysis.

Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center's MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers.

Systematic Analysis of Homologous Recombination Deficiency Testing in Ovarian Cancer-Development of Recommendations for Optimal Assay Performance.

Homologous recombination deficiency (HRD) assays are an important element of personalized oncology in ovarian carcinomas, but the optimal tissue requirements for these complex molecular assays remain unclear. As a result, a considerable percentage of assays are not successful, leading to suboptimal diagnoses for these patients. In this study, we have systematically analyzed tumor and tissue parameters for HRD analysis in a large cohort of real-world cancer samples. The aim of this study is to give recommendations for pathologists and gynecologic oncologists for selection of tissue samples to maximize the success rate of HRD analyses. Tumor samples from 2702 patients were sent to the Institute of Pathology of the Philipps-University Marburg between October 2020 and September 2022, of which 2654 were analyzed using the Myriad MyChoice HRD+ CDx assay. A total of 2396 of 2654 samples (90.3%) were successfully tested, of which 984 of 2396 (41.1%) were HRD positive and 1412 (58.9%) were HRD negative. Three hundred sixty-three of 2396 samples (15.2%) were BRCA1/2-mutated; 27 samples had a BRCA1/2 mutation and a genomic instability score (GIS) < 42. Twenty-two samples (0.9%) failed GIS measurement but displayed a BRCA1/2 mutation. BRCA1/2-mutated samples showed significantly (P < .0001) higher GIS values than those with a wild-type BRCA1/2 status. Tumor cell content, tumor area, and histology significantly (P < .0001) affected the probability of successfully analyzing a sample. Based on a systematic analysis of tumor cell content and tumor area, we recommend selecting patient high-grade serous ovarian cancer samples that display a tumor cell content ≥30% and a tumor area ≥0.5 cm2 (based on their hematoxylin and eosin) for HRD testing to allow for optimal chances of a successful analysis and conclusive results. Considering histologic and sample conditions, success rates of up to 98% can be achieved. Our comprehensive evaluation contributes to further standardization of recommendations on HRD testing in ovarian cancer, which will have a large impact on personalized therapeutic strategies in this highly aggressive tumor type.

Challenging ChatGPT 3.5 in Senology-An Assessment of Concordance with Breast Cancer Tumor Board Decision Making.

With the recent diffusion of access to publicly available large language models (LLMs), common interest in generative artificial-intelligence-based applications for medical purposes has skyrocketed. The increased use of these models by tech-savvy patients for personal health issues calls for a scientific evaluation of whether LLMs provide a satisfactory level of accuracy for treatment decisions. This observational study compares the concordance of treatment recommendations from the popular LLM ChatGPT 3.5 with those of a multidisciplinary tumor board for breast cancer (MTB). The study design builds on previous findings by combining an extended input model with patient profiles reflecting patho- and immunomorphological diversity of primary breast cancer, including primary metastasis and precancerous tumor stages. Overall concordance between the LLM and MTB is reached for half of the patient profiles, including precancerous lesions. In the assessment of invasive breast cancer profiles, the concordance amounts to 58.8%. Nevertheless, as the LLM makes considerably fraudulent decisions at times, we do not identify the current development status of publicly available LLMs to be adequate as a support tool for tumor boards. Gynecological oncologists should familiarize themselves with the capabilities of LLMs in order to understand and utilize their potential while keeping in mind potential risks and limitations.

[Clinically relevant molecular pathological diagnostics in breast cancer]. / Klinisch relevante molekularpathologische Diagnostik beim Mammakarzinom.

In breast cancer, the current guideline for pathological workup includes recommendations for advanced molecular analysis of certain predictive molecular markers in addition to basic immunohistochemical diagnostics. These markers are determined depending on tumor stage, including sequencing techniques and immunohistochemical methods. This comprises the systematic investigation of molecular alterations such as PIK3CA or BRCA1,2 mutations, NTRK fusions, or microsatellite instability as a basis for targeted therapy. Further alterations, for example in the PI3K pathway, ESR1 alterations, or ERBB2 mutations, may also be relevant for individual therapy decisions especially in the context of resistant or relapsed disease. Thus, particularly in advanced stages, a more comprehensive molecular characterization of the tumor may reveal genetic alterations that act as tumor drivers and provide targets for personalized therapies. Due to the large number of potential molecular targets, NGS panel diagnostics are a suitable approach in this conjunction with immunohistochemical characterization and the individual clinical situation. Molecular based therapeutical strategies outside of entity-specific approvals should be discussed in an interdisciplinary team within the framework of a molecular tumor board.

Gynecologic Oncology: Pelvic Exenteration for Advanced or Recurring Cervical Cancer - A Single Center Analysis.

