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Carbonaceous asteroids, such as (101955) Bennu, preserve material from the early Solar System, including volatile compounds and organic molecules. We report spacecraft imaging and spectral data collected during and after retrieval of a sample from Bennu’s surface. The sampling event mobilized rocks and dust into a debris plume, excavating a 9-meter-long elliptical crater. This exposed material is darker, spectrally redder, and more abundant in fine particulates than the original surface. The bulk density of the displaced subsurface material was 500 to 700 kilograms per cubic meter, which is about half that of the whole asteroid. Particulates that landed on instrument optics spectrally resemble aqueously altered carbonaceous meteorites. The spacecraft stored 250 ± 101 grams of material, which will be delivered to Earth in 2023.

In marine systems, the availability of inorganic phosphate can limit primary production leading to bacterial and phytoplankton utilization of the plethora of organic forms available. Among these are phospholipids that form the lipid bilayer of all cells as well as released extracellular vesicles. However, information on phospholipid degradation is almost nonexistent despite their relevance for biogeochemical cycling. Here, we identify complete catabolic pathways for the degradation of the common phospholipid headgroups phosphocholine (PC) and phosphorylethanolamine (PE) in marine bacteria. Using Phaeobacter sp. MED193 as a model, we provide genetic and biochemical evidence that extracellular hydrolysis of phospholipids liberates the nitrogen-containing substrates ethanolamine and choline. Transporters for ethanolamine (EtoX) and choline (BetT) are ubiquitous and highly expressed in the global ocean throughout the water column, highlighting the importance of phospholipid and especially PE catabolism in situ. Thus, catabolic activation of the ethanolamine and choline degradation pathways, subsequent to phospholipid metabolism, specifically links, and hence unites, the phosphorus, nitrogen, and carbon cycles.

The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.

The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which allosterically increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.

Background and aim Gestational trophoblastic disease (GTD) is a heterogeneous group of disorders characterised by abnormal proliferation of trophoblastic tissue. Since GTD and its malignant sequel gestational trophoblastic neoplasia (GTN) are rare diseases, little evidence is available from randomised controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centres within countries. One of the goals of the ‘European Organisation for Treatment of Trophoblastic Diseases’ (EOTTD) is to harmonise treatment in Europe. To provide a basis for European standardisation of definitions, treatment and follow-up protocols in GTD, we composed a set of guidelines for minimal requirements and optimal management of GTD. Methods Members from each EOTTD country attended multiple workshops during annual EOTTD meetings. Clinical guidelines were formulated by consensus and evidence where available. The following guidelines were discussed: diagnostics of GTD and GTN, treatment of low-risk GTN, high-risk GTN, ultra-high-risk GTN, placental site and epithelioid trophoblastic tumours and follow-up. Results Between 40 and 65 EOTTD members from 17 European countries and 7 non-European countries attended the clinical workshops held on 6 occasions. Flow diagrams for patient management were composed to display minimum and best practice for most treatment situations. New agreed definitions of recurrence and chemotherapy resistance were formulated. Conclusions Despite the many differences between and within the participating countries, an important step in uniform treatment of GTD and GTN within Europe was made by the Clinical Working Party of the EOTTD. This is an example on how guidelines and harmonisation can be achieved within international networks.

