bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA–based detection of molecular residual disease as a biomarker for recurrence monitoring predict disease recurrence in patients with ovarian cancer.
Authors: Lv Tianjiao , Shi Xinyi , Zhao Dan , Sun Jing , Wang Bo , Lu Kai , Zou ShiPing , Wang Jing , Wang Qiang , Feng Weiwei
Published: June 2023

e17542

Background: Despite recent advances in cancer diagnostics and treatments, nearly 75% ovarian cancer patients relapse within two years of primary therapy and become candidates for treatment of recurrent diseases. A novel approach to post-surgical risk stratification for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes. Methods: We analyzed a cohort of 22 stage Ⅰ-Ⅳ ovarian cancer patients which were followed up at median 6 (range,3-15) times between July 2017 and December 2020. Among the 22 patients, stage I, II, III and Ⅳ comprised 9%, 5%, 50% and 36%, respectively. Tumor tissue and blood samples of all subjects were collected at Ruijin Hospital, Shanghai Jiao Tong University.Somatic mutations were identified by whole exome sequencing and assessed from plasma collected during treatment using personalized tumor-informed MRDtect assays with a median of 25（range,17-30） amplicons/assay targeting tumor-specific variants unique to each patient, sequenced at mean 200,000X depth. Plasma samples with ≥2 variants detected were considered MRD-positive and ctDNA levels were reported in mean tumor molecules per mL (MTM/mL) of plasma. Sequencing data were analyzed using PiVAT secondary analysis software and MRD positive was concluded when at least two variants were detected in plasma. Results: CtDNA was preoperatively detectable in 18 (85.7%) patients, and the positive rate became 38.8% (7/18) after surgery. Serial ctDNA analysis during surveillance after definitive treatment of the 22 patients with longitudinal collected plasma samples identified relapse with 100% sensitivity and 100% specificity. The median lead time from ctDNA detection in plasma to relapse detection by standard-of-care computed tomography was 135 days (range,45-387days). Variants from a total of 526 genes were selected from the WES results of these 22 patients. Among these 526 genes, 96% (505 genes) were selected for only one patient, 3.4% (18 genes) were selected for two patients and 0.2% (one gene) were selected for three patients. Compared with tumor-agnostic assay, tumor-informed assay is a more accurate route that is more consistent with the heterogeneity of tumor and can maximize the ability to reflect the real situation of each patient. Conclusions: Sensitive methods for risk stratification, therapeutic efficacy monitoring, and early relapse detection may have a major impact on treatment decisions and patient management for ovarian cancer patients. MRD can be used as an effective biomarker to prompt prognosis and recurrence risk, providing powerful assistance for accurate diagnosis and treatment for patients.
Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage ovarian cancer: A prospective multicentre study (SELLY).
Authors: Nero Camilla , Bizzarri Nicolò , Di Berardino Stefano , Sillano Francesca , Vizzielli Giuseppe , Cosentino Francesco , Vargiu Virginia , De Iaco Pierandrea , Perrone Myriam , Vizza Enrico , Chiofalo Benito , Uccella Stefano , Ghezzi Fabio , Turco Luigi Carlo , Corrado Giacomo , Giannarelli Diana , Pasciuto Tina , Fagotti Anna , Scambia Giovanni
Published: June 2023

e17579

Background: Comprehensive surgical staging of early epithelial ovarian cancer includes systematic paraaortic and bilateral pelvic lymphadenectomy but its therapeutic role is controversial and it is associated with potential severe morbidity. The feasibility of sentinel lymph-node (SLN) identification in early stage ovarian cancer has been shown only. We did a prospective multicenter study to assess the feasibility, detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status in patients with early stage ovarian cancer. Methods: This is a phase II single arm study (EUDRACT 2019-001088-58) including patients with presumed stage I-II epithelial ovarian cancer planned for immediate or delayed minimally-invasive comprehensive staging. The ovarian pedicle is injected with 2 mL of a 1.25 mg/mL indocyanine green (ICG) solution. The pelvic and lumbo-aortic retroperitoneum is then accessed and inspected to identify and remove SLNs. Staging is then completed including systematic pelvic and para-aortic lymphadenectomy and an histopathological examination of all nodes is performed. The primary endpoint was estimation of the sensitivity and sensibility of SLN in predicting nodal status. Assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (i.e. the maximum marginal error) d=5%, a type I error α = 0.05, a sample size of 141 patients is needed to test the general hypothesis (i.e. to answer whether SLN(s) identified with ICG can accurately predict nodal status at histology of patients with apparently early EOC). Assuming a drop-out rate of 20%, a total of 176 patients will be enrolled in the study. Results: One-hundred and seventy-six patients were included with a drop-out rate of 22%. Sentinel node was identified in 102 patients (detection rate, 58%, [95% CI: 51-65]). There were no clinical differences between patients with successful or unsuccessful mapping. Both the infundibolopelvic ligament and the legamentum ovarii proprium were injected in 29.0% of cases. Twenty-one patients had positive nodes and 71% of them showed successful mapping. Among the latter, a negative sentinel node was identified in 3 patients (Sensitivity 78.6% [95% CI: 57-100]; Specificity 100%; Accuracy 97% [95% CI: 94-100]; PPV 100%; NPV 96,6% [95% CI: 93-100]). Twenty-two (12.5%) intra- and 25 (14.2%) postoperative complications occurred (12 G1; 9 G2; 2 G3, 2 G4). Clinical trial information: EUCTR2019-001088-58 .
Levels of ANGPTL3 and characterization of other circulating cholesterol-related factors in high-grade serous ovarian cancers.
Authors: Wong Chong Emilie Yan Pin , Joncas France-Hélène , Douville Pierre , Bachvarov Dimcho , Bergeron Ann-Charlotte , Blais Jonatan , Seidah Nabil Georges , Calon Frédéric , Diorio Caroline , Gangloff Anne
Published: June 2023

e17583

Background: Cancer cells require important amounts of cholesterol to sustain their growth. High-grade serous ovarian carcinomas (HGSOC), as an aggressive form of ovarian cancer, are no exception. Mechanisms allowing HGSOC to secure their lipid supplies are not yet fully elucidated. Recent years have highlighted ANGPTL3, PCSK9 and Apo CIII as key players in lipid metabolism. To date, impact of HGSOC on these key lipid-regulating factors is scantly documented. Herein, we compared ANGPTL3, PCSK9, Apo CIII and Lp(a) levels in women with HGSOC versus benign ovarian lesion (BOL) to better understand lipid metabolism in HGSOC. Methods: Plasma samples from 31 women with a HGSOC and 40 women with a BOL were assayed for ANGPTL3, PCSK9, and Apo CIII levels by ELISA. The lipid panel, Apo B and Lp(a) levels were measured on a Roche Modular analytical platform. Results: Higher levels of ANGPTL3 was observed in HGSOC (84 ng/ml, SD ±29 ng/ml, n = 31) vs. BOL (67 ng/ml, SD ±31 ng/ml, n = 40); HGSOC vs BOL p = 0.019. Receiver operating characteristic (ROC) curve analyses for ANGPTL3 combined with age indicated an area under curve of 67.7% (p = 0.005). Partial correlations indicated associations between the lipid panel and ANGPTL3, but only for BOL. Conclusions: In this cohort of 71 women, ANGPTL3 levels were higher in patients with HGSOC. This finding requires further validation in a larger cohort of HGSOC patients.
Role of BRCA1 promotor methylation (BRCA1meth) in homologous recombination deficiency (HRD) in high-grade epithelial ovarian cancer.
Authors: Zeimet Alain G , Schnaiter Simon , Reimer Daniel Uwe , Wimmer Katharina , Schamschula Esther , Leitner Katharina , Steger Katharina , Marth Christian , Fiegl Heidi
Published: June 2023

e17592

Background: In TCGA data BRCA1meth was found to be inferior to BRCAmut regarding prognosis in high-grade ovarian cancer. This was explained by a probably lower sensitivity to platinum-based chemotherapy. Methods: In 151 high-grade epithelial ovarian cancers (HGOC) tested for BRCA status, BRCA DNA methylation was determined using MethyLight PCR. Additionally, genome-wide loss of heterozygosity (LOH) and Aneuploidy Normalized Telemetric imbalance (ANTI) by means of SNP-Array analysis (GSA-24 v 3.0/Ilumina) as surrogates for “genomic scaring” in BRCA-independent HRD. For both parameters a “clinical-threshold” was calculated on the basis of platinum-response determined at the first recurrence according to the platinum-free interval. Both variables were integrated in a common HRD-Score with a cut-off value of ≥ 10.3 for HRD positivity. Results: In the present cohort PFS of BRCA1meth HGOC (n = 15; 10%) was not revealed to be inferior to BRCAmut HGOC. Worst PFS was observed in the subgroup of BRCAwt-unmethylated HGOC (p = 0.013) as compared to HGOC with genetic and epigenetic BRCA alterations. In line, neither LOH nor ANTI and consecutively also HRD-Score did prove to be statistically different in BRCAmut - and BRCA1meth-HGOC. However, BRCAwt-unmethylated HGOC exhibited significantly lower HRD-, LOH- and ANTI-Scores when compared with BRCAmut (p < 0.001) and BRCA1meth-HGOC (p < 0.005). All but one of the HGOC classified as platinum-refractory or -resistant at first relapse (92%) were BRCAwt-unmethylated. None of the BRCA1meth cancers were rated platinum-refractory or -resistant at progression and only one of the BRCAmut cancers was associated with platinum-resistant first relapse. 99% of the recurrences from HGOC with genetically or epigenetically altered BRCA genes were platinum sensitive, from which 78% were classified as “high-sensitive”. In multivariate analysis, HRD-Score was found to be of independent prognostic significance regarding PFS (p = 0.022); this was mainly due to the prognostic power of ANTI-Score (multivariate: p = 0.014) but not to that of genome wide LOH (univariate: p = 0.771). Conclusions: HGOC without genetic or epigenetic BRCA alterations exhibit the most unfavorable PFS. This is related to impaired platinum sensitivity. From a clinical point of view BRCA1 promotor methylation seems to confer an equivalent detrimental effect on the homologous recombination DNA repair mechanism than do pathogenic mutations of the BRCA genes. This is corroborated by a nearly identical extent of genome-wide scaring in both cancer subgroups.
TABLET: Relative bioavailability and bioequivalence study of niraparib tablets and capsules in patients with advanced solid tumors.
Authors: Falchook Gerald Steven , Patnaik Amita , Sharma Manish , Harvey R. Donald , Hamilton Erika P. , Hafez Navid , Wise-Draper Trisha M. , Barve Minal A. , Patel Manish R. , Dowlati Afshin , Richardson Debra L. , Faltermeier Christina , Ewesuedo Reggie , Kneissl Michelle , Potocka Elizabeth
Published: June 2023

e17603

Background: Niraparib is a poly (ADP-ribose) polymerase inhibitor, approved as a maintenance treatment (tx) for patients (pts) with advanced ovarian cancer and under investigation in solid tumors, available in 100 mg capsules (starting dose: 200 or 300 mg/day). Compared with capsules, tablets have improved stability in hot and humid conditions. This study assessed the relative bioavailability (BA; Stage 1 [S1]) and bioequivalence (BE; Stage 2 [S2]) between niraparib tablets and capsules. Methods: This was a US, open-label, multicenter, single-cohort, randomized-sequence study with an optional extension phase. Eligible pts were ≥18 years, had histologically/cytologically confirmed advanced solid tumors (metastatic or local), disease progression despite standard therapy (if available), and ECOG performance scores of 0–2. Pts were dosed 1x300 mg tablet or 3x100 mg capsules then crossed over to the other tx after full washout. Pharmacokinetic (PK) parameters were assessed up to 168 hours post-niraparib dose; safety was assessed throughout and for 30 days after last dose (90 days for serious adverse events). A comparison of the log-transformed PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration [AUC0–t] and from time 0 extrapolated to infinity [AUC0–∞]) was carried out to evaluate the formulations using a linear mixed-effects model with fixed effects for sequence, period, and tx and random effect for pt nested within sequence. Results: Pts in both stages completed study drug and washout/PK periods and had sufficient PK samples to estimate PK parameters in both periods. In S1 (n=29), a comparable BA performance of both formulations was demonstrated; the 90% confidence intervals (CI) of the geometric least square means (LSM) for Cmax, AUC0–t, and AUC0–∞ for tablet/capsule were within prespecified 0.80–1.25 limits (intra-pt variability: 12.4–21.9%). An initial 7-day washout period between PK assessments was extended to 14 days in S2 due to significant carryover reported in 6 pts in S1. In S2 (n=108), niraparib PK characteristics were similar following dosing with tablet or capsule (Table); LSM ratios of the key parameters were close to unity and 90% CI for the ratio of Cmax, AUC0–t, and AUC0–∞ were within prespecified 0.80–1.25 limits required to demonstrate BE. No new safety signals were reported. Conclusions: Both niraparib formulations were bioequivalent and can be used interchangeably. Editorial support was provided by Fishawack Health, funded by GSK. Clinical trial information: NCT03329001 . [Table: see text]
Targeting HE4 for treatment of endometrial cancer using a novel small molecule inhibitor.
Authors: Morell Alexandra , Miller John , Zhang Naixin , Snyder Cameron , Khazan Negar , Strawderman Myla S. , Singh Rakesh , Kim Kyu Kwang , Turner Rachael , Moore Richard G.
Published: June 2023

e17616

Background: HE4 expression is upregulated in endometrial cancer and has been shown to have prognostic significance in endometrial cancer patients. High-throughput screening and lead optimization led us to discover UR-238, a novel small molecule inhibitor of HE4. The purpose of this study was to investigate the in vitro and in vivo effects of UR-238 in treatment of endometrial cancer. Methods: UR-238 was identified by focused medicinal chemistry. Six endometrial cancer cell lines (ECC1, AN3CA, HEC1A, MFE296, MFE280, and KLE) were grown in cell culture and treated with 8 concentrations of UR-238 (125 nM, 250 nM, 375 nM, 500 nM, 625 nM, 750 nM, 875 nM, and 1000 nM) or DMSO (control). Cell proliferation was assessed using SRB assays at 24 and 48 hours. Effects of UR-238 on the cell cycle were assessed by flow cytometry and related cell-cycle proteins were targeted via Western blots. An ELISA was performed to evaluate UR-238 treatment effect on HE4 expression. An AN3CA xenograft mouse model was used to assess in vivo effects of UR-238. Mice were treated with vehicle control or UR-238 (5 mg/kg, IP, 3 days/week) for 20 days (N=5/group). Tumor volume and weight were evaluated over time using a repeated measures ANOVA. Results: UR-238 resulted in decreased cell proliferation in a dose-dependent manner in all 6 endometrial cancer cell lines. UR-238 increased expression of p21 and p27 and induced M/G2 cell cycle arrest. UR-238 also downregulated HE4 expression. In vivo treatment with UR-238 of AN3CA expressing xenograft mice caused a significant reduction (p=0.02) in mean tumor volume compared with vehicle control after 20 days (control mean 1068.13 mm3, SE 239.76; UR-238 mean 265.62 mm3, SE 68.82). Conclusions: UR-238 inhibits cell proliferation in endometrial cancer cell lines and exhibits antitumorigenic effects in xenograft mouse models. Future studies are warranted as UR-238 may be a promising therapeutic agent for treatment of endometrial cancer.
Lynch screening and genetic testing in endometrial cancer in a diverse population.
Authors: Kim Kee-Hwan Michael , Hayek Judy , Acker Cheyenne , An Anjile , Zhang Peilin , Gorelick Constantine , Kanis Margaux Jenna
Published: June 2023

e17619

Background: Lynch syndrome (LS) accounts for most of the inherited endometrial cancers. Universal screening of endometrial tumors for defects in DNA mismatch repair (MMR) is recommended using immunohistochemistry (IHC) to identify which patients qualify for genetic counseling and testing. We report Lynch screening and genetic testing rates at a New York City tertiary care center with a large minority population, while investigating any potential disparities. Methods: This is a retrospective cohort study of patients with newly diagnosed endometrial cancer between January 2014 and June 2022. Data were obtained from pathology and chemotherapy databases at the NewYork-Presbyterian Brooklyn Methodist Hospital. Variables including age, race, ethnicity, BMI, insurance, language, family history of cancer, date of diagnosis, stage, MMR IHC, and genetic counseling/testing status were manually extracted. Descriptive statistics were used. Chi-square/Fisher’s exact tests were used to examine the association between genetic counseling/testing and categorical variables. Wilcoxon rank-sum/t-tests were used for continuous factors. The Mann-Kendall trend test was used to determine the significance of time trends. Results: 373 patients were identified. 45% identified as white, 42% black, 1.3% Asian, 12% other/unknown; 8.3% were of Hispanic ethnicity and 18% were non-English speaking. Mean age at diagnosis was 66 years (SD:10). 207 (55%) patients were screened using MMR IHC. 82 (40%) of these patients had MMR deficiencies on IHC. Of these, 63 (77%) received genetic counseling. 62 (98%) of those counseled subsequently underwent genetic testing, and ultimately 7 (11%) were diagnosed with LS. The overall rate of LS detected was 1.9% in the study population. The rate of MMR IHC testing has been increasing, reaching 95% in 2021 and 100% in 2022. It was associated with significant differences in mean age at diagnosis (p < 0.01) and insurance type (p = 0.04). 45% of patients that received MMR IHC had private insurance, compared to 34% of patients that did not. The rate was not influenced by race, language, BMI, family history of cancer, or stage. The proportion of patients that received genetic counseling and testing for endometrial cancer also showed a significant upwards trend over time (p < 0.01). Genetic counseling and testing rates were significantly different by ethnicity (p = 0.03), with only 3.0% of patients receiving genetic counseling/testing identifying as Hispanic. 98% of genetic counseling was performed by a gynecologic oncologist, as opposed to a genetic counselor. Conclusions: There were no disparities in access to initial IHC screening in this diverse patient population, however more work must be done to reach all ethnicities for genetic counseling and testing. The rate of LS detected was less than the known prevalence in endometrial cancer, possibly indicating demographic differences or gaps in screening.
Treatment with lenvatinib plus pembrolizumab in recurrent or advanced endometrial cancer: A systematic review and meta-analysis.
Authors: Moraes Francisco Cezar A , Vilbert Maysa , B Carnevalli Sarah Vitoria , Almeida Gustavo de Oliveira , Feio Danielle , Stecca Carlos , Da Costa Alexandre Andre B. A.
Published: June 2023

e17630

Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I2 statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.
Survey of carboplatin desensitization therapy: JCOG Gynecologic Cancer Study Group multicenter retrospective study.
Authors: Komatsu Hiroaki , Matsumoto Koji , Nishio Shin , Morita Mitsunori , Nagasawa Takayuki , Nishio Hiroshi , Suzuki Jiro , Ishikawa Mitsuya , Satoh Toyomi
Published: June 2023

e17631

Background: The purpose of the present study was to investigate the real-world experience with carboplatin desensitization (CD) therapy in Japan, along with its safety, and establish a strategy to address carboplatin-induced hypersensitive reactions (HSRs). Methods: The present study included patients diagnosed with gynecologic cancer (ovarian, endometrial, or cervical cancer, i.e., OC, EC, and CC, respectively) who underwent CD therapy between 2016 and 2020 at Japan Clinical Oncology Group Gynecologic Cancer Study Group (JCOG-GCSG) participating centers. CD therapy was performed at each institution, and cases of implementation were registered in online case report forms. We examined patient information, treatment regimens, frequency and dose of carboplatin administration, administration rates, and CD practices. This study was approved by the Ethics Committee of the Tottori University. Results: Overall, 20 of 51 JCOG-GCSC-participating facilities performed CD therapy. The present study enrolled 136 patients (OC, 108; EC, 17; CC, 11). Of these, 37 (27.2%) patients had pre-existing allergies, and 29 (20.5%) exhibited prodromal symptoms at the time of treatment prior to the onset of HSRs. The most common symptoms were erythema and itching. At the onset of HSRs, erythema was the most common symptom, occurring in 93 (68.4%) patients, followed by itching in 72 (52.9%), reduced oxygen saturation in 43 (31.6%), and loss of consciousness in 3 (2.2%). The onset of HSRs was most common during treatment of the first recurrence (47%). The mean total carboplatin dose until the appearance of HSRs was 7331 (2620–18282) mg, and the mean number of doses was 14 (4–63). Six centers discontinued CD therapy owing to the appearance of breakthrough HSRs. CD therapy was completed in 75% of patients, with 25% (34/136) experiencing breakthrough HSRs. HSR-related mortality was not observed. The associated risk factors with HSR were not selected in the present study. Conclusions: Although patients who undergo CD therapy in Japan have a high probability of safely completing planned therapy, erythema and pruritus are important signs of breakthrough HSRs. Breakthrough HSRs were most frequent during the first cycle of desensitization. [Table: see text]
Uterine sarcoma patients who underwent morcellation: Who are they? Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA- NOGGO RU1).
Authors: Roser Eva , Mirbach Rebecca , Reichardt Peter , Zocholl Dario , Klar Maximillian , Harter Philipp , Kommoss Stefan , Ulrich Uwe Andreas , Mustea Alexander , Wimberger Pauline , Weigel Michael , Frank Matthias , Schmalfeldt Barbara , Hanker Lars Ch. , Flörcken Anne , Arndt Tjadina , Pietzner Klaus , Sehouli Jalid
Published: June 2023

e17632

Background: Uterine sarcomas represent a group of rare malignant mesenchymal neoplasms with most types of them being associated with poor prognosis. In clinical practice, it is challenging to distinguish them from the most common benign tumors in women, so-called leiomyomas. Due to erroneous diagnosis, there is a risk of morcellating an occult sarcoma. This often leads to the distribution of malignant tissue in the abdominal cavity and a worse prognosis in most of the patients. In order to better understand this high-risk group of patients we analyzed their characteristics and management based on data of the real-world German registry for gynecological sarcoma (REGSA). Methods: REGSA is a real-world multicenter prospective registry including patients with gynecologic sarcomas in the primary and the recurrent situation of disease. For this work, we performed a descriptive analysis with data from all available patients with documented morcellation of uterine sarcoma. Results: 8.7% (n=76) of a total of 874 patients (registration period 09/2015-05/2022) were morcellated. Those 76 patients had a median age of 50.5 years. Thirty-seven patients (48.7%) were ≥50 years of age at the time of surgery. Leiomyosarcoma was the most common histopathological subtype (n=42; 50.3%). Fifty-eight patients (76.3%) had laparoscopic operations. A subtotal hysterectomy was the most common procedure used in 40.8% (n=31). Diagnostic curettage was performed in 5.3% of all cases (n=4). The predominant preoperative symptom was "bleeding disorders" in 19 patients (25.0%). Follow-up treatment after morcellation was heterogeneous. 17 patients received chemotherapy, with docetaxel and gemcitabine being the most frequently used regimen (n=8; 47.1%), followed by combinations with anthracyclines in 5 patients (29.4%). Conclusions: Many patients were over 50 years of age at the time of morcellation, although it is undisputed that the risk of morcellating occult uterine sarcoma increases with age. Whether curettage has diagnostic value needs to be further investigated. There is a high clinical need to define a consensus on further management of this high-risk group, regarding adjuvant therapy and follow-up care for there seems to be a great deal of uncertainty regarding adjuvant management.
Genomic characterization of vulvar squamous cell carcinoma to reveal differential gene expression based on clinical outcome.
Authors: Gordinier Mary E. , Schau Geoffrey , Pollock Shanna Brotzge , Shields Lisa , Talwalkar Sameer S.
Published: June 2023

e17633

Background: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. Methods: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumor and matched normal samples from 21 patients were assayed by a broad NGS panel covering 648 genes, including whole exome and transcriptome sequencing. Immunohistochemistry (IHC) for PD-L1 (22C3) and p16 was also performed. Results: Whole transcriptome data revealed 6 genes that were strongly differentially expressed between the aggressive and indolent groups: ACVR2A, TGM3, ROS1, NFEL2, CCND1 and BCL6. Biologically relevant DNA mutations were significantly greater in the aggressive cohort versus the indolent cohort: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. TP53 alterations occurred almost exclusively in group A. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable, and tumor mutational burden was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. Conclusions: We report that TGM3 and ACVR2A genes are significantly under-expressed in tumors with poor outcome. Further investigation into the silencing of these genes may advance knowledge of the pathogenesis of VSCC and potentially yield therapeutic targets. Clinical outcome of VSCC appears independent of MSI, TMB or PD-L1 status. [Table: see text]
Clinical characterization of responders to first line (chemo)immunotherapy in platinum-sensitive recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC).
Authors: Buriolla Silvia , Cavalieri Stefano , Franza Andrea , Rota Simone , Bergamini Cristiana , Alfieri Salvatore , Nuzzolese Imperia , Colombo Elena , Ottini Arianna , Licitra Lisa F. , Resteghini Carlo
Published: June 2023

e18017

Background: RM HNSCC patients (pts) with combined positive score (CPS) ≥1 benefit from immunotherapy (IO), either alone or with chemotherapy (CIO). No survival outcome indicators are available. We aim to characterize a real world cohort of RM HNSCC pts treated at a tertiary cancer center. Methods: We analyzed 37 consecutive RM HNSCC pts treated with IO or CIO from 2016 to 2022. We divided pts in responders (R) and non responders (NR) if they achieved an objective response or disease stability/progression as best response. For group comparisons, we considered the following clinical variables: age, gender, smoking status, primary HNSCC site, HPV status, ECOG performance status, disease sites at RM diagnosis (local, regional, distant), time to RM diagnosis (TTR). For categorical variables, we compared the clinical characteristics of the 2 groups using the chi squared or Fisher’s exact tests, as appropriate. For age we used the Mann-Whitney test. For TTR we used the Cox proportional hazard model. Outcomes (progression free and overall survival, PFS and OS, respectively) were assessed with Kaplan Meier method and compared with log-rank test. Statistical significance was set at 0.05. Results: Clinical characteristics are reported in the table. Objective response rate (ORR) was 32%, median DoR 7.5 months (95% confidence interval, CI 2.07-not reached). None of the examined clinical variables were significantly different in the groups (R vs NR in the overall population, in IO- and CIO-treated pts). The only major difference between cohorts was survival, which was significantly longer in R vs non-R (Table). Conclusions: With the limits of a retrospective analysis, we observed a longer survival in R compared to NR. None of the main clinical characteristics were predictive of objective response to (C)IO. Further studies are needed to define predictive factors of response, and to enhance the ORR in first-line IO-based treatments. [Table: see text]
Impact of EBV positivity on clinical outcomes in nasopharyngeal cancer.
Authors: Ghimire Bipin , Karki Ujjwal , Herrman Emma , Thapa Shrinjaya , Shrotriya Shiva , Poudel Shyam K. , Anusim Nwabundo Ifeyinwa , Ezekwudo Daniel , Jaiyesimi Ishmael A.
Published: June 2023

e18021

Background: Nasopharyngeal carcinoma (NPC) is a rare malignancy with unique geographical distribution. Epstein Barr virus (EBV) plays a key role in the pathogenesis of NPC, with pre and post-treatment serum EBV DNA level as an established prognostic indicator. However, evidence regarding the impact of the tumor cells’ EBV positivity on clinical outcomes is inconsistent. Methods: After IRB approval, we performed a retrospective chart review on NPC patients aged above 18 years seen at Corewell Health William Beaumont University Hospital between July 2015 and December 2020. The Epstein Barr encoding region in-situ hybridization from the biopsy sample determined EBV positivity. We compared progression-free survival (PFS) and overall survival (OS) based on EBV positivity status. Results: A total of 60 NPC patients were included: 19 were EBV-positive, 20 were EBV-negative, and 21 were EBV-unknown. The median age at diagnosis was 50.7 years, and 58.3 years in EBV-positive and negative groups respectively. Most patients in both groups were male (68.4% vs 65%) and had advanced (stage III or stage IV) disease (84.2% vs 75%). The median follow-up duration was 37.3 months. Median PFS and OS were 41 months and 114 months respectively in EBV-negative patients, while median PFS and OS were not reached in EBV-positive patients. There was no significant difference in PFS (0.944) and OS (0.117) among the EBV-positive and negative groups. Among advanced-stage patients, the median PFS was 33 months and 31 months in EBV-negative and EBV-positive groups, respectively, while median OS was not reached in both groups; the difference in PFS (p = 0.821) and OS (0.240) was statistically non-significant. When compared among patients with EBV-positive, negative, and unknown status, PFS was statistically non-significant (p = 0.347) but there was a statistical difference in OS (0.027). Conclusions: Our analysis suggests that the EBV status of the tumor cells does not predict clinical outcomes (PFS or OS) in NPC patients. Even though the OS trend favored EBV-positive patients overall and among those with advanced disease, it was not statistically significant. A difference in OS was seen when patients with unknown status were included and analyzed together with EBV-positive and negative patients, which raises the question of whether the outcome would be different if the majority of patients with unknown status belonged to either the EBV-positive or negative group. With studies in the literature reporting disparate findings, larger prospective studies are needed to better illustrate the impact of tumor cells' EBV positivity on clinical outcomes in NPC.
Adenocarcinoma in villous adenoma: Demographics analysis.
Authors: Sinai Erin , Hsia Beau , Cook Madison , Luker Andrew , Wu Xinxin , Silberstein Peter T. , Keirns Darby
Published: June 2023

e18024

Background: Adenocarcinoma in Villous Adenoma (AVA) is a metastatic disease that arises from villous adenomas. These adenocarcinomas can arise from different tissues, particularly this analysis looked at AVA arising from the head and neck region. Treatment for otolaryngological AVA varied depending on grade, but the majority of patients received surgery or radiation. Despite its rarity, 16.7% of patients pass within 90 days after receiving surgery for this cancer. Given the rarity, data analysis of demographic findings could provide important information regarding its occurrence and distribution in the population. Methods: Patients from the National Cancer Database (NCDB) with a confirmed diagnosis of otolaryngological AVA from 2004–2017 were used in a retrospective cohort analysis (N = 33). Factors analyzed by descriptive statistics and regression analysis include sex, race, average household income, Charlson-Deyo score, palliative care obtained, and year of diagnosis. Results: A total of 33 patients were identified in the database with a confirmed diagnosis of AVA in the head and neck between 2004 – 2017 with a steady incidence of patients diagnosed per year (R2 = 0.0). The average age of diagnosis was 69 years (SD = 9.7, range = 51-85 years). The top primary site was the esophagus (90.9%). Most individuals (60.6%) had Charlson/Deyo comorbidity scores of 0. The majority of the patients were Non-Hispanic and White (97.0%). There was an equal distribution of income earners in the first and second quartile (33.3% and 33.3%) compared to those in the third or fourth quartiles (upper and middle quartiles are defined as over $74,063 and $57,857 to $74,062, respectively). A higher percentage of patients were insured by Medicare (57.0%) or privately insured (36.4%), compared to those who were uninsured. Most patients lived in metropolitan counties with a population greater than 1 million (51.6%). The majority of patients were treated in a comprehensive community cancer program (54.5%). Most patients did not receive palliative care (97.0%) and 16.7% of patients died within 90 days of receiving surgical treatment. Conclusions: With most data showing extensive data analysis on AVA stemming from the colon, this is the only analysis of demographic data from this cancer originating from the head and neck region. From the NCDB data, the majority of patients are non-Hispanic and White with a primary-site diagnosis presenting in the esophagus. This is the first time that specific AVA socio-economic data has been analyzed: patients with this cancer tend to be in upper or middle income brackets, live in crowded metropolitan areas, and have Medicare as their insurance coverage. To further our understanding of otolaryngological AVA, it would be necessary to examine the relationship between demographic and socioeconomic factors, and the diagnosis, treatment options, and survival rates for individuals with AVA.
Induction and concomitant chemoradiotherapy (CCRT) using modified TPF (docetaxel, cisplatin and 5-FU) for the patients with stage IVB advanced head and neck cancer.
Authors: Shiga Kiyoto , Katagiri Katsunori , Saitoh Daisuke , Oikawa Shin-ichi , Tuchida Kodai , Kusaka Takahiro , Ohashi Yu
Published: June 2023

e18031

Background: Efficacy of TPF chemotherapy has been reported mainly in the induction chemotherapy (IC) for head and neck squamous cell carcinoma (HNSCC) so far. The aim of this study was to determine the safety and efficacy of CCRT using modified TPF protocol in patients with Stage IVB HNSCC. Methods: Patients with previously untreated, histologically proven Stage IVB disease of the head and neck were eligible for the study. Twenty-six patients of the HNSCC were enrolled between January 2018 and October 2021 including 6 HPV(-) oropharyngeal, 5 hypopharyngeal, 4 ethmoid, 4 maxillary, 2 primary unknown and 5 other cancers. There were 14 T4b and 13 N3b tumors. CCRT consisted of radiotherapy administered once daily to a total dose of 70 Gy, concomitant with 120-hour infusions of 5-FU (600 mg/m2/day), Docetaxel (50 mg/m2, day 2) and Cisplatin (60 mg/m2, day 2) given during first and fifth week of radiotherapy. These drug doses were determined from the results of our former phase I study to assess the dose limiting toxicity of this protocol. Median follow-up period was 21 months. Results: Eight patients with Stage IVB HNSCC underwent IC and CCRT with this modified TPF protocol. Eight patients underwent CCRT using 2 courses of modified TPF. Five patients underwent CCRT with CDDP, three of them underwent arterial infusion of CDDP by super-selective angiography via external carotid artery. Three other patients underwent CCRT using other protocols and two underwent RT without chemotherapy. Bone marrow suppression was the most common adverse event observed through this study. Although all patients showed dermatitis and mucositis at any grade, other grade 3 or 4 adverse events in these patients were not common. Complete response was obtained in all patients except four patients. The progression-free and over-all survival rates at 24 months of all the patients with Stage IVB HNSCC in our series were 53.4% and 59.1%, respectively. Those of the patients who underwent IC and CCRT with modified TPF protocol were 58.3% and 80.0%, respectively and significantly better than those of the patients with other treatment protocols. Conclusions: Our results suggested that IC followed by CCRT using modified TPF was feasible and very effective in patients with Stage IVB HNSCC.
Radiation-sensitive genetic prognostic model to identify individuals at risk for radiation resistance in head and neck squamous cell carcinoma.
Authors: You Peimeng , Li Qiaxuan , Zhou HaiYu
Published: June 2023

e18042

Background: The advantages of radiotherapy for head and neck squamous cell carcinoma (HNSCC) depend on the radiation sensitivity of the patient. Here, we established and verified radiological factor-related gene signature and built a prognostic risk model to predict whether radiotherapy would be beneficial. Methods: Data from The Cancer Genome Atlas, Gene Expression Omnibus, and RadAtlas databases were subjected to LASSO regression, univariate COX regression, and multivariate COX regression analyses to integrate genomic and clinical information from patients with HNSCC. HNSCC radiation-related prognostic genes were identified, and patients classified into high- and low-risk groups, based on risk scores. Variations in radiation sensitivity according to immunological microenvironment, functional pathways, and immunotherapy response were investigated. Results: We built a clinical risk prediction model comprising a 15-genes signature and used it to divide patients into two groups based on their susceptibility to radiation: radiation-sensitive and radiation-resistant. Overall survival was significantly greater in the radiation-sensitive than the radiation-resistant group. Further, our model was an independent predictor of radiotherapy response, outperforming other clinical parameters, and could be combined with tumor mutational burden, to identify the target population with good predictive value for prognosis at 1, 2, and 3 years. Additionally, the radiation-resistant group was more vulnerable to low levels of immune infiltration, which are significantly associated with DNA damage repair, hypoxia, and cell cycle regulation. Tumor Immune Dysfunction and Exclusion scores also suggested that the resistant group would respond less favorably to immunotherapy. Conclusions: Our prognostic model based on a radiation-related gene signature has potential for application as a tool for risk stratification of radiation therapy for patients with HNSCC, helping to identify candidates for radiation therapy and overcome radiation resistance.
Prognosis-related molecular subtyping of nasopharyngeal carcinoma.
Authors: Ding Qin , Chen Xiaochuan , Qiu Sufang
Published: June 2023

e18047

Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a mRNA -based prognostic model for prediction of treatment efficacy. Methods: We retrospectively collected a total of 193 NPC tissue samples from 2016 to 2018 for mRNA sequencing. Consensus clustering was performed to identify new molecular subgroups based on the ssgsea algorithm. Then, weighted gene co-expression network analysis (WGCNA) was used to recognize molecular subtype-associated hub genes. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of recurrence and metastasis. Results: Three NPC subtypes (immune, proliferation and metabolism) were identified that are molecularly distinct and clinically relevant, of which proliferation subtype is associated with poor prognosis. Immune subtype characterized by higher expression of immune checkpoint, immune cells infiltration and immunesore. Interestingly, compared with other cells, tumor cells in TME exhibited the most active metabolism pathway in single-cell sequencing analyses. The Cox regression model built on hub genes showed a close correlation with outcome (AUC = 0.81). We further validated the results using the GEO database. Conclusions: Based on biological characteristics, NPC can be novelly stratified into three subtypes. Our study identified and validated a promising prognostic model associated with molecular subtype, which may accurately anticipate the survival of NPC patients.
Radiation induced lymphopenia in unilateral versus bilateral radiochemotherapy in treatment of head and neck cancer: A retrospective case-control study.
Authors: Bendavid Jerome , Sun Roger , Blanchard Pierre , Deutsch Eric , Gorphe Philippe , Tao Yungan , Nguyen France , Chaffai Ines , Billard Sandu Camelia , Even Caroline
Published: June 2023

e18065

Background: Grade 3+ radiation-induced lymphopenia is a frequent biological complication of external beam radiotherapy (RT) in the management of head and neck cancers, likely due to the large irradiated cervical volume. This complication has been shown to be a significant prognostic factor for mortality. The aim of this study is to evaluate the difference in lymphopenia and prognosis between unilateral and bilateral prophylactic lymph node irradiation in head and neck cancers. Methods: This is a retrospective, single center case – control study in patients who received unilateral or bilateral radio chemotherapy for head and neck cancers between 2014 and 2020. Cases (unilateral neck irradiation) were matched to controls (bilateral neck irradiation) according to initial TNM, histology, tumor location, postoperative status. The comparison of the evolution of the lymphocyte count during treatment was evaluated by univariate analysis, as well as the evaluation of the overall survival (OS) and the progression free survival (PFS) between these two groups. Another univariate analysis is used to compare OS and PFS in these two groups between patients who developed Grade 3 or higher lymphopenia during treatment and those who did not. Results: In this retrospective study, 94 patients were analyzed (n = 47 in the RT unilateral group and n = 47 in the RT bilateral group). All patients received concomitant systemic therapy. Median age was 59,3 years in the unilateral group (vs 59 years in the control group). Radiotherapy was given postoperatively in 66% vs 53.2% of patients. Squamous cell carcinoma was the most frequent histological subtype with 93,6% in each RT group. All patients were treated in Intensity modulated radiation therapy (IMRT). Median follow up was 38 months in the case group and 37,6 months in the control group. Biological data from the start of radiotherapy to day 100 posttreatment was available for 90 patients (45 in each group). A linear regression model as a function of time and lymphocyte count estimated a -0.011 G/l decrease in lymphocyte count each day and a higher lymphocyte count with unilateral neck irradiation of 0.16 G/l. This was consistent with a mixed model considering the patient as a random effect. In univariate analysis, the lymphocyte nadir was significantly higher in the unilateral group 0.30 [0.15- 0,42] vs 0.37 [0,26-0.48] p = 0,029, with no significant difference in OS and PFS between these two groups. In each of the two groups, there was no significant difference in OS and PFS according to the presence or absence of grade 3 or higher lymphopenia during the treatment. Conclusions: This study, although retrospective, showed a slight benefit on radiation-induced lymphopenia in the context of unilateral radiotherapy without negative impact on OS and PFS.