Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

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.

Phase 2 study of neoadjuvant enzalutamide and paclitaxel for luminal androgen receptor-enriched TNBC: Trial results and insights into "ARness".

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC.

Total phenolic contents, cytotoxic, free radicals, porcine pancreatic α-amylase, and lipase suppressant activities of Artemisia dracunculus plant from Palestine.

Artemisia dracunculus: L. (A. dracunculus) is a popular vegetable and spice cultivated across many Middle Eastern countries. The herb's aqueous extract has significant folkloric medicinal importance for treating various disorders. Hence, the present investigation aimed to investigate A. dracunculus hydrophilic extract phytochemical constituents and pleiotropic biological potentials, as no previous studies have investigated the antilipase and anti-α-amylase effects of the A. dracunculus plant. Total phenol content and phytochemical screening assays were performed utilizing standard analytical methods. While the α-amylase inhibition, free radical-scavenging, antilipase, and cytotoxic activities were determined using dinitrosalicylic acid (DNSA), DPPH, p-nitrophenyl butyrate (PNPB), and MTS assays, respectively. The standard phytochemical analysis of A. dracunculus aqueous extract shows that this extract contains only a phenolic group. The total phenol content was 0.146 ± 0.012 mg GAE/g of the plant dry extract. The A. dracunculus aqueous extract exhibited potent DPPH free radical inhibitory (IC50 dose of 10.71 ± 0.01 µg/mL) and anti-lipase activities (IC50 dose of 60.25 ± 0.33 µg/mL) compared with Trolox (IC50 = 5.7 ± 0.92 µg/mL) and Orlistat (IC50 = 12.3 ± 0.35 µg/mL), respectively. However, it showed a weak anti-α-amylase effect (IC50 value > 1,000 µg/mL) compared with Acarbose (IC50 = 28.18 ± 1.27 µg/mL). A. dracunculus has a cytotoxic effect against the HeLa cancer cell line compared with the chemotherapeutic agent Doxorubicin. The extract has the same percent of inhibition as Doxorubicin (99.9%) at 10 mg/mL. Overall, these results pointed out for the first time the importance of considering A. dracunculus effects as a favorite candidate for preventing and treating metabolic disorders. Also, our results confirm the findings of previous reports on the role of A. dracunculus in the management of cancer and disorders resulting from the accumulation of harmful free radicals. On the contrary, the current study concluded that the antidiabetic role of A. dracunculus could be minimal. Further in-depth investigations are urgently warranted to explore the importance of A. dracunculus in pharmaceutical production.

Pre-Operative Malnutrition in Patients with Ovarian Cancer: What Are the Clinical Implications? Results of a Prospective Study.

BACKGROUND: Malnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian cancer (EOC) and impact on survival. METHODS: In our prospective observational monocentric study, we included the patients with primary and recurrent EOC, tubal or peritoneal cancer conducted. We assessed serum laboratory parameters, body mass index, nutritional risk index, nutritional risk screening score (NRS-2002), and bio-electrical impedance analysis. RESULTS: We recruited a total of 152 patients. Patients > 65 years-old, with ascites of >500 mL, or with platinum-resistant EOC showed statistically significant increased risk of malnutrition when evaluated using NRS-2002 (p-values= 0.014, 0.001, and 0.007, respectively). NRS-2002 < 3 was an independent predictive factor for complete tumor resectability (p = 0.009). The patients with NRS-2002 ≥ 3 had a median overall survival (OS) of seven months (95% CI = 0-24 months), as compared to the patients with NRS-2002 < 3, where median OS was forty-six months (p = 0.001). A phase angle (PhAα) ≤ 4.5 was the strongest predictor of OS. CONCLUSIONS: In our study, we found malnutrition to be an independent predictor of incomplete cytoreduction and independent prognostic factor for poor OS. Preoperative nutritional assessment is an effective tool in the identification of high-risk EOC groups characterized by poor clinical outcome.

Side Effects from Cancer Therapies and Perspective of 1044 Long-Term Ovarian Cancer Survivors-Results of Expression VI-Carolin Meets HANNA-Holistic Analysis of Long-Term Survival with Ovarian Cancer: The International NOGGO, ENGOT, and GCIG Survey.

The aim of this survey was to increase the knowledge on the characteristics and health concerns of long-term survivors (LTS; survival > 5 years) after ovarian cancer in order to tailor follow-up care. This international survey was initiated by the NOGGO and was made available to members of ENGOT and GCIG. The survey is anonymous and consists of 68 questions regarding sociodemographic, medical (cancer) history, health concerns including distress, long-term side effects, and lifestyle. For this analysis, 1044 LTS from 14 countries were recruited. In total, 58% were diagnosed with FIGO stage III/IV ovarian cancer and 43.4% developed recurrent disease, while 26.0% were receiving cancer treatment at the time of filling in the survey. LTS who survived 5-10 years self-estimated their health status as being significantly worse than LTS who survived more than 10 years (p = 0.034), whereas distress also remained high 10 years after cancer diagnosis. Almost half of the cohort (46.1%) reported still having symptoms, which were mainly lymphedema (37.7%), fatigue (23.9%), pain (21.6%), polyneuropathy (16.9%), gastrointestinal problems (16.6%), and memory problems (15.5%). Almost all patients (94.2%) regularly received follow-up care. Specialized survivorship care with a focus on long-term side effects, lifestyle, and prevention should be offered beyond the typical five years of follow-up care.

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.

Photovoice techniques and art therapy approaches with refugee and immigrant adolescents.

This paper describes a program informed by art therapy and Photovoice approaches and techniques aimed at helping new immigrant and refugee teens to navigate personal and cultural identities by reflecting on their experiences as new residents in the US. Photovoice is a photography and social action method that encourages participants to photograph aspects of their daily lives, reflect on their meaning and significance and galvanize necessary changes. The program began in February 2020 at the Arab-American National Museum (AANM), but was adapted for an online format and re-framed towards a reflection on the COVID-19 pandemic. Broad questions teens explored included: What is good? What is challenging? What is sustaining during challenging times? What needs to change? and What about your culture and background are you proud of and wish to share with other US residents? Highlights of the sessions demonstrate how art therapy interventions paralleled photography-assigned themes of self, home, and community and encouraged group interaction and mutual support. A virtual museum exhibition culminated the program and reached community leaders. Self-reports from select participants highlight changes in posttraumatic stress, anxiety, and somatic symptoms over the course of programming.

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.

Can a morphological description of the peritoneal carcinomatosis in advanced ovarian cancer add prognostic information? Analysis of 1686 patients of the tumor bank ovarian cancer.

Background: Peritoneal carcinomatosis in ovarian cancer is frequent and generally associated with higher stage and poorer outcome. The clinical features of peritoneal carcinomatosis are diverse and their relevance for surgical and long-term outcome remains unclear. We conducted this prospective study to describe intraoperatively the different features of peritoneal carcinomatosis(PC) and correlate them with clinicopathological features, progression-free(PFS) and overall survival (OS),. Methods: We performed a systematic analysis of all patients with documented intraoperative PC and a primary diagnosis of epithelial ovarian, tubal, or peritoneal cancer from January 2001 to September 2018. All data were evaluated by using the systematic tumor bank tool. Specific PC features included texture(soft-hard), consistency(coarse-fine or both), wet vs dry(PC with ascites vs. PC without ascites), and localization(diffuse-local). PC characteristics were then evaluated for correlation with age, FIGO-stage, histology, lymph-node involvement, grade, and presence of residual tumor at primary surgery. Moreover, the influence of PC characteristics on OS and PFS was analyzed. Results: A total of 1686 patients with PC and primary epithelial ovarian cancer were included. Majority of the patients were characterized by diffuse PC(73.9%). The majority of peritoneal nodules were fine in texture (55.3%) and hard in consistency (87.4%). Moreover, 27.6% of patients had dry PC. Diffuse PC localization was significantly associated with higher FIGO-stage (p<0.001), high-grade (p=0.003) and serous tumors (p=0.006) as well as residual tumor as compared to local PC (p<0.001). Wet PC also significantly correlated with diffuse localization (p <0.001) and residual tumor as compared to dry PC (p<0.001). Coarse PC was significantly associated with residual tumor as compared to fine PC (p=0.044). All other PC features didn´t correlate with clinicopathological features. As for survival outcomes, diffuse peritoneal localization (p<0.001), wet PC (p<0.001), and additional lymph node involvement (p<0.001) were associated with lower OS and PFS rates. Other PC features did not significantly impact survival. Conclusion: Diffuse localization of peritoneal carcinomatosis was significant predictor of recurrence. Lower OS and PFS were associated with diffuse peritoneal localization, wet PC, and additional lymph node involvement. Further prospective trials are warranted with the inclusion of translational research aspects to better understand the different peritoneal carcinomatosis patterns.

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.

Prognostic Value and Therapeutic Implications of Pleural Carcinosis and Malignant Pleural Effusion in Advanced Epithelial Ovarian Cancer.

AIM: To demonstrate the prognostic value of pleural carcinosis/effusion in a cohort of patients with advanced epithelial ovarian cancer (EOC) and the associated therapeutic implications. PATIENTS AND METHODS: Overall, data for 388 patients with EOC with confirmed malignant pleural effusion (MPE) or pleural carcinosis were retrospectively analyzed. Exclusion criteria were non-epithelial ovarian malignancies and presence of other comorbidities associated with pleural effusions. RESULTS: The prognosis after the occurrence of MPE during the EOC in relapsed cases was poor with an overall survival of 9.9 months. In the multivariate analysis, the time point of the manifestation of the pleural effusion (p<0.001), platinum sensitivity (p=0.003), performance status (p=0.045) and presence of ascites (p=0.004) were significant prognostic factors for overall survival. CONCLUSION: Even in this less favorable collective, well-established EOC prognostic factors were associated with a significantly better overall survival. This suggests that the overall behavioral pattern of the disease has strong similarities in patients with and without pleural effusion or carcinosis and merits an equally high therapeutic effort.

A systematic review of Antimicrobial Stewardship Program implementation in Middle Eastern countries.

BACKGROUND: Antimicrobial resistance is a serious threat to global health. Antimicrobial Stewardship Programs (ASPs) are adopted by healthcare systems worldwide. This review aimed to evaluate the published practices of ASPs in Middle Eastern countries. METHODS: Searches were carried out in PubMed/MEDLINE, Embase, EBSCO, Cochrane Library, Google, and Google Scholar electronic databases for studies published from January 2005 to December 2020 that assessed ASP practices in Middle Eastern countries, following PRISMA guidelines. RESULTS: Of the 422 titles identified, 20 studies met the inclusion criteria. Eight studies were conducted in the Kingdom of Saudi Arabia, five in Qatar, two each in Lebanon and Jordan, and one each in Palestine and UAE; there was also one multinational study. Different ASP practices, including prospective auditing and feedback, pre-authorization, tracking, antibiotic restriction, education, de-escalation, and intravenous-to-oral switch, were reported. ASP practices correlated with improved susceptibility rates and decreases in antimicrobial use. CONCLUSION: The outcomes of this review reveal the scarcity of data on ASP practices. The introduction of ASPs in hospitals in Middle Eastern countries has led to favorable clinical effects. Policymakers and stakeholders should promote and invest in implementing these programs as an essential component of their healthcare systems.

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.