Background: In patients with inoperable local regional recurrences of breast cancer in previously irradiated areas, local control is difficult to maintain and treatment options are limited. The Dutch standard treatment for such recurrences is reirradiation combined with hyperthermia. Apart from enhancing the effect of reirradiation, hyperthermia is also known to improve local effects of chemotherapy like cisplatin. This randomized phase-II trial compares reirradiation and hyperthermia versus the same treatment combined with cisplatin. Patients and methods: From December 2010 up to January 2019, 49 patients were randomized, 27 in the standard arm and 22 in the combined arm. A total of 32 Gy was given in eight fractions of 4 Gy in 4 weeks, at two fractions per week. After January 2015, the radiation schedule was changed to 46 Gy in 23 fractions of 2 Gy, at five fractions per week. Hyperthermia was added once a week after radiotherapy. The combined arm was treated with four cycles of weekly cisplatin 40 mg/m2. Results: Complete response rate was 60.9% in the standard arm and 61.1% in the combined arm (p = 0.87). Partial response rate was 30.4% in the standard arm and 33.3% in the combined arm (p = 0.79). One-year overall survival was 63.4% in the standard arm and 57.4% in the combined arm. One-year local progression-free interval was 81.5% in the standard arm and 88.1% in the combined arm (p = 0.95). Twenty-five percentage of patients in the standard arm experienced grade 3 or 4 acute toxicity and 29% of patients in the combined arm (p = 0.79). Conclusion: No potential benefit could be detected of adding cisplatin to reirradiation and hyperthermia in patients with recurrent breast cancer in a previously irradiated area. With or without cisplatin, most patients had subsequent local control until last follow-up or death.

Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic yield was highest in patients referred for seizures and developmental delay/intellectual disability. The genetic diagnosis had an impact on clinical management in 52% of patients. Referrals to other health professionals and changes in therapy were the most frequently reported clinical consequences. In conclusion, despite limited financial resources, our genetics service resulted in a reasonably high molecular diagnostic yield. Even in this resource-limited setting, a genetic diagnosis had an impact on clinical management for the majority of patients. Our approach with a visiting clinical geneticist may be an example for others who are developing genetic services in similar settings.

Contains fulltext : 288341.pdf (Publisher’s version ) (Open Access) BACKGROUND: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). METHODS: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. RESULTS: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. CONCLUSION: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.

Febrile neutropenia (FN) is an inflammatory response causing fever that may develop during cancer therapy-induced neutropenia. FN may herald life-threatening infectious complications and should therefore be considered a medical emergency. Patients presenting with FN are routinely subjected to careful history taking and physical examination including X-rays and microbiological evaluations. Nevertheless, an infection is documented clinically in only 20–30% of cases, whereas a causative microbial pathogen is not identified in over 70% of FN cases. The oral cavity is generally only visually inspected. Although it is recognized that ulcerative oral mucositis may be involved in the development of FN, the contribution of infections of the periodontium, the dentition, and salivary glands may be underestimated. These infections can be easily overlooked, as symptoms and signs of inflammation may be limited or absent during neutropenia. This narrative review is aimed to inform the clinician on the potential role of the oral cavity as a potential source in the development of FN. Areas for future research directed to advancing optimal management strategies are discussed.

Based on the principles of biomedical ethics, the authors conducted a survey focusing on the ethical aspects of, didactic benefits of and possible alternatives to live surgery events. This work provides an investigation of the ethics of live surgery events in an interdisciplinary and multicentre setting. Critical ethical concerns regarding the justification of such events are highlighted through evaluation of attendees and surgeons.

