bluuebunny/crossref_metadata_2025 huggingface dataset:
Classification of molecular subtypes of high-grade serous ovarian cancer by MALDI-Imaging.
Authors: Kassuhn Wanja Nikolai , Klein Oliver , Darb-Esfahani Silvia , Lammert Hedwig , Handzik Sylwia , Taube Eliane T , Schmitt Wolfgang D , Dorigo Oliver , Horst David , Keunecke Carlotta , Dreher Felix , George Joshy , Bowtell David , Hummel Michael , Sehouli Jalid , Blüthgen Nils , Kulbe Hagen , Braicu Elena Ioana
Published: June 2021

e17544

Background: High-grade serous ovarian cancer (HGSOC) can be separated by gene expression profiling into four molecular subtypes with clear correlation of the clinical outcome. However, these gene signatures have not been implemented in clinical practice to stratify patients for targeted therapy. This is mainly due to a lack of easy, cost-effective and reproducible methods, as well as the high heterogeneity of HGSOC. Hence, we aimed to examine the potential of unsupervised matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to stratify patients, which might benefit from targeted therapeutic strategies. Methods: Molecular subtyping of paraffin-embedded tissue samples from 279 HGSOC patients was performed by NanoString analysis (ground truth labeling). Next, we applied MALDI-IMS, a novel technology to identify distinct mass profiles on the same paraffin-embedded tissue sections paired with machine learning algorithms to identify HGSOC subtypes by proteomic signature. Finally, we devised a novel strategy to annotate spectra of stromal origin. Results: We elucidated a MALDI-derived proteomic signature (135 peptides) able to classify HGSOC subtypes. Random forest classifiers achieved an area under the curve (AUC) of 0.983. Furthermore, we demonstrated that the exclusion of stroma associated spectra provides tangible improvements to classification quality (AUC = 0.988). False discovery rates (FDR) were reduced from 10.2% to 8.0%. Finally, novel MALDI-based stroma annotation achieved near-perfect classifications (AUC = 0.999, FDR < 1.0%). Conclusions: Here, we present a concept integrating MALDI-IMS with machine learning algorithms to classify patients according to distinct molecular subtypes of HGSOC. This has great potential to assign patients for targeted therapies.
Integrating the genomic and TCR repertoire signatures predicts prognosis in primary epithelial ovarian cancer.
Authors: Xiang Yang , Zhu Shan , Cao Dongyan , Wan Xi-Run , Zhang Chunliu , Yang Junjun , Yang Jiaxin , Yu Mei , Zhang Ying , Ren Tong , Wang Jing , Li Peiling , Zhang Guo-Nan , Bai Jing , Guan Yanfang , Xia Xuefeng
Published: June 2021

e17547

Background: Epithelial ovarian cancer is one of the common causes of gynecologic cancer death around the world. Histologically, EOC is classified into 5 major sub-types: high-grade serous (HGSOC), low grade serous (LGSOC), clear cell (CCOC), endometrioid (ENOC) and mucinous (MOC). Baseline genomic and immunomicroenvironmental characteristics of treatment-naive patients may offer an insight into recurrent risks. Methods: 101 patients with treatment-naive EOC were enrolled, including 60 HGSOC, 14 LGSOC, 8 ENOC, 14 CCOC, 5 MOC. Tumor tissues and paired peripheral blood samples were collected and performed with target sequencing of 1021 genes and TCR repertoire sequencing. Patients were intensively followed up for at least one year. To explored the molecular characteristic among 5 sub-types, genomic features and TCR repertoire signature were evaluated. Results: The mutation rate of PTEN loss was comparable among 5 sub-types for 53.3% (32/60) in HGSOC, 57.1% (8/14) in LGSOC, 42.9% (6/14) in CCOC, 50% (4/8) in ENOC, 40% (2/5) in MOC. Patients with PTEN loss tended to have lower tumor mutation burden (p = 0.077, Wilcoxon test), especially in HGSOC (p = 0.048, Wilcoxon test). Patients with CCOC and ENOC had significantly higher clonality, which indicates T cell expansion, than SOC tumor (HGSOC, LGSOC) (p = 0.036, Wilcoxon test). Moreover, the proportion of top 10, top 50 and top 100 T cell clones were all significantly higher in CCOC and ENOC than that in SOC(p = 0.0072, 0.0041, 0.0058, Wilcoxon test).In addition, richness and Shannon-index, two metrics for T cell diversity, were significantly higher in SOC comparing with CCOC and ENOC(p = 0.032, 0.0018, Wilcoxon test). After integrated the genomic and TCR features, more favorite disease-free survival (DFS) was found in patients with PTEN loss wild type, higher TMB, higher clonality and lower Shannon-index (p = 0.041, HR = 0.24, Mantel–Cox test). Conclusions: Our results highlight the traits of genomic and TCR repertoire in different subtypes of epithelial ovarian cancer and their prognostic significance. Interestingly, higher T cell clonality in CCOC and ENOC patients were found, which suggested the anti-cancer immune response was better activated. However, our study gets a preliminary result, and further verification work is needed.
Evaluation of immunohistochemical expression of mismatch repair proteins in endometrioid and seromucinous borderline ovarian tumors a 10-year experience in a large health care institution.
Authors: Chavarria Hector , Frimer Marina , Kauff Noah D. , John Veena S. , Khutti Seema
Published: June 2021

e17557

Background: Borderline tumors (BT) are atypical proliferation of epithelium in the ovary in the absence of destructive stromal invasion, representing for 15% of all epithelial ovarian cancers. [1] Around 10% of the ovarian tumors are hereditary, and approximately 10% of all the hereditary forms of epithelial ovarian tumors are result of a loss of DNA mismatch repair (MMR). [2] Endometrioid borderline tumor (EBT) and Seromucinous borderline tumors (SMBT) are rare tumors in ovary and there is limited literature available on immunohistochemical (IHC) expression of Mismatch repair proteins(MMRP)in these tumors.[3, 4] The aim of this study is to evaluate IHC expression of MMRP in EBT and SMBT of ovary. Methods: Pathology database was searched for ovarian Endometrioid borderline tumor (EBT) and Seromucinous borderline tumor (SMBT) for a 10-year period (2010-2020). The cohort consisted of 10 EBT (6 of which had focal microinvasion or carcinoma) and 12 SMBT(2 of which had focal carcinoma ). For comparison, 1 borderline Brenner. 15 serous borderline tumors (SBT) and 15 mucinous borderline tumors (MBT) were also included. After reviewing slides, a block with adequate borderline tumor was selected for IHC stains. For the cases with carcinoma, two different blocks with each component were selected. In all selected blocks, IHC stains for four MMRP (MLH1, PMS2, MSH2, MSH6) were performed. The complete absence of nuclear staining in tumor cells was considered as “loss” of the MMRP expression. Any “weak” or “focal” nuclear staining was considered intact. Results: Total 53 cases were evaluated for MMRP IHC. All cases had intact MMRP expression. In cases with carcinoma, both components (BT and carcinoma) have intact MMR IHC expression. See table. Conclusions: Our study did not show loss of MMRP IHC expression in EMT or SMBT. However, our study consisted of a small number of cases. Multi Institutional study with a large number of cases can be helpful in future to further evaluate the role of MMRP IHC in EMT and SMBT. [Table: see text]
Upregulation of HSPB1 heat shock gene and ERCC1 gene on serous ovarian cancer cell line in HIPEC in vitro model.
Authors: Andrade Warne Pedro , Gonçalves Bryan Ôrtero Perez , Silva Luciana Maria , Dasilva Filho Agnaldo Lopes
Published: June 2021

e17559

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with the presence of chemoresistance contributing to the poor prognosis. Approximately 80% of cases are diagnosed in stage III C and are treated with cytoreduction surgery followed by adjuvant chemotherapy. However, 70 percent of these patients have pelvic and peritoneal recurrences. Heat Shock Proteins are produced in response to pathophysiological stress and take part in several stages of carcinogenesis, acting primarily as anti-apoptotic agents. They are also implicated in resistance to chemotherapy in several types of tumors. In an attempt to improve oncological results, new therapeutic approaches such as intraperitoneal chemotherapy and HIPEC have been proposed in recent studies with gains in overall survival (OS). However, some questions have not yet been answered. Methods: in the study cultures of ovarian cancer cells were performed TOV-21G (clear cell carcinoma), SK-OV-3 (platinum-resistant serous carcinoma) and OV-90 (high-grade serous). Cell cytotoxicity (MTT) assay was performed. The ovarian cancer cells lines were treated with cisplatin in normothermia (37 degrees Celsius) and cisplatin in hyperthermia (41 degrees Celsius) and a control group treated with PBS saline solution at (37 degrees Celsius and 41 degrees Celsius) for 24 hours followed by new supplementation and a new 3-hours incubation. Clonogenic assay was performed. Then they were submitted to RNA extraction and reverse transcription. qRT-PCR was performed to compare the expression of TRAP1, HSPB1, HSPD1, HSPA1A, HSPA1L and ERCC1 in different treatments. Results: There was no statistical difference in relation to cytotoxicity between treatment with heated cisplatin compared to treatment with normothermia. It was not possible to evaluate the expression of the heat shock genes in the SK-OV3 lineage.The HSPB1, HSPD1, TRAP1 and ERCCC1 genes were positively regulated in OV-90 submitted to hyperthermia in relation to normothermia and there were no significant changes in expression in the TOV-21-G. Conclusions: In conclusion, we suggest that OV-90 Serous ovarian cancer cell line was more susceptibly at hyperthermia by cisplatin. The HSPA1A, HSPA1L, TRAP1 and HSPB1 heat shock genes and ERCC1 genes were upregulated in the heated cisplatin group and contribute to a poor prognosis related to resistance. The HSPB1 and ERCC1 genes had the greatest expression with 1000x higher.Thus, it is necessary to evaluate these genes in a clinical study of HIPEC.
Feasibility of ovarian preservation as a stage in correcting the quality of life in young patients after gynecologic surgeries.
Authors: Chernikova Natalia V. , Verenikina Ekaterina V. , Poryvaev Yuriy A. , Myagkova Tatiana Yu. , Menshenina Anna P.
Published: June 2021

e17560

Background: The purpose of the study was to analyze the structure and activity of the blood flow in the preserved ovaries after gynecologic surgeries. Methods: We monitored 50 patients (mean age 35.8±0.5 years) using sonography after ovary-sparing hysterectomy for benign, precancerous and preinvasive malignant uterine diseases. For revascularization, the preserved ovaries were attached to the lateral wall of the small pelvis or to the base of round ligaments of the uterus. Results: Ovarian hypertrophy was recorded in 3 women during the first year of the follow-up; the ovaries returned to the initial size without correction by 24 months. By the third year of observation, 94% of women had normal gonadal sizes, and only 2 women had ovarian hypoplasia. During the entire observation period (3 years), in 91% of cases, we could visualize the regular maturation of follicles in the preserved ovaries, which indicated the preservation of ovulatory function. The use of Doppler techniques during 24 months of the follow-up demonstrated that the blood circulation in the attached ovaries after hysterectomy was decreased on the average by 20.3%, compared to the intact ovaries. Conclusions: After the critical period of hysterectomy, the blood flow in the ovaries in almost all patients remains sufficient during the first 2-3 years, stimulating the regular growth of follicles and maintaining the gonadal activity. The quality of life of the operated patients during the first three years of follow-up remains optimal without additional correction with hormone replacement therapy.
Overall survival differences between women and men with leiomyosarcomas.
Authors: Wadhawan Ashna , Khunger Arjun , Samuels Shenae , Niu Jianli , Adames Jorge , Sareli Candice , Raez Luis E. , Salzberg Matthew Philip , Vulfovich Michel , Hussein Atif Mahmoud
Published: June 2021

e17562

Background: Leiomyosarcomas (LMS) are one of the most frequently occurring subtypes of soft tissue sarcomas and are associated with poor prognosis and high risk of recurrence even in the early stages of the disease. Primary management involves surgical excision followed by chemotherapy for all stages. We sought to determine the prognostic factors on associated with leiomyosarcoma survival. Methods: The National Cancer Database from 2004-2016 was utilized to obtain demographics, tumor characteristics and treatment factors of LMS. LMS was divided into three groups for analysis- women with uterine LMS, women with ex-uterine LMS and men with LMS. Univariate and backward stepwise multivariate logistic regression models were used to determine prognostic factors associated with long-term survival in each group. Kaplan-Meier method with log rank test was used to compare overall survival (OS) rates among the three groups. Results: A total of 23194 patients were identified. Only 18.7% of men with LMS utilized chemotherapy as compared to 47.4% women with uterine and 25.0% with ex-uterine LMS. Both men and women had comparable palliative care use- 3.9% in women with uterine LMS, 3.5% in women with ex-uterine LMS and 3.0% in men with LMS. There were statistically significant differences (P=0.000) between overall survival among the three groups. Median OS was highest among men with LMS (72m) followed by women with ex-uterine LMS (57.2m) and women with uterine LMS (36.7 m). On multivariate analysis, in women with uterine LMS, increasing age (OR =0.95, P=0.018), presence of lymphovascular invasion (OR=0.25, P=0.000) were associated with decrease in the likelihood of survival. In women with ex-uterine LMS, increasing age (OR=0.97, P=0.000), increasing stage (I-IV) (OR=0.56, P=0.000), presence of tumor (OR=0.39, P=0.001), those with residual tumor and surgical margins (OR=0.87, P=0.009), and patients who received systemic therapy and surgery (OR= 0.85, P=.0016) had a reduced likelihood of survival. In men with LMS, factors such as increasing age (OR=0.96, P=0.000), increasing number of regional lymph nodes (OR=0.91, P=0.027), having had a surgical diagnostic or staging procedure (OR= 0.69, P=0.004), increasing stage (OR = 0.64, P=0.005), and residual tumor or margins (OR=-0.76, P=0.013) were associated with reduced likelihood of survival. Results also suggest that increasing year of diagnosis was associated with an increased likelihood of survival (OR=1.51; P=0.000). Conclusions: Women were found to comprise almost two third of the patient population with LMS. Men were found to have longer survival than women with LMS, despite low utilization of chemotherapy. It may be due to poor prognosis of LMS in the female reproductive organs while LMS in the extremities has better prognosis. Future prospective trials should stratify based on sex and in women location.
Prognosis of endometrial cancer depends on intracrine ratio of sex steroids.
Authors: Moiseenko Tatiana I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Adamyan Meri L. , Cheryarina Natalia D. , Ardzha Anna Yu.
Published: June 2021

e17564

Background: Local imbalance of sex steroids (SS) plays a leading role in the development of gynecologic tumors. The purpose of the study was to investigate the effect of changes in SS and E6 protein levels on the course of endometrial cancer (EC). Methods: 50 patients with EC T1-2N0M0 (histologically - endometrioid adenocarcinoma, AC), aged 53.4±3.2 years, were recruited. Levels of SS and E6 protein were determined by standard ELISA systems in tumor samples. The coefficient of estrogens to the amount of testosterone and progesterone – C = (E1+E2):(T+P4) was calculated. Intact endometrium (IE) obtained in surgical treatment for uterine fibroids was used as the intact tissue. Results: AC patients demonstrated elevated estrone (E1) levels, compared to IE: by 2.2 times in 88% and by 5.9 times in 12% cases (p < 0.05). Levels of estradiol (E2) were similar in AC and IE. Progesterone (P4) levels in 32 patients were 1.5 times lower than in IE, and testosterone (T) 1.5 times higher (p < 0.05). P4 in 18 patients was 3 times lower than in IE, and T – 1.4 times lower in 12 women and 2.2 times lower in 6 women (p < 0.05). The C coefficient increased in 32 patients by 1.3 times (p< 0.05), in 12 patients by 2.7 times, in 6 patients by 8.2 times (p < 0.05). E6 protein was found in tumor tissue of 18 patients with elevated C. 6 of 18 women with C = 24.54±2.4 and E6 = 420±32 ng/g of tissue developed recurrence during 6 months, and 12 patients with C = 8.15±1.2 and E6 = 28±2.1 ng/g of tissue developed recurrence in a period of 6 months to 1 year. Women with C = 4.04±0.39 without E6 oncoprotein in tumor tissue had a relapse-free period for more than 1 year. Conclusions: An analysis of C and E6 oncoprotein in tumor tissues allows identification of high-risk patients and a personalized approach to adequate treatment.
Risk and distribution of venous thromboembolic events during treatment for advanced endometrial cancer.
Authors: Salinaro Julia Rose , Goins Emily , Havrilesky Laura J , Davidson Brittany Anne
Published: June 2021

e17565

Background: Understanding the incidence and timing of venous thromboembolic (VTE) events among patients receiving treatment for advanced endometrial cancer (EC) may help to inform VTE risk stratification and consideration of thromboprophylaxis. We aimed to describe the rate of VTE at each stage of primary treatment for advanced EC as well as the baseline Khorana Score (KS) distribution in this population. Methods: This was a retrospective cohort study of patients diagnosed with stage IVB EC from January 2001 to July 2020 at a single academic institution. The primary outcome was VTE incidence at each stage of primary treatment (at diagnosis, during neoadjuvant chemotherapy [NACT] if applicable, post-operatively [< 30 days from surgery], or during adjuvant chemotherapy). Subjects who were anticoagulated at EC diagnosis were excluded. Khorana score was calculated according to established parameters (1 point each for gynecologic malignancy, pre-chemotherapy platelet count ≥ 350, hemoglobin < 10 or use of red blood cell growth factors, leukocyte count >11, and BMI ≥ 35). Descriptive statistics were used for analysis. Results: There were 76 patients diagnosed with stage IVB EC, 2 of whom were excluded for anticoagulation at cancer diagnosis. Of the remaining 74 patients, 58 underwent primary surgery (78%) and 16 received NACT (22%). A total of 59 received adjuvant chemotherapy after either primary or interval debulking surgery. The two predominant tumor histologies were serous (48%) and endometrioid (20%).A total of 16 VTE occurred during the primary treatment course (22%), 11 among the cohort receiving primary surgery (19%) and 5 among the cohort receiving NACT (31%). The distribution of VTE by stage of primary treatment is shown in Table. The rate of VTE was highest during adjuvant chemotherapy. There were 62 patients for whom a Khorana score could be calculated either before NACT or adjuvant chemotherapy. The distribution of KS was: 17 (27%) with KS 1 (low risk) and 45 (73%) with KS ≥ 2 (intermediate – high risk). Of the 11 non-postoperative VTE, 3 patients (27%) had KS 1 and 8 (73%) had KS ≥ 2. Conclusions: The incidence of VTE among patients with advanced EC was high regardless of whether treatment was initiated with NACT or primary surgery. The majority of VTE occurred among patients with a high KS, but those with a low KS remained at risk. Thromboprophylaxis among all patients with advanced EC may be warranted, and larger studies are needed to determine the performance of KS as a VTE predictor in advanced EC.[Table: see text]
Systematic literature review of the real-world burden and use of chemotherapies for treatment of advanced or recurrent endometrial carcinoma.
Authors: Zhao Qi , Hughes Rachel , Altaf-Haroon Ishaaq , Schiller Emma , Kadambi Ananth
Published: June 2021

e17571

Background: Women diagnosed with advanced or recurrent endometrial cancer (EC) have a poor prognosis, with a 5-year survival of only 15% to 17%. While a multi-modality approach is often used for newly diagnosed EC including platinum-based chemotherapy, there are no definitively approved standard treatment options for advanced or recurrent EC following prior systemic therapy (FPST). The real-world evidence surrounding the effectiveness of chemotherapies in this setting is not well characterized. We conducted a systematic literature review to attempt to fill this evidence gap. Methods: Systematic searches were run in Embase, MEDLINE, and the Cochrane Library to identify English-language publications from January 2000 to July 2020. Additional hand searches of 5 key conferences held from 2018 to 2020 were also conducted. The review included observational studies reporting the clinical effectiveness, safety, or treatment patterns of pharmacological treatments in adult women with advanced or recurrent EC. Results: Seventy-seven observational studies met the inclusion criteria, of these 63 studies reported on the effectiveness of chemotherapies. While 57 studies described adjuvant chemotherapy use, 6 described use of chemotherapies FPST, including 1 study in the second line or later. Only one of these 6 studies reported a sample size greater than 100 patients. Chemotherapy FPST included paclitaxel/carboplatin (3 studies), doxorubicin (2 studies), etoposide (1 study), or any platinum-based chemotherapy (1 study). Shorter median overall survival (OS) was observed in patients with treatment-free intervals (TFI) < 6 months from prior systemic therapy (5.5-11.3 months; 2 studies) compared to those with TFI > 6 months (13.0-27.0 months; 3 studies). Similarly, shorter median progression-free survival (PFS) was seen in patients with TFI < 6 months from prior systemic therapy (2.0-3.2 months; 2 studies) vs. those with TFI > 6 months (6.0-10.0 months; 3 studies). Conclusions: Women with advanced or recurrent EC have poor OS and PFS with current chemotherapy regimens, especially for those with TFI < 6 months. The time at recurrence from prior systemic therapy seems to correlate with the outcomes of subsequent treatment. Novel efficacious treatment strategies are required to improve patients’ outcomes in the FPST setting. While extensive real-world evidence exists for patients with EC receiving adjuvant chemotherapy, real world data is limited for use of chemotherapy in advanced or recurrent setting, warranting further research in larger samples of patients.
Vaginal biocenosis in patients with gynecological cancers.
Authors: Nikitina Vera P. , Zykova Tatiana A. , Shevyakova Elena A. , Zhenilo Oksana E. , Verenikina Ekaterina V. , Ivanova Viktoria A. , Kruze Polina A.
Published: June 2021

e17574

Background: The purpose of the study was to assess vaginal biocenosis in patients with gynecological cancers (GCs) and in non-cancer women. Methods: The study included 50 patients aged 52.3+2 years with histologically verified GCs (cervical cancer – 23, endometrial cancer – 27) – group 1, and 22 non-cancer women aged 42.4+2.3 – group 2. Vaginal swabs were taken prior to antitumor treatment. Real-time PCR was used to determine the total bacteria mass (TBM) and DNAs of 16 groups of microorganisms: Lactobacillus spp., Enterobacteriaceae, Streptococcus spