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A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% with placebo.

IntroductionEarly endometrial cancer is primarily treated surgically via hysterectomy, adenectomy and, depending on tumor stage and subtype, lymphadenectomy. Systematic lymph node dissection is known to cause surgical complications. The aim of the present study was to investigate morbidity and mortality rates associated with lymphadenectomy in patients with endometrial cancer who underwent surgery in a routine clinical setting. MethodsWe collected data from 232 patients who were operated for endometrial carcinoma between 2006 and 2018 at the University of Lubeck, Germany. Surgical complications were viewed in relation to surgical risk factors. Additionally, a questionnaire concerning long-term lymphatic complications and survival was completed. Survival was compared between patients who underwent lymphadenectomy (group I) and those who did not (group II). ResultsPatients in group I needed revision surgery significantly more often due to postoperative complications (such as lymphoceles) compared to those in group II (p = 0.01). The results indicate more serious complications in patients who underwent a systematic lymphadenectomy and in those with lymph node metastases. 15% of patients who underwent a systematic lymphadenectomy had lymph node metastases. Recurrences occurred in 12.5% of cases and were significantly more frequent in patients who had undergone a lymphadenectomy, even if the lymph nodes were negative (p = 0.02). A comparison of survival data during the follow-up period revealed no significant difference. The study highlighted the need for a better preoperative risk stratification and the avoidance of lymphadenectomy for surgical staging alone.

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan–Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical–histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer.

Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.

The heparan sulfate proteoglycan syndecan-3 (SDC3) is a critical regulator of cell–matrix interactions. While other syndecan family members contribute to the progression of multiple cancers, SDC3’s functional contributions to tumor biology remain largely unexplored. This study investigates the potential role of SDC3 in the pathogenesis of breast cancer. By conducting an in-silico analysis of publicly available datasets, including TNM-plot, The Human Protein Atlas, and Kaplan–Meier Plotter, we observed that SDC3 is upregulated in breast cancer tissue. Notably, high SDC3 expression correlates with improved relapse-free survival in breast cancer patients. In vitro experiments revealed that SDC3 depletion significantly impairs cell viability, cell-cycle progression, cell migration, and 3D-spheroid-formation in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, SDC3 depletion results in dysregulated gene expression of matrix metalloproteinases (MMP1, MMP2, MMP9) in MDA-MB-231 cells, and upregulation of E-cadherin (CDH1) and vascular endothelial growth factor A (VEGFA) in MCF-7 cells. Activation of proto-oncogene tyrosine-protein kinase Src was inhibited when SDC3 depletion was combined with tissue factor pathway inhibitor treatment. These findings demonstrate that breast cancer cell-derived SDC3 plays a pivotal role in tumor progression.

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.

Introduction/BackgroundIn the phase 3 RUBY trial (NCT03981796) dostarlimab + carboplatin-paclitaxel (CP) significantly improved progression-free survival (PFS) vs CP alone in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; hazard ratio [HR], 0.28) and overall populations (HR, 0.64) with a favourable overall survival (OS) trend (HR, 0.64). Four molecular endometrial cancer subgroups were identified for prognostic and potential predictive value. Readily available validated surrogate methods include POLε mutation (mut), dMMR, TP53 abnormal, and no specific molecular profile (NSMP). Here, we present exploratory efficacy outcomes by molecular classification.MethodologyPatients with primary advanced or recurrent endometrial cancer were randomised 1:1 to receive dostarlimab or placebo, plus CP, followed by dostarlimab or placebo monotherapy for up to 3 years. POLε and TP53 status were determined by DNAseq; MMR/MSI status was determined by testing used for study enrolment (immunohistochemistry, polymerase chain reaction, or next-generation sequencing). Order of classification was POLεmut → dMMR/MSI-H → TP53mut → NSMP. PFS and OS were assessed for each subgroup.ResultsOf 494 patients enrolled and randomised, mutational data were available for 400 patients (81.0%), classified as 5 (1.3%) POLεmut, 91 (22.8%) dMMR/MSI-H, 88 (22.0%) TP53mut, and 216 (54.0%) NSMP. PFS and OS results favoured the dostarlimab + CP arm in the dMMR/MSI-H, TP53mut, and NSMP subgroups, with the largest benefit observed in the dMMR and TP53mut groups. No patients with POLεmut had progression in either arm as of data cut (table 1).Safety was reported previously.Abstract 625 Table 1ConclusionDostarlimab + CP is associated with improved PFS and OS in the dMMR/MSI-H, NSMP, and TP53 subgroups and adds prognostic value in primary advanced or recurrent endometrial cancer. Patients with POLεmut had the best prognosis, as expected. Further research may help to validate these exploratory findings.DisclosuresDisclosures: This study (NCT03981796) was sponsored by GSK (Waltham, MA, USA).Third-party medical writing support: Writing and editorial support, funded and coordinated by GSK, was provided by Shannon Morgan-Pelosi, PhD, and Mary C. Wiggin, of Ashfield MedComms, an Inizio company.COI: Dr Mirza reports consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zailab; speakers’ bureau fees from AstraZeneca and GSK; research funding (to institution) from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors).Dr Shahin reports institutional grants from AstraZeneca, GSK, and Merck; honoraria from AstraZeneca, GSK, Merck, and Seagen; expert testimony fees from Robinson & Havens PSC, Lexington, KY; advisory board fees from Seagen; and board member for Unite for Her.Dr Cibula reports participation on an advisory board from Akesobio, AstraZeneca, GSK, MSD, Novocure, Roche, Seagen, and Sotio.Dr Raspagliesi reports institutional grants or contracts from AstraZeneca; honoraria from MSD and GSK; travel support from GSK; and advisory board fees from PharmaMar.Dr Hanker reports consulting/advisory fees from Amgen, AstraZeneca, Clovis, Eisai, GSK, Intuitive Surgery, Janssen, MSD, Novartis, Pfizer, Pharma Mar, Roche and Tesaro.Dr Coleman reports grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, and Roche/Genentech; consulting fees from AbbVie, Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Novocure, Merck, OncoQuest, Onxerna, Regeneron, and Roche/Genentech; honoraria from AstraZeneca, Clovis, Merck, and Roche/Genentech; and participation on a data safety monitoring board or advisory board from Eisai/BMS and VBL Therapeutics.Dr Boere reports institutional research grant from GSK, and institutional advisory board meeting fees from AstraZeneca and GSK.Dr Gilbert reports institutional grants from Alkermes, AstraZeneca, Clovis, Esperas, IMV, ImmunoGen Inc, Karyopharm, Merck Sharp & Dohme, Mersana, Novocure GmbH, OncoQuest Pharmaceuticals, Pfizer, Roche, and Tesaro; consulting fees from Merck; honoraria from Alkermes, AstraZeneca, Eisai, Eisai-Merck, and GSK.Dr Slomovitz reports advisory fees from AstraZeneca, Clovis, Genentech, GSK, GOG Foundation, Merck, Myriad, Jazz Pharma, Onconova, Nuvation Bio, EQRX, Regeneron, Eisai, and Incyte; and board of directors for GOG Foundation and HOW: Hearing Ovarian Cancer Whispers.Dr Powell reports consulting fees from GSK, Tesaro, Merck, Eisai, SeaGen, Clovis Oncology, and AstraZeneca.Dr Stuckey reports royalties as an UptoDate reviewer.Dr Buscema, Dr Fleming, Dr Herrstedt, Dr Ring, Dr Schneider, Dr Sharma, and Dr Teneriello have nothing to declare.Dr Ghosh and Dr Stevens are employees of GSK.

BackgroundRecently, 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 reviewA 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.ConclusionOur 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.

Totally implanted venous access devices (TIVAD) are increasingly used in the treatment of cancer patients. The aim of this study was to assess the incidence of early and late complications resulting from subcutaneous TIVADs in patients with breast cancer. Between 2004 and 2009, we reviewed patients with breast cancer who had a TIVAD placed. Early and late complications, as well as risk factors for TIVAD-associated thrombosis were retrospectively assessed. A total of 281 patients were included. Complications occurred in 26% of patients, the majority of which were late complications (21.4%.) The development of TIVAD associated thrombosis was the most frequent late complication (16.4%). In the univariate analysis followed by a multivariate model, risk factors for TIVAD associated thrombosis were not identified. Only within the subgroup of metastatic breast cancer patients an increased risk of TIVAD-associated thrombosis of left compared to right venous access was detected (p=0.015). TIVAD implantation done in a gynecological outpatient setting is feasible and safe.

Background Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. Methods TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). Results We found associations of higher TGIF protein expression with smaller tumor size ( p  = 0.015), well differentiated phenotype ( p  < 0.001) and estrogen receptor (ER)-positive BC ( p  < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59–0.95], log-rank p =  0.019) and overall survival (OS: HR 0.69 [95%CI 0.50–0.94], log-rank p  = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51–1.16]; p  = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51–0.91]; log-rank p  = 0.009, interaction p  = 0.130; OS: HR 0.60 [95%CI 0.41–0.88], log-rank p  = 0.008, interaction p  = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50–0.88], log-rank p  = 0.004, interaction p  = 0.034; OS: HR 0.57 [95%CI 0.40–0.81], log-rank p  = 0.002, interaction p  = 0.015). Conclusions Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer. Trial registration This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .