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Ocean mass change is one of the main drivers of present-day sea-level change (SLC). Also known as barystatic SLC, it is driven by the exchange of freshwater between the land and the ocean, such as melting of continental ice from glaciers and ice sheets, and variations in land water storage. While many studies have quantified the present-day barystatic contribution to global mean SLC, fewer works have looked into regional changes. This study provides a comprehensive analysis of regional barystatic SLC trends since 1993 (the satellite altimetry era), with a focus on the uncertainty budget. We consider three types of uncertainties: intrinsic (the uncertainty from the data/model itself); temporal (related to the temporal variability in the time series); and spatial-structural (related to the location/distribution of the mass change sources). We collect a range of estimates for the individual freshwater sources, which are used to compute regional patterns (fingerprints) of barystatic SLC and analyse the different types of uncertainty. When all the contributions are combined, we find that the barystatic sea-level trends regionally ranges from −0.43 to 2.55 mm year−1 for 2003–2016, and from −0.39 to 2.00 mm year−1 for 1993–2016, depending on the choice of dataset. When all types of uncertainties from all contributions are combined, the total barystatic uncertainties regionally range from 0.62 to 1.29 mm year−1 for 2003–2016, and from 0.35 to 0.90 mm year−1 for 1993–2016, also depending on the dataset choice. We find that the temporal uncertainty dominates the budget, although the spatial-structural also has a significant contribution. On average, the intrinsic uncertainty is almost negligible. The main source of uncertainty is the temporal uncertainty from the land water storage contribution, which is responsible for at least 50 % of the total uncertainty, depending on the region of interest. The second main contributions come from the spatial-structural uncertainty from Antarctica and land water storage, which show that different locations of mass change can lead to trend deviations larger than 20 %. As the barystatic SLC contribution and its uncertainty vary significantly from region to region, better insights into regional SLC are important for local management and adaptation planning.

Introduction/Background* The COVID-19 pandemic caused drastic healthcare changes worldwide. To date, the impact of these pandemic-induced alterations in gynaecological oncology healthcare is unknown. We assessed the impact of the COVID-19 pandemic on gynaecological oncology healthcare in the Netherlands by analysing data of the Dutch Gynaecological Oncology Audit (DGOA). Methodology All patients in The Netherlands undergoing surgery for ovarian, vulvar, endometrial or cervical cancer are registered in the DGOA since 2014. To evaluate whether the COVID-19 pandemic influenced care, we compared the following parameters that are available in the DGOA: surgical volume, time to first treatment (TTFT), length of hospital stay (LOHS), postoperative complications and 30-day mortality. Four periods were identified in 2020 based on incidence of COVID-19 infections in The Netherlands: ‘Pre-COVID-19’, ‘First wave’, ‘Interim period’ and ‘Second wave’. Using descriptive statistics, results from 2020 were compared with the same four periods of 2018-2019 combined. Result(s)* A total of 12.447 surgical procedures were analysed. Analysing the four periods in 2020, compared to the average volumes of 2018-2019, the surgical volume for the four tumour types decreased during the first COVID-19 wave and interim period (figure 1). This was due to a decrease in surgical volume for cervical cancer only (17.2% in 2020), while volumes for ovarian, vulvar and endometrial cancer remaining stable. Moreover, during the interim period, only 51% of the expected cervical cancer procedures were performed. A significantly shorter median TTFT was observed in all four malignancies in 2020, compared to 2018-2019 (table 1). No differences in LOHS, postoperative complications and 30-day mortality were observed (table 1). Conclusion* The COVID-19 pandemic clearly impacted gynaecological oncology healthcare in The Netherlands. During the first COVID-19 wave, surgical volume for gynaecological oncological procedures dropped considerably, mainly due to a substantial drop in surgical volume for cervical cancer. This is probably caused by the temporary interruption of the population screening program. During the COVID-19 pandemic, waiting time to start therapy was shorter. The quality of perioperative healthcare was not negatively impacted by the pandemic.

Introduction/Background* The treatment of cervical high-grade squamous intraepithelial lesion (cHSIL) by topical imiquimod (Aldara®) is investigated as an alternative for surgical large loop excision of the transformation zone (LLETZ), because of the latter‘s risk of causing cervical insufficiency and subsequent premature birth in following pregnancies. Imiquimod is effective in ~60% of cHSIL patients, at present we are not able to select women likely to succesfully respond. Therefore, studies on predictive biomarkers are needed to enable personalised therapy and to prevent unnecessary potential side effects. Here, we performed an in-depth analysis of the role of the pre-existing immune microenvironment in cHSIL in response to topical imiquimod. Methodology Histologically confirmed cHSIL of 35 patients biopsied before and 10 weeks after treatment with topical imiquimod were analyzed by two multispectral seven-color immunofluorescence panels to investigate the T cell (CD3, CD8, FOXP3, PD1, TBET, TIM3, DAPI) and Myeloid cell (CD68, CD163, CD11c, CD14, CD33, PDL1, DAPI) composition in relation to treatment response. All 70 samples were scanned with the Vectra multispectral imaging system. Cells were automatically identified using a deep learning multispectral image analysis approach (inForm software). Result(s)* Our data show that the immune microenvironment of complete responders (CR) prior to imiquimod therapy is characterized by a coordinated infiltration with T helper cells (activated PD1+/type 1 Tbet+) and pro-inflammatory M1 macrophages (CD68+CD163-) and dendritic cells (CD11c+). The lesions of non-responders (NR) lacked such a pro-inflammatory response and displayed an impaired influx of these pro-inflammatory lymphoid and myeloid cells. In contrast, the NR showed an increased infiltration by immunosuppressive regulatory T cells (CD3+FOXP3+). After 10 weeks of topical imiquimod application, the influx of pro-inflammatory CD4+ and CD8+ T cells was further increased in the CR but not in the NR patients, and the infiltration by macrophages was decreased. Conclusion* Response of cHSIL to topical imiquimod is associated with the presence of a pre-existing pro-inflammatory process, resulting in the coordinated influx of several types of immune cells, which is then further amplified. Our findings indicate major potential of the immune microenvironment as predictive biomarker for the selection of cHSIL patients responding to topical imiquimod immunotherapy.

Introduction/Background* High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers opting for surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. Methodology Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose between the standard risk-reducing salpingo-oophorectomy or a novel strategy, risk-reducing salpingectomy with delayed oophorectomy. The Cancer Worry Scale was obtained before and three and twelve months after surgery. Cancer worry patterns were analysed using latent class growth analysis and factors associated with cancer worry were identified with regression analysis. Result(s)* Of all 577 BRCA1/2-PV carriers, 320 (55.5%) had high (≥14) cancer worry pre-surgery and 70.2% had higher cancer worry pre-surgery than post-surgery. Based on the course of cancer worry, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56.4%), persistently high cancer worry (6.3%), and fluctuating cancer worry that mainly declined over time (37.3%). Factors associated with persistently high cancer concerns were: age below 35 (BRCA1) or 40 (BRCA2) years, unemployment, previous breast cancer diagnosis, lower education and more recent diagnosis with the BRCA-PV. Conclusion* High cancer worry is common among BRCA1/2-PV carriers and mainly declines after risk-reducing surgery. However, cancer worry remains high in 6% of the women and they should be identified and offered support. It should be realized that in this group, surgery does not reduce cancer concerns.

The uterine carcinosarcoma (UCS) is a rare entity with poor prognosis. Treatment of FIGO I-II UCS usually consists of surgery with or without adjuvant treatment. Due to the high metastatic potential, aggressive combined modality adjuvant treatment approaches, consisting of chemo- and radiotherapy, have been of interest. Our systematic review aims to compare survival, disease control and toxicity profiles in patients receiving adjuvant chemoradiation to other adjuvant strategies (e.g.observation, chemotherapy or radiotherapy). A total of ten studies were included for a combined cohort size of 6520 patients. Generally, the studies showed a trend towards improved disease control and survival in patients undergoing adjuvant multimodal treatment, although statistical significance was often not reached. Selection bias and non-randomized treatment allocation pose serious challenges to extrapolate these outcomes to clinical practice. We recommend additional prospective research on the role of adjuvant chemoradiation in FIGO I-II UCS.

Introduction/Background About 5% of ovarian tumours have a non-epithelial histology, including germ cell tumours (GCTs), sex cord-stromal tumours (SCSTs), and sarcomas. Since the rarity of these non-epithelial ovarian tumours and the scarcity of population-based studies, the aim of this population-based study is to describe trends in incidence, treatment, and survival of these women in the Netherlands. Methodology All Dutch women diagnosed with non-epithelial ovarian malignant tumours between 1989 and 2015 were identified from the Netherlands Cancer Registry. Demographics, tumour characteristics, and initial treatment were collected and overall survival was analysed. Results A total of 1258 women were diagnosed with non-epithelial ovarian tumours in the Netherlands, including 752 GCTs (60%), 341 SCSTs (27%), and 165 sarcomas (13%). The European age standardized incidence rate (ESR) was 0.4 per 100,000 persons per year for GCTs, 0.2 for SCSTs and 0.1 for sarcomas. Approximately 97% of patients underwent surgical resection for the primary tumour, whereas 31% received systemic treatment and 3% radiotherapy. Five-year overall survival improved for all histologic subtypes between the late 1980’s until 2015: GCTs from 73% to 88% (p=0.03) SCSTs from 64% to 81% (p=0.57) and sarcomas from 20% to 29% (p=0.14). Conclusion Malignant GCTs and SCSTs are rare and its incidence did not significantly change during the last decades. They have a good prognosis which also improved slightly. Women with primary sarcomas of the ovary are extremely rare and still have a poor prognosis. Disclosure Nothing to disclose.

Introduction/Background High-grade cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Treatment is usually performed by large loop excision of the transformation zone (LLETZ), but is associated with an increased risk of premature birth in subsequent pregnancies. Topical imiquimod cream may be an alternative treatment modality. This study aims to provide evidence on treatment efficacy and side-effects of topical imiquimod cream compared to standard LLETZ treatment. Methodology A multi-centre, non-randomized controlled trial was performed among women with a histological diagnosis of CIN 2/3. Women who opted for standard treatment, underwent LLETZ treatment. Successful treatment was defined as no need for second LLETZ after 6 months follow-up. Women who opted for imiquimod treatment, administered 6.25 mg imiquimod 5% cream vaginally up to three times per week during 16 weeks. Treatment efficacy was evaluated with colposcopy at 20 weeks follow-up and defined as CIN 1 or less. Results 123 patients were included. 62 women underwent LLETZ treatment, which was successful in 58 women (95%). 37% of women reported severe side-effects (Visual analogue scale [VAS] ≥ 8). 61 women underwent topical imiquimod treatment. Twelve women discontinued treatment due to side effects. Treatment was successful in 27 (59%) of remaining women. Side effects were reported by all women who underwent imiquimod treatment and consisted most frequently of headache and fatigue. 69.0% of women reported severe side-effects (VAS ≥ 8). All reported side-effects can be found in tables 1 and 2. Conclusion Topical imiquimod is a feasible alternative treatment for patients with high-grade CIN, although efficacy is considerably lower than LLETZ treatment. It could be an alternative treatment, especially for women with a future pregnancy desire. Predictive biomarkers are necessary to better select those patients who will benefit from imiquimod treatment. Disclosure The authors declare that they have no competing interests. This study and manuscript preparation were funded by the Academic Hospital of Maastricht (Academic Fund) and MedaPharma. Both funding bodies were not involved in the study design and will not be involved in the collection, analysis, and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