TPS5603 Background: Despite the use of platinum-taxane doublets ± bev in eligible patients (pts), overall survival (OS) outcomes for pts with r/mCC remain poor. With the US approval of pembro + chemotherapy ± bev in the 1L setting for r/mCC with ≥1% of programmed death ligand 1–positive cells in the tumor, an unmet need remains for pts who do not meet this threshold and for pts who progress or are intolerant to standard treatment (tx). TV is a tissue factor–directed antibody–drug conjugate that has been granted accelerated approval in the United States for the tx of adults with r/mCC with disease progression on or after chemotherapy. To develop more effective treatments, we investigated TV in combination with agents with known activity in cervical cancer. We conducted a 2-part, multicohort phase 1b/2 trial, ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081), to evaluate TV in combination with bev, pembro, or carbo. The phase 1b dose-escalation phase of innovaTV 205 established the recommended phase 2 dose (RP2D) and the feasibility of these doublet combinations (Monk et al, IGCS 2021). Moreover, we recently reported encouraging antitumor activity from the dose-expansion cohort of TV + carbo (1L; confirmed objective response rate [ORR], 55%; median duration of response [DOR], 8.3 mo) and TV + pembro (second-line; confirmed ORR, 38%; median DOR, 13.8 mo) (Vergote et al, ESMO 2021). The current report describes the design of a new, ongoing dose expansion cohort in the innovaTV 205 study to evaluate the combinations of TV, pembro, and carbo ± bev. Methods: A new cohort has been added to the innovaTV 205 study, comprising adult pts with recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma of the cervix with no prior systemic therapy and an Eastern Cooperative Oncology Group score of 0 or 1. Pts will be treated with the RP2D of TV (2.0 mg/kg) + carbo (AUC 5 mg/mL), pembro (200 mg), and bev (15 mg/kg) every 3 weeks or with TV + carbo (AUC 5 mg/mL) and pembro (200 mg). To assess the regimen’s initial tolerability, there will be a dose-limiting toxicity evaluation period that will consist of completion of 1 tx cycle of 21 days for 6 pts enrolled to receive the quadruplet combination. The primary endpoint of this dose expansion phase is confirmed ORR per RECIST v1.1; secondary endpoints include DOR, time to response, progression-free survival, OS, and safety. Enrollment is ongoing in the United States and Europe, with additional sites planned globally. Clinical trial information: NCT03786081.

5507 Background: TV monotherapy has received US accelerated approval for previously treated r/mCC with disease progression on or after chemotherapy based on clinically meaningful tumor response rate and duration of response (DOR) reported from the GOG-3023/ENGOT-cx6/innovaTV 204 study (Coleman et al., Lancet Onc. 2021). Recently, the recommended phase 2 dose (RP2D) and feasibility of TV + pembro, TV + carboplatin (carbo), and TV + bevacizumab in r/mCC were reported from the dose-escalation phase (Monk et al, IGCS 2021); interim safety and efficacy data from 2 dose-expansion cohorts, 1L TV + carbo and second-line/third-line (2L/3L) TV + pembro (Vergote et al, ESMO 2021) from the ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081) study, were also reported. Here we report interim safety and efficacy results from a third dose-expansion cohort evaluating 1L TV + pembro in patients with r/mCC. Methods: Patients with r/mCC who had not received prior systemic therapy (excluding chemoradiation) for r/mCC were treated with the RP2D of TV 2.0 mg/kg + pembro 200 mg intravenously every 3 weeks. The primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1; secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), and safety. Results: 33 pts were treated with 1L TV + pembro (median 6 cycles). At data cutoff (July 1, 2021), median duration of exposure to TV + pembro was 5.1 mo (range 1-17) and median follow-up was 12.2 mo (range 1-17). Confirmed ORR among 32 evaluable patients was 41% (95% CI 24-59), with 3 (9%) complete responses and 10 (31%) partial responses. Median time to response was 1.4 mo (range 1.2-2.8); median DOR was not reached, with response ongoing in 7/13 patients. Median PFS was 5.3 mo (95% CI 4.0-12.2); median OS was not reached. The most common treatment-emergent AEs (TEAEs) were alopecia (61%), diarrhea (55%), epistaxis (49%), conjunctivitis (46%), and nausea (46%). Grade ≥3 TEAEs occurred in 67% of patients, the most common being anemia (12%); asthenia (9%); hypokalemia (9%); and increased alanine aminotransferase, decreased white blood cell count, dyspnea, and acute kidney injury (6% each). Three grade 5 TEAEs were reported of which one, disseminated intravascular coagulation, was considered treatment-related. Prespecified AEs of interest (grade 1-2/grade ≥3) with TV included ocular (58%/9%), peripheral neuropathy (45%/3%), and bleeding (61%/6%). Updated results with longer follow-up for this cohort and the 1L TV + carbo and 2L/3L TV + pembro cohorts will be provided at the meeting. Conclusions: TV + pembro demonstrated encouraging, durable antitumor activity with a manageable and acceptable safety profile as a 1L regimen for patients with r/mCC. This trial is ongoing and final analyses will be reported in the future. Clinical trial information: NCT03786081.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

Combined administration of intravenous (iv) and intraperitoneal (ip) (iv/ip) chemotherapy is an effective adjuvant treatment option after primary debulking surgery (PDS) for advanced ovarian cancer (OC). Increased toxicityand patient burden limit its use in daily practice.To assess toxicity and survival outcomes of iv/ip chemotherapy in daily practice in the Netherlands.This retrospective cohort study included 81 women who underwent at least an optimal PDS for FIGO stage III OC followed by iv/ip chemotherapy according to the Armstrong regimen, in four hospitals in the Netherlands between January 2007 and May 2016. We collected information on surgical procedure, abdominal port implantation, toxicity, and recurrence-free and overall survival.All participants underwent PDS, of whom 60 (74%) had their ip catheter implanted during PDS. Most frequently reported all grade toxicity was haematological n = 44 (54%). Forty-four patients (54%) completed all six cycles of iv/ip chemotherapy. The most frequent causes of discontinuation of iv/ip administration were renal dysfunction (12/37 = 32%) and catheter problems (7/37 = 19%). Median recurrence-free survival and overall survival were 24 months (range 0 - 108) and 80 months (range 4-115), respectively. Surgical outcome, completion of more than three courses of treatment and intra-abdominal localisation of recurrent disease were associated with better survival outcomes.In daily practice, 54% of patients with advanced OC could complete all scheduled cycles of iv/ ip chemotherapy with acceptable morbidity and toxicity, leading to outcomes comparable with the results of published trials on iv/ip chemotherapy.

Introduction/Background Clear cell carcinoma (CCC) is a rare subtype of ovarian and endometrial cancer. It carries a poor prognosis and response to chemotherapy in recurrent disease is low. As angiogenesis pathways are activated in CCC, we performed a trial comparing nintedanib (BIBF1120), an orally available, triple kinase inhibitor targeting VEGFR, PDGFR and FGFR with physician’s choice of chemotherapy. As the first randomised trial in relapsed CCC, it gives important information on the efficacy and toxicity of both nintedanib and chemotherapy. Here we report the ovarian cancer (OC) results. Methodology This was an international, multi-centre, randomised, open label phase II, 3 outcome design. Patients were randomised to nintedanib 200 mg PO twice daily or chemotherapy (paclitaxel (80 mg/m2 IV Day 1,8,15), pegylated liposomal doxorubicin (40 mg/m2 IV) or topotecan (4 mg/m2 IV Day 1,8,15) every 28 days). Treatment was given until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS) in the ovarian cohort. Secondary objectives included overall survival (OS), response rate (RR), disease control rate (DCR) and patient reported outcomes. With 90 OC patients, the study was powered to detect an improvement in median PFS from 3 to 5 months (HR=0.6) with >90% power, 20% 1-sided significance. A statistically significant PFS difference at the 1-sided 10% level (Nintedanib superior) would give a clear signal that a phase III study is warranted. A statistically significant result at the 1-sided 20% level would require other supportive evidence. EudraCT Ref:2013-002109-73. ISRCTN No:ISRCTN50772895. Results 91 OC patients were included in the analysis. Median age was 54 years. Median number of previous lines was 2. After a median follow up of 20.7 months the median PFS was 2.3 months with nintedanib and 1.9 months with chemotherapy (hazard ratio=0.79, 80% CI=(0.58,1.06), p(1-sided)=0.1521. Median OS was 9.0 and 4.9 months, respectively. Difference in OS estimates at 6 and 12 months were 19.7% and 8.9% demonstrating non-proportional hazards. RR was 2.1% and 0%, and DCR at 16 weeks was 23.4% and 9.1% (odds ratio=5.81, 80%CI=(1.79,18.89), p(1-sided)=0.0276) with nintedanib and chemotherapy, respectively. Conclusion The study failed to demonstrate sufficient activity of nintedanib as a monotherapy to support a phase III trial. However, the benefit in PFS, DCR and OS suggests it may be interesting to combine nintedanib with other agents in OCCC. Chemotherapy is ineffective and the outcomes for women with OCCC are extremely poor confirming the need for continued research into novel targets and therapies. Translational research is on-going (figures 1 and 2). Disclosures The study was funded by an educational grant from Boehringer Ingelheim and supported by Cancer Research UK Grant ref: C8361/A15600. Author disclosures Rosalind Glasspool: Grant funding for clinical trials from Boehringer Ingelheim, Lilly/Ignyta and Clovis. Consultancy fees, travel support and/or speaker fees for AstraZeneca, GSK/Tesaro, Clovis, Immunogen and Sotio. Site PI for studies sponsored by AstraZeneca, GSK/Tesaro, Clovis, Immunogen, Lilly and Pfizer. Samantha Hinsley: none. Jonathan Ledermann: Advisory Board and Lecture fees from AstraZeneca, Pfizer, Clovis Oncology, MSD/Merck, Eisai, Artios Pharma, GSK and grant funding from AstraZeneca and MSD/Merck. IDMC fees from Regeneron. Iain McNeish: Advisory Board fees from AstraZeneca, Clovis Oncology, Tesaro/GSK, Roche, Scancell and Carrick Therapeutics. Institutional grant funding from AstraZeneca. Jerome Alexandre: Grant funding from Janssen, MSD. Consultancy fees, travel support and/or speaker fees for AstraZeneca, GSK/Tesaro, MSD, Eisai, Novartis, Pharmamar. Site PI for studies sponsored by AstraZeneca, GSK/Tesaro, MSD, Agenus, Merck Serono, Seattle Genetics Anneke Westermann: none. Claire Lawless: none Nelleke Ottevanger: none Mansoor Raza Mirza: Personal Financial Interests: AstraZeneca, Biocad, Clovis Oncology, Geneos, Genmab, Karyopharm Therapeutics, merck, msd, Oncology Centre, Pfizer, Roche, SeatleGenetics, Sera Prognostics, Sotio, Tesaro-GSK, ZaiLab. Institutional financial interests (study grants): AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Tesaro-GSK Isabelle Ray-Coquard: Honoraria (self) from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; honoraria (institution) from GSK, MSD, Roche and BMS; advisory/consulting fees from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; research grant/funding (self) from MSD, Roche and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca and Merck Sereno; and travel support from Roche, AstraZeneca and GSK.

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PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

Background: Diagnosis and treatment of incurable cancer as a life-changing experience evokes difficult existential questions. Aim: A structured reflection could improve patients’ quality of life and spiritual well-being. We developed an interview model on life events and ultimate life goals and performed a randomized controlled trial to evaluate the effect thereof on quality of life and spiritual well-being. Design: The intervention group had two consultations with a spiritual counselor. The control group received care as usual. EORTC QLQ-C15-PAL and the FACIT-sp were administered at baseline and 2 and 4 months after baseline. Linear mixed model analysis was performed to test between-group differences over time. Participants: Adult patients with incurable cancer and a life expectancy ⩾6 months were randomized in a 1:1 ratio to the intervention or control group. Results: A total of 153 patients from six different hospitals were included: 77 in the intervention group and 76 in the control group. Quality of life and spiritual well-being did not significantly change over time between groups. The experience of Meaning/Peace was found to significantly influence quality of life ( β = 0.52, adj. R2 = 0.26) and satisfaction with life ( β = 0.61, adj. R2 = 0.37). Conclusion: Although our newly developed interview model was well perceived by patients, we were not able to demonstrate a significant difference in quality of life and spiritual well-being between groups. Future interventions by spiritual counselors aimed at improving quality of life, and spiritual well-being should focus on the provision of sources of meaning and peace.

Adult hepatoblastoma (AHB) is a rare liver tumor with a poor prognosis in adolescents and adults. This contrasts with hepatoblastoma in children and is not fully understood. Here we describe two adolescents with AHB who were treated in our hospital. Adolescents are likely to receive less intensive chemotherapy protocols and are treated in hospitals with less experience in pediatric oncology, resulting in poor outcome. More research is necessary for optimal treatment of AHB in adolescents. Adolescents with AHB should be referred to hospitals experienced in pediatric oncology and receive intensive chemotherapy, followed by hemihepatectomy.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

Contains fulltext : 229154.pdf (Publisher’s version ) (Closed access) Cisplatin is the first choice treatment in mediastinal germ cell tumors. However, concerns regarding increased toxicity of cisplatin hamper its administration in patients with impaired renal function. We describe a 42-year-old man with chronic kidney disease stage 4 who was diagnosed with a mediastinal germ cell tumor and metastases in lung and brain. Treatment with cisplatin-etoposide was considered essential for a chance of cure. In order to administer the full cisplatin dose, 4-hour hemodialysis sessions were performed after each cisplatin infusion. During treatment cycle 3, 4 and 5, total and unbound plasma platinum concentrations were measured. Trough concentrations and half-life were at the higher end of the range of those observed in patients with adequate renal function who received the same dose of cisplatin. Hemodialysis aided platinum clearance, although our patient was also able to clear some platinum by his own renal function. With this full dose treatment, our patient obtained a favorable tumor response, with a strong decrease of beta-human chorionic gonadotropin and tumor size. The side effects experienced by our patient were serious, although not worse than what could be expected with this type of treatment. His renal function remained stable during the treatment period.

5519 Background: Lower responses to chemotherapy and the unique molecular profile of LGSO led to the adoption of MEK-inhibitors for this disease. Updated analysis from the MILO/ENGOT-ov11 phase III study of binimetinib vs PCC in recurrent LGSOC showed response rate of 24% in those treated with binimetinib (JCO, 2020; NCT01849874). Here we present results of the post-hoc tumor tissue biomarker analysis performed with MILO/ENGOT-ov11. Methods: Mutational/copy number analysis was performed via Foundation Medicine on archival tissue obtained prior to randomization. Unbiased univariate analysis was used to test association between mutation status and outcomes in binimetinib and PCC treated patients. Outcomes examined were progression free survival (PFS), binary response by local RECIST 1.1 (complete or partial response [CR/PR] vs. stable [SD] or progressive disease [PD]), and ordinal response. Kaplan-Meier was used to estimate PFS. Cox regression, binary logistic regression, and ordinal logistic regression were used to examine relationship between mutation status and outcomes. Results: MILO/ENGOT-OV11 enrolled 341 patients from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or PCC. Based on January 1, 2020 data cut-off the data is as-is, amongst those patients treated with binimetinib with molecular results available, PFS data is available for 144 and response rate (RR) data for 135. There were 47 mutations detected in ≥5% of patients, most commonly KRAS (33%). Patients harboring a KRAS mutation had 3.4 times the odds of responding to treatment with binimetinib as patients without KRAS mutation (95% CI 1.57,7.67; p-value 0.002). There was no difference in effect of KRAS G12V mutation vs other KRAS mutation on PFS (PFS HR 1.06; 95% CI:0.53, 2.12; p value 0.9). In the 135 patients with binimetinib RR data, other MAPK mutations were identified as follows; NRAS in 11(8.1%), BRAFV600E in 8(5.9%), RAF1 in 2 (1.5%), NF1 in 7 (5.2%). In patients with MAPK mutation (as defined above) the RR was 41% vs 13% in those without MAPK mutation. PFS was significantly better in patients treated with binimetinib harboring MAPK mutation vs those without (HR 0.5; 95% CI 0.31, 0.79; p = 0.003). In patients treated with PCC there was a nonsignificant trend towards improved PFS in those with MAPK mutation vs those without (HR 0.82; 95% CI 0.43,1.59; p = 0.6). A test for interaction between treatment and MAPK pathway was not significant by Cox regression model (p = 0.32). Conclusions: While this hypothesis generating analysis is limited by multiple testing, higher response rates and longer PFS were seen in those patients with LGSOC treated with binimetinib who harbored MAPK mutations, most commonly in KRAS. Somatic tumor testing should be routinely performed in patients with recurrent LGSOC to aid in clinical decision making. Clinical trial information: NCT01849874.

Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects.

The structure of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-stabilized colloidal tetracosane emulsions was investigated by photon correlation spectroscopy and small-angle X-ray and neutron scattering, using emulsions with different neutron scattering contrasts. Special emphasis was placed on the structure of the DMPC stabilizer layer covering the emulsion droplets. A monolayer, structurally similar to a half DMPC bilayer, with a thickness of 16 Å is found. Thereby, the phosphocholine headgroups arrange flat at the oil-water interface. A deep penetration of the tetracosane oil into the stabilizer layer can be ruled out.

The prognosis of recurrent or metastatic endometrial cancer is poor, with five-year survival of only 10-20 %. First-line therapy consists of either platinum-based chemotherapy or hormonal therapy. No standard subsequent-line therapy has been identified. In recent years, significant progress has been made in the knowledge on underlying molecular biology of endometrial cancer and potential targets for therapy have been identified. Targeted therapies as poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy as PD-1/PD-L1 checkpoint inhibitors have the potential to be effective against specific subtypes of endometrial cancer. Preclinical studies have shown that combining these agents may result in a synergistic effect. In this review, we focus on the molecular basis of checkpoint inhibition and targeted therapy as PARP inhibition in endometrial cancer and summarize available clinical data, and ongoing and planned clinical trials that investigate these agents as mono- or combination therapies in endometrial cancer and where relevant, other gynecological cancers.

Background: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management. © 2019 The Authors

Introduction. Nonsurgical management of patients with desmoid-type fibromatosis (DF) is increasing. This study tries to provide insight on type, usage, and outcome of first-line nonsurgical management strategies. Patients and Methods. From the Dutch Pathology Registry (PALGA), patients with extra-abdominal or trunk/abdominal wall DF, diagnosed between 1993 and 2013, were identified. First-line treatment was analyzed. Best response (BR) using RECIST criteria from start of treatment/surveillance until change of treatment or last follow-up was analyzed. Results. Ninety-one of the 1141 identified patients had first-line nonsurgical management. The percentage of patients treated nonsurgically increased from 0.6% in 1993–1998 to 12.8% in 2009–2013. Thirty-seven patients had surveillance (41%), 35 radiotherapy (38%), and 19 systemic treatment (21%). BR for surveillance was complete response (CR) in 2/37, partial response (PR) in 4/37, stable disease (SD) in 21/37, progressive disease (PD) in 5/37, and unknown in 5/37 patients. BR for radiotherapy was CR in 4/35, PR in 11/35, SD in 16/35, and unknown in 4/35. BR for systemic treatment was CR in 1/19, PR in 1/19, SD in 10/19, PD in 2/19, and unknown in 5/19. Totally, 91% of patients did not progress. Discussion. Given the low percentage (9%) of PD of nonsurgical management, these data can be used in shared decision making with the patient regarding optimal treatment.

Autosomal-dominant hypertension and brachydactyly syndrome (HTNB; Bilginturan syndrome) is known to cause stroke before age 50 when untreated. We report a novel PDE3A gene mutation in a mother and daughter affected with dominant brachydactyly of the hands and feet, a short stature, and hypertension. The hypertension was medically responsive to anti-hypertensive treatment. The 3-bp deletion in the PDE3A gene presented de novo in the mother. Here, we expand the list of PDE3A mutations identified in Bilginturan syndrome and emphasize the importance of standardized genetic testing of HTNB patients to improve diagnostics at an early age. We recommend extended phenotyping in patients with brachydactyly, a short stature or hypertension in clinical practice.

