Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma.

The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins of a primary cancer. We used a novel approach to prioritize immunotherapy targets and identified a cell surface protein not previously implicated in myeloma, semaphorin-4A (SEMA4A). Using knock-down by short-hairpin RNA and CRISPR/nuclease-dead Cas9 (dCas9), we show that expression of SEMA4A is essential for normal myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate the protein to avoid detection. We further show that SEMA4A would not be identified as a myeloma therapeutic target by standard CRISPR/Cas9 knockout screens because of exon skipping. Finally, we potently and selectively targeted SEMA4A with a novel antibody-drug conjugate in vitro and in vivo.

Patient care and access to clinical trials in gynaecological oncology: global implications of the early phase of the COVID-19 pandemic.

PURPOSE: Our prospective international survey evaluated the impact of the early phase of the COVID-19 pandemic on the management gynaecological malignancies from the multidisciplinary physicians' perspective with particular focus on clinical infrastructures and trial participation. METHODS: Our survey consisted of 53 COVID-related questions. It was sent to healthcare professionals in gynaecological oncology centres across Europe and Pan-Arabian region via the study groups and gynaecological societies from April 2020 to October 2020. All healthcare professionals treating gynaecological cancers were able to participate in our survey. RESULTS: A total of 255 answers were collected from 30 countries. The majority (73%) of participants were gynaecological oncologists from university hospitals (71%) with at least an Intensive Care Unit with cardiopulmonary support available at their institutions. Most institutions continued to perform elective surgeries only for oncological cases (98%). Patients had to wait on average 2 weeks longer for their surgery appointments compared to previous years (range 0-12 weeks). Most cases that were prioritised for surgical intervention across all gynaecological tumours were early-stage disease (74%), primary situation (61%) and good ECOG status (63%). The radicality of surgery did not change in the majority of cases (78%) across all tumour types. During the pandemic, only 38% of clinicians stated they would start a new clinical trial. Almost half of the participants stated the pandemic negatively impacted the financial structure and support for clinical trials. Approximately 20% of clinicians did not feel well-informed regarding clinical algorithm for COVID-19 patients throughout the pandemic. Thirty percent stated that they are currently having trouble in providing adequate medical care due to staff shortage. CONCLUSION: Despite well-established guidelines, pandemic clearly affected clinical research and patientcare. Our survey underlines the necessity for building robust emergency algorithms tailored to gynaecological oncology to minimise negative impact in crises and to preserve access to clinical trials.

Social media ambassadors and collaboration with OncoAlert: a European Network of Young Gynae Oncologists study of comparative Twitter analysis of #ESGO2021 and #ESGO2022.

OBJECTIVE: The primary objective was to reveal the impact of social media ambassadors and the collaboration between the European Society of Gynaecological Oncology (ESGO) and the OncoAlert Network on Twitter during the ESGO 2022 Congress by comparing it with the ESGO 2021 Congress. We also aimed to share our experience on how to organize a social media ambassador program and evaluate the potential benefits for the society and the ambassadors. METHODS: We defined the impact as promoting the congress, sharing the knowledge, change in follower count, and change in tweet, retweet, and reply counts. We used the Academic Track Twitter Application Programming Interface to retrieve data from ESGO 2021 and ESGO 2022. We used the keywords of ESGO2021 and ESGO2022 to retrieve data for each of the conferences. The time range in our study captured interactions from before, during, and after conferences. We collected the ambassadors', ESGO's, and the European Network of Young Gynae Oncologists' (ENYGO's) follower data on Twitter from November 2021 to November 2022 for comparative analysis. RESULTS: There was a 7.23-fold increase in the use of the official congress hashtag in 2022 compared with 2021. Compared with #ESGO2021 data, the main interventions of the Social Media Ambassadors and OncoAlert partnership determined 7.79-, 17.36-, 5.50-, 10.58-, and 8.50-fold increases with #ESGO2022 data in the mentions, mentions in retweet, tweet, retweet, and replies, respectively. Similarly, all other most commonly used hashtags in the top 10 list indicated a range from 2.56- to 7.00-fold increase. Compared to the ESGO 2021 congress month, ESGO and the majority (83.3%, n=5) of ambassadors gained more followers during ESGO 2022 congress month. CONCLUSIONS: An official social media ambassadors program and collaboration with influential accounts in the field of interest are beneficial for congress-related engagement on a social media platform (Twitter). Individuals participating in the program can also benefit from gaining higher visibility among specific audience.

Subspecialty training in Europe: a report by the European Network of Young Gynaecological Oncologists.

BACKGROUND: ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees. METHODOLOGY: National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used. RESULTS: National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system. CONCLUSION: Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training.

Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma.

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

Role of predictive markers for severe postoperative complications in gynecological cancer surgery: a prospective study (RISC-Gyn Trial).

BACKGROUND: Surgery for gynecological cancer involves highly invasive and complex procedures potentially associated with various complications, which can cause extended hospital stays and delay of subsequent therapy, with a detrimental effect on the prognosis. The aim of this study was to explore and define the predictors of severe postoperative complications in patients undergoing surgery for gynecologic cancer. METHODS: Patients undergoing surgery for gynecologic cancers were analyzed prospectively from October 2015 through January 2017. Using validated assessment tools preoperatively, we assessed comorbidities, performance status, quality of life, nutritional and body composition by bioelectrical impedance analysis, and the surgical data of each patient. Surgical complications were graded using the Clavien-Dindo criteria. Using stepwise logistic regression models, we identified predictive markers for postoperative complications. RESULTS: Of the 226 enrolled patients, 40 (17.7%) experienced a grade ≥IIIb complication according to the Clavien-Dindo criteria. In the regression analysis, overweight/obesity (body mass index >25) (OR 6.41, 95% CI 2.38 to 17.24; p<0.001) and impaired physical functioning defined by a quality of life questionnaire (OR 4.19, 95% CI 1.84 to 9.50; p=0.001) emerged as significant predictors of postoperative complications. Moreover, postoperative complications were predicted by phase angle of bioelectrical impedance analysis <4.75° (OR 3.11, 95% CI 1.35 to 7.16; p=0.008) and Eastern Cooperative Oncology Group (ECOG) performance status >1 (OR 2.51, 95% CI 1.06 to 5.92; p=0.04). Intraoperative factors associated with higher risk of postoperative complications were increased use of norepinephrine (>11 µg/kg/min) (OR 5.59, 95% CI 2.16 to 14.44; p<0.001) and performance of large bowel resection (OR 4.28, 95% CI 1.67 to 10.97; p=0.002). CONCLUSION: In patients undergoing surgery for gynecological cancer, preoperative evaluation of performance status according to ECOG, domains of quality of life and nutritional status, as well as intraoperative monitoring of risk factors, might help to identify patients at high risk for severe postoperative complications, and thus reduce surgical morbidity and mortality.

Unmet family planning needs among female refugees and asylum seekers in Germany - is free access to family planning services enough? Results of a cross-sectional study.

BACKGROUND: After the 1968 United Nations International Conference on Human Rights, access to family planning services became a human right. Such a service is of central importance to women's empowerment and is empirically needed to provide adequate healthcare. For registered refugees and asylum seekers in Germany complementary family planning services, including all forms of contraception, are free of charge. Yet, the success of these services remains unclear. The aim of this study is to describe the current reproductive health status of female refugees and to provide an initial overview of their existing unmet family planning and contraception needs. METHODS: Over the course of 2 years, from December 2015 to December 2017, a set of 50 female-only discussion groups were conducted in community shelters for registered refugees in Berlin. A total of 410 women between the ages of 14 and 74 participated. A convenience sampling strategy was then applied and a total of 307 semi-structured questionnaires covering 41 items related to demographic data and women's health were distributed to volunteering female participants over the age of 17. The statistical analysis of the questionnaires was performed using SPSS (IBM, PASW, Version 24). P-values less than or equal to 0.05 were considered statistically significant. RESULTS: Of the 307 participants, the majority were from Syria and Afghanistan (30% respectively). The mean age was 33 years (range: 18-63). On average, each woman had 2.5 births (range: 0-10). Twenty-four women (8%) were pregnant and fifty-four of the women (18%) were trying to become pregnant. The majority of women were classified as "requiring contraception" (n = 195; 63%) of which 183 gave further information on if and how they used family planning methods. The calculated unmet need for family planning in this group was 47%. Of the remaining 53% of the women who used contraception, many utilised "traditional" methods (34% withdrawal method; 8% calendar method) which have a pearl index of 4-18 and can therefore be classified as rather insufficient birth control methods. Intrauterine contraceptive devices were used by 30%. CONCLUSION: Our study revealed that despite the provision of complementary family planning services, there remains unmet family planning and education needs in the female refugee community in Berlin. This study indicates that there is a major access gap to these services. Further research needs to be carried out to evaluate the access gap and clearly identify and implement action plans to address possible causes such as language barriers, lack of childcare and traumatic experiences.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

OVQUEST - Life after the diagnosis and treatment of ovarian cancer - An international survey of symptoms and concerns in ovarian cancer survivors.

OBJECTIVES: Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC). METHODS: OvQuest is an international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs. RESULTS: The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains. CONCLUSION: Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL.

A report on the Marrakech International Women's Cancer Days: dialogs and implications.

The MarrakechInternational Women's Cancer Days showcased a first-time international meeting of healthcare professionals worldwide to discuss, over the course of 3 days, aspects of public health, prevention, and treatment of gynecological cancers in the Arabic region. The focus was particularly on promoting globally sustainable research initiatives. The event was a joint initiative organized by the Gynecological Cancer Intergroup and the Pan-Arabian Research Society of Gynecological Oncology. The first conference day focused on the early diagnosis and screening of cervical cancer and the required action to establish equity within screening programs and improve cancer control strategies in the Euro-Mediterranean region. The second day highlighted current screening, diagnosis, and treatment strategies for ovarian cancer in the Arabic region, with particular discussion on the incidence of germline mutations in Arabic women with ovarian cancer. Centers from the Arabic region such as Jordan, Tunesia, Sudan, and Morocco presented their own data on ovarian cancer patients and local clinical practice, and barriers to treatment. It was highlighted that more support is required in surgical training and medical therapies. On the third day , the focus was on cervical cancer therapies and treatment. Interesting surveys on patient awareness of screening programs and cervical cancer were presented from various centers including Lebanon, Sudan, and the UAE. The conference ended with emphasis on patient education, and quality of life. The meeting provided a first-time platform for sustainable worldwide dialog and exchange on all aspects of gynecological cancers focusing on the Arabic woman and the particular barriers, unchartered territories, and challenges this patient population presents to the global healthcare community.

Impact of right upper quadrant cytoreductive techniques with extensive liver mobilization on postoperative hepatic function and risk of liver failure in patients with advanced ovarian cancer.

OBJECTIVE: Evaluate postoperative hepatic-function in patients with advanced ovarian cancer (OC) who underwent extensive right upper-quadrant (RUQ) cytoreduction in primary, relapsed or interval settings. METHODS: We retrospectively reviewed all patients with OC who underwent liver resection, mobilization and/or diaphragmatic-stripping between 01/2013 and 12/2016. Postoperative liver enzyme function (LFTs), assessed by alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin (Bil), was correlated with postoperative complications. RESULTS: 132 patients were identified. 81 patients (61%) underwent upfront, 25(19%) interval and 26(20%) secondary cytoreduction. The surgical procedures were right diaphragmatic peritoneal stripping (81/132;61%), full-thickness resection (42/132;32%), liver-capsule resection (85/132;64%), porta-hepatis tumor resection (11/132;8%) and partial hepatectomy (5/132;4%). 74%(98/132) of patients increased their LFTs postoperatively with a peak at 24-hours. Highest ALT median was 1.7-fold of upper normal limit (UNL), with the highest ALT value rising up to 28-fold UNL on the 1st postoperative day (PoD)(range 6-1792 IU/L). Median value of highest ALP was within normal, with the highest ALP value rising up to 4-fold UNL on PoD 5(range 22-512 IU/L). Median value of highest Bilirubin level was also within normal, with highest Bilirubin level rising up to 6-fold UNL on PoD 5(range: 2-120 µmol/L). Mean LFT-normalization time was 7 days (range: 3-14 days). No significant morbidity was directly linked to LFT deterioration, apart from one case (0.8%) of fatal fulminant hepatic-failure. CONCLUSION: RUQ-cytoreduction is almost always associated with a transient LFT-increase, with no significant clinical implications and spontaneous normalization within the first postoperative week. Due to the existing risk of fulminant liver failure, albeit rare and difficult to predict, postoperatively elevated LFTs should be monitored, until normalization. Large prospective studies are required to assess the predictive value of LFTs and other risk factors for postoperative hepatic failure in patients with OC undergoing extensive RUQ-cytoreduction.

A Review of Thoracic and Mediastinal Cytoreductive Techniques in Advanced Ovarian Cancer: Extending the Boundaries.

The aim of this study was to review the surgical and clinical outcomes of intrathoracic and mediastinal surgical cytoreduction in stage IV epithelial ovarian cancer (EOC). Relevant articles were identified from MEDLINE and EMBASE. Only analyses or reports that described actual intrathoracic cytoreduction via pleurectomy and/or resection of cardiophrenic/mediastinal lymph nodes were included. Imaging articles that merely described thoracic tumor patterns were excluded. A total of nine studies were identified, the oldest originating in 2007. Procedures described were transdiaphragmatic resection of cardiophrenic lymph nodes and pleural disease (n = 5) and video-assisted thoracoscopic and mediastinal tumorectomies including pleurectomy (n = 4). The number of operated patients ranged between 1 and 30 with complete cytoreduction rates ranging between 68 and 100%. No surgical deaths directly related to the thoracic cytoreduction were reported and only one patient (1/30) experienced a postoperative complication in terms of a pneumothorax. None of the studies presented a direct comparison of survival to patients with thoracic disease who did not undergo thoracic cytoreduction, and therefore the survival benefit of thoracic cytoreduction could not be quantified. In conclusion, thoracic cytoreduction in advanced EOC seems feasible and with acceptable morbidity while offering a better understanding of the extent of disease and hence allowing the tailoring of intraabdominal resections. Nevertheless, its direct impact on patients' survival by a potential overruling of a more adverse tumor biology remains to be established in larger-scale prospective and ideally randomized trials.

Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate.

Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing.

OBJECTIVE: Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample. MATERIALS AND METHODS: We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis. RESULTS: We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18. CONCLUSIONS: We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.