Introduction/Background Introduction: GROINSS-V II investigated whether radiotherapy is a safe alternative for inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). Methodology Methods: In GROINSS-V II, a prospective multicentre phase II trial, patients were included with early-stage squamous cell carcinoma (SCC) of the vulva (diameter Results From December 2005 until October 2016, 1552 eligible patients were registered. SN-metastasis occurred in 324/1552 (21%) patients. After 54 months of inclusion the stopping-rule for SN-positive patients was activated; interim analysis showed an increased risk for groin recurrence in case of SN-metastasis >2 mm and/or extranodal extension (ENE). After amendment of the protocol only patients with SN-micrometastasis ≤2 mm received radiotherapy, while those with SN metastasis >2 mm underwent IFL (with radiotherapy if >1 metastasis or ENE). Final analysis after ≥2 years of follow-up revealed six isolated groin recurrences in 157 patients with a SN-micrometastasis (3.8%). Four could not be considered radiotherapy failures: two developed recurrence in the contralateral (SN-negative) groin, two refused radiotherapy. Twenty-eight patients did not get radiotherapy (2 recurrences;7.1%). Among 129 patients who received radiotherapy to the groin(s) only two isolated groin recurrences were diagnosed (1.6%: 95%CI:0–3.8%). The combination of radiotherapy with SN was associated with minimal toxicity: 5/118(4.2%) grade 3 toxicity, no grade 4 or 5 toxicity. In 38/1222 SN-negative patients (3.1%: 95%CI:2.1–4.1%) isolated groin recurrences were diagnosed with clear protocol violations in 6 patients: incomplete treatment of the groin (n=3); primary tumor >4cm (n=1); not all SNs visualized on the lymphoscintigram removed (n=2). After exclusion of these protocol violations an isolated groin recurrence rate of 2.6% (95%CI:1.7–3.5%) was observed. Conclusion Radiotherapy to the groins is a safe alternative for IFL in patients with SN metastasis ≤2 mm, with minimal toxicity. We further established the safety of omitting IFL in patients with SCC of the vulva 2 mm, radiotherapy with a total dose of 50Gy was no safe alternative for IFL; dose escalation and/or chemoradiation should be investigated in these patients. Disclosure Funded by Dutch Cancer Society.

British Journal of Cancer (2011) 104, 221–222. doi:10.1038/sj.bjc.6606000 www.bjcancer.comPublished online 23 November 2010& 2011 Cancer Research UKSir,We read with interest the paper by Polterauer et al (2010) inwhich they evaluated the prognostic value of lymph node density(LND) in patients with lymph node-positive cervical cancer. LNDis defined as the ratio of the number of metastatic lymph nodesto the total number of lymph nodes removed. They showed thatLND410% is associated with an impaired disease-free and overallsurvival. Lymph node involvement and lymph vascular spaceinvolvement have always been noted to be a poor prognostic factorin cancer of the cervix (Pecorelli, 2006), and thus this confirms thefact that the higher the number of lymph nodes involved,the worse the prognosis of the patient becomes. The benefit ofusing LND could be that it also incorporates the extent of surgicalstaging. Indeed, it is probably true that when you perform acomplete lymph node dissection instead of a sampling you havemore chance of finding all involved lymph nodes. However, thereis more to it than positive lymph nodes and surgical skills.Although the authors gave the mean/median number ofremoved lymph nodes and positive lymph nodes for all patients,we were not able to discern this information for the LNDp10% orLND410% group separately. We believe that this information ispivotal in a study that examines the ratio of both parameters. In aratio, both the numerator and denominator have an equal role. Theauthors state that they performed a systemic lymphadenectomy inall patients. This means that the mean/median number of removedlymph nodes cannot be statistically different in both groups. As aconsequence, only the denominator will become important, andthus the number of positive lymph nodes will become theprognostic factor. If for any reason the total number of lymphnodes removed in both groups is different, then one must questionthe reasons why. Did the surgeon stop the operation prematurelybecause during the operation he/she discovered bulky involvedlymph nodes? This would make a complete systemic lymphade-nectomy redundant, as the patient is already known to be lymphnode positive based on these few lymph nodes. This is generallyaccepted as an indication for (chemo-)radiotherapy, and thecombination of a radical surgery and pelvic (chemo-)radiotherapywill increase therapy-related morbidity (Quinn et al, 2006). Maybethe pathologist stopped looking intensively for other lymph nodesbecause he/she already found several positive lymph nodes.Second, with respect to the technique used, they referred to aprevious study in which a laparoscopic pelvic lymph node stagingwas described (Polterauer et al, 2008). In this study, patients wereincluded between 1995 and 2007 and, remarkably, the mediannumber of lymph nodes was 15, being more than 3 lymph nodesless than in the present study. Does this implicate a learning curverelated to the laparoscopic technique used? If yes, once more asurgical bias is introduced.Third, we question the cutoff value and how it was established.The authors mentioned that this was based on preliminary datafrom a study by Ooki et al (2007). We wonder how welloesophageal cancer can be compared with cervical cancer. Bothorgans are located in completely different anatomic regions, with adifferent lymph vessel drainage system and lymph node distribu-tion. Did the authors try different cutoff points or was the 10%cutoff the only value examined? If the authors tried different cutoffpoints, one could argue that the authors should have used anindependent validation set to validate this cutoff point.Fourth, with a median of 18.5 lymph nodes (range 12–27),Polterauer et al demonstrated that they routinely performedcomplete lymph node dissections. As the ratio of the mediannumber of involved lymph nodes (n¼2) to the median number ofremoved lymph nodes (n¼18.5) was 10.8%, removing one or twolymph nodes would more or less determine whether the patientbelonged to the category of patients with LNDp10% or LND410%. This would implicate that the surgeon could influence towhich prognostic group the patient will belong. After all, it sufficesto remove more lymph nodes to shift the patient from theLND410% group to the LNDp10% group. It is contradictory thatthe surgeon has to remove more ‘healthy’ lymph nodes to‘improve’ the prognosis of the patient. With more healthy lymphnodes the denominator will become bigger and thus the LNDsmaller. This strikes us as ironic.In conclusion, as LND is influenced by surgical technique,anatomic circumstances and the quality and accuracy of thepathological analysis, we believe that LND is not an objectiveparameter and should not influence the decision on what kind ofadjuvant treatment should be given to a patient. We believe thatthe number of positive lymph nodes is probably the true predictor,but as the number of patients in each of the different groups (1 vs 2vs 42) was low, the authors were unable to reach significance.Using a ratio solved this problem by creating two arbitrary groupsof patients and by using denominators that enlarged the differencePublished online 23 November 2010 between the numerators.*Correspondence: Dr T Van Gorp; E-mail: toon.van.gorp@mumc.nl

We investigated the physiological regulation of renal function by nitric oxide (NO) and its interactions with the endothelial cyclooxygenase products in the conscious, chronically catheterized rat. A subpressor dose of NO inhibitor nitro-L-arginine methyl ester (L-NAME) produced renal vasoconstriction that was unaffected by cyclooxygenase inhibition with indomethacin (Indo). Acute, high-dose L-NAME produced a pressor response of approximately 40 mmHg and marked renal vasoconstriction. Indo selectively amplified the renal vasoconstriction, whereas inhibition of the thromboxane-endoperoxide receptor had no effect. Chronic NO inhibition for 5 wk led to sustained hypertension and renal vasoconstriction; the latter was amplified by acute Indo. These data suggest that in the normal, conscious rat the kidney is under important NO-dependent tone. There is no obvious interaction between NO and the cyclooxygenase products in control of basal renal function. When systemic NO inhibition is produced with either acute or chronic high-dose L-NAME, the kidney is severely vasoconstricted. The renal vasoconstriction is not ameliorated by thromboxane-endoperoxide antagonism but is exacerbated by cyclooxygenase blockade, suggesting that vasodilator cyclooxygenase products compensate for the renal hypoperfusion because of severe NO deficiency.