Eight university medical centres in the Netherlands have established clinical genetic services. Patients receive intensive, and therefore costly, genetic counselling before genetic testing takes place. In recent years the number of patients referred to clinical genetic services has risen dramatically, creating waiting-list backlogs. Knowing your carrier status in hereditary cancers, for instance for a BRCA1/2 mutation, can have consequences for surveillance, treatment, and prevention; however, 90% of patients with breast cancer do not have a mutation. We, therefore, argue that the pathway to genetic testing should be reconstructed in order to safeguard timely and adequate genetic testing for an increasing number of patients. The treating physician should be able to request a DNA test in carefully-selected patient-populations, and only refer patients for genetic counselling after a positive finding. Prerequisites for this 'mainstream pathway' are adequate training for medical specialists, good communication with genetics' departments, and guaranteed referral in uncertain or complex cases.

ObjectivesThe Gynecologic Cancer InterGroup aimed to provide an overview of uterine and ovarian leiomyosarcoma management.MethodsPublished articles and author experience were used to draft management overview. The draft manuscript was circulated to international members of the Gynecologic Cancer InterGroup for review and comment, and appropriate revisions were made.ResultsThe approach to management of uterine and ovarian leiomyosarcoma management is reviewed.ConclusionsUterine and ovarian leiomyosarcomas are rare and aggressive cancers that require specialized expertise for optimal management.

High-grade undifferentiated sarcomas (HGUSs) are rare uterine malignancies arising from the endometrial stroma. They are poorly differentiated sarcomas composed of cells that do not resemble proliferative-phase endometrial stroma. High-grade undifferentiated sarcomas are characterized by aggressive behavior and poor prognosis. Cyclin D1 has been reported as a diagnostic immunomarker for high-grade endometrial stromal sarcoma with an YWHAE-FAM22 rearrangement. YWHAE-FAM22 endometrial stromal sarcomas (ESS) represent a clinically aggressive subtype of ESS classified as high-grade endometrial sarcomas, and its distinction from the usual low-grade ESS with JAZF1 rearrangement and from HGUS with no identifiable molecular aberration may be important in guiding clinical management. Median age of the patients is between 55 and 60 years. The most common symptoms are vaginal bleeding, abdominal pain, and increasing abdominal girth.Disease is usually advanced with approximately 70% of the patients staged III to IV according to the International Federation of Gynecology and Obstetrics classification. Preferential metastatic locations include peritoneum, lungs, intra-abdominal lymph nodes, and bone. Median progression-free survival ranged from 7 to 10 months, and median overall survival ranged from 11 to 23 months. There is no clear prognostic factor identified for HGUS, not even stage. The standard management for HGUS consists of total hysterectomy and bilateral salpingo-oophorectomy. Systematic lymphadenectomy is not recommended. Adjuvant therapies, such as chemotherapy and radiotherapy, have to be discussed in multidisciplinary staff meetings.

Endometrial stromal sarcoma (ESS) accounts for approximately 20% of all uterine sarcomas and presents, at a mean age, around 50 years of age. Half of the patients are premenopausal. ESS often manifests as an endometrial polyp and 60% of cases present with FIGO stage I disease. The natural history is one of slow growing indolent disease. Typical microscopic findings include a uniform population of endometrial stromal-type cells invading the myometrium and myometrial vessels. Imaging studies cannot reliably diagnose ESS preoperatively, so surgical resection for a presumed fibroid is a common scenario. Hysterectomy is the cornerstone of treatment for localized ESS, but morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome. Leaving the ovaries in situ does not worsen survival and this is of importance especially for young women. The data support the current practice to administer adjuvant hormonal treatment, although several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Repeat surgery for recurrent disease that is indolent and hormone sensitive appears to be an acceptable approach. Systemic treatment for recurrent disease is mainly hormonal.