BACKGROUND/AIM: Cervical cancer is the most common gynecological indication for pelvic exenteration (PE). It is an ultima ratio approach to cure advanced or recurring tumors. This study aimed to evaluate data from a Single Center Institution in order to assess morbidity, mortality and survival data. PATIENTS AND METHODS: Data of 24 patients, who underwent anterior (APE) or total PE (TPE) for cervical cancer at the University Hospital Marburg between 2011 and 2016, were extracted and retrospectively evaluated. Survival analysis was conducted using the Kaplan-Meyer method. RESULTS: Lymph node status was pN0, pN1 and pNX in 33.3%, 20.8% and 45.8% respectively. Negative margins could be achieved in 70.8%. A total of 16.7% of patients presented with metastatic disease, while 20.8%, 37.5% and 20.8% received 1, 2 or 3 modalities of treatment respectively; 20.8% underwent up-front PE. Predominant urinary diversion was an ileum conduit (66.7%). No complications were noted for 16.7%, major complications (≥Clavien Dindo 3) in 41.7%. Overall survival was 29.2% with a median overall survival (mOS) of 19.1 months. Curative PE was undertaken in 20 cases, with 2- and 3-year survival rates of 52.6% and 29.4% respectively. and a mOS of 24 months. Positive margins, metastatic disease, positive lymph nodes, TPE and a surgical time >6 h had a significant impact on OS. CONCLUSION: PE for cervical cancer remains a feasible option in cases of advanced or recurring tumors when alternative treatment options would fail. For selected patients it may represent a chance of cure with acceptable complication and satisfactory survival rates.

[High clinical value of bone scintigraphy as a staging method for breast cancer]. / Hohe klinische Wertigkeit der Skelettszintigrafie beim Staging des Mammakarzinoms.

BACKGROUND: Bone scintigraphy is a sensitive method for imaging bone metastases in patients with breast cancer. Despite its firm establishment in clinical routine, there are hardly any reliable data from larger homogeneous collectives on the value of bone scintigraphy in the context of staging of first diagnosed breast cancer patients. AIM: The aim of our work was to evaluate the real-life performance of bone scintigraphy as a staging examination in female patients with the initial diagnosis of breast cancer. PATIENTS AND METHODS: We retrospectively evaluated the data of the patients examined in the year 2015 with the first diagnosis of breast cancer at the University Hospital Marburg by bone scintigraphy. In addition a follow-up over a period of 30 months after the first bone scintigraphy was performed. For this purpose we evaluated whether the results of this initial diagnostic could be confirmed in following diagnostic. RESULTS: 207/258 patients showed no suspicious findings in the initial bone scintigraphy, 48 had an unclear finding, which is why 42 patients received further diagnostics. In follow-up, new bone metastases were found in 4 patients, all of these had scintigraphic findings in the primary diagnosis, which were considered "unclear". Depending on the evaluation of the event (suspicious for metastasis/suspicious for metastasis and unclear), the sensitivity was 37.5%/100%, the specificity 100%/80%, the positive predictive value 100%/15.7% and the negative predictive value 98%/100%. CONCLUSION: By using bone scintigraphy and, if necessary, subsequent further imaging or histological clarification, a clinically significant diagnosis was obtained in 99,2% of the examined patients and confirmed in the follow-up. This result shows the good real-life performance of bone scintigraphy as a staging examination in patients with first diagnosed breast carcinomas.

"Leaving the placenta in situ approach" (LISA) in a patient with placenta increta leading to delayed spontaneous delivery of the placenta.

Aim: Based on the recent FIGO recommendations, we wish to report on preservation of the uterus in a patient with placenta increta by applying the leaving the placenta in situ approach.Methods: A 30-year-old gravida 2, Para 1 was referred at 25 + 5 gestational weeks due to a placenta previa bipartita increta diagnosed by transvaginal ultrasound, a history of a cesarean and vaginal bleeding. After informed consent, the parents opted for conservative treatment. The patient was admitted and the options of treatment were communicated within a multidisciplinary team. At 31 + 4 gestational weeks, severe recurrent hemorrhage led to a repeat cesarean.Results: A boy of 1910 g was delivered and the placenta was left in situ. Estimated blood loss was <200 ml. An MRI on day 13 still showed regular placental circulation, but after 4 weeks, perfusion and HCG levels had significantly decreased. The patient was examined every 3 days and readmitted after 6 weeks with a sudden rise of d-dimers. Within 24 hours, the complete placenta was delivered. On postoperative day 54, MRI confirmed uterine involution without a placental tissue.Conclusions: Delayed placental delivery in patients with abnormal placental invasion is a legitimate option to preserve fertility and possibly to reduce intrapartum hemorrhage.

Pregnancy-associated transient osteoporosis of the hip: results of a case-control study.

The etiology and underlying mechanisms of transient of osteoporosis of the hip (TOH) during pregnancy are still unclear, since no systematic analyses exist. Our results support the hypothesis that TOH is a multifactorial disease, which is associated with immobility, dental problems, and lack of exercise in childhood. INTRODUCTION: Pregnancy-associated transient osteoporosis of the hip (TOH) is a rare but severe form of osteoporosis, which may affect a subgroup of women in the last trimester of pregnancy or immediately postpartum. Common symptoms include acute pain of the hip(s) due to bone marrow edema or even hip fractures. The exact underlining mechanisms of this disorder are still unknown since no published systematic analyses exist. METHODS: Out of a total of 52 TOH patients, 33 TOH patients could be matched with 33 healthy controls according to age, region, and gravity. The aim of this retrospective case-control study was to evaluate the risk factors for TOH in a homogenous population of women. RESULTS: The baseline characteristics of the two study groups were similar. Overall, 12.1% of the TOH patients sustained a hip fracture. Expectedly, 90.9% of the TOH patients complained about pain of the hip (p ≤ 0.001). TOH patients suffered more frequently from severe dental problems during childhood (p = 0.023) and performed less often sports before and after puberty (p ≤ 0.001), whereas the frequency of immobilization during pregnancy was threefold higher compared to the control group (p = 0.007). We found a significant increase of the TOH risk in patients with dental problems in childhood (OR 3.7; CI 1.3-10.7) as well as in patients with lack of exercise during childhood (OR 4.2; CI 1.3-12.9). CONCLUSIONS: Our results support the hypothesis that pregnancy-associated TOH is a multifactorial disease, to which several individual factors may contribute. Hereby, we found significant associations with immobility, dental problems, and lack of exercise in childhood.

Evaluation of efficacy, safety and effects on symptoms of androgenization of a generic oral contraceptive containing chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg.

BACKGROUND: This prospective noninterventional study assessed the contraceptive efficacy, safety and the effects on signs of androgenization of the generic oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) in a real-world setting. STUDY DESIGN: A total of 1440 women were investigated during a six-cycle period by 229 gynecological practices throughout Germany. RESULTS: The adjusted Pearl index was 0.136 (unadjusted: 0.271). Of 463 patients with cycle irregularities at baseline, 83.4% had regular cycles after six cycles. Likewise, 74.1% of 162 patients with spotting or breakthrough bleeding at baseline were free from these symptoms at the end of study. The percentage of patients with dysmenorrhea decreased significantly from baseline (36.5%) to visit 3 after six cycles (12.3%; p=.0001), with a significant reduction in the use of pain medication (p<.0001). Additionally, the number of patients with skin and hair problems was significantly reduced (skin: 56.3% at baseline, 19.6% after six cycles; hair: 45.7% at baseline, 13.4% after six cycles; p=.001). CMA/EE was well tolerated by the patients, and 89.44% of the gynecologists were satisfied with the treatment. CONCLUSION: Generic CMA/EE exhibits very good contraceptive efficacy, cycle control and dysmenorrhea reduction. Furthermore, treatment with generic CMA/EE led to a favorable reduction of skin and hair problems in our study.

Treatment with teriparatide in a patient with pregnancy-associated osteoporosis.

INTRODUCTION: The decrease of BMD during a physiological pregnancy can in rare cases be intensified and lead to dramatic microarchitectural changes, which causes an increase incidence of fractures, preferably at the spine. This dramatic clinical picture is called pregnancy-associated osteoporosis. CASE HISTORY: We present the case of a 40-year-old woman (gravida IV, para II) with acute back pain right after delivery due to four fractures of the spine. The diagnosis was confirmed by dual-energy X-ray absorptiometry measurement result (T-score -4.1 SD (0.598 g/cm(2)) at the lumbar spine (L1-L4), T-score -1.5 SD (0.759 g/cm(2)) at the total hip). Due to the severity of symptoms, a therapy with teriparatide (20 mg daily) was started for a period of 18 months. RESULTS: After end of therapy, the T-score had significantly increased at the lumbar spine as well as at the hip (T-score of -2.1 (0.813 g/cm(2)) and -0.6 (0.864 g/cm(2)), respectively. The relative increase of BMD at the spine and total hip was 36% and 13.8%, respectively. DISCUSSION: Our report demonstrates the successful use of teriparatide underlined by the increase of bone mineral density and the improvement of clinical symptoms in a case of severe pregnancy-associated osteoporosis for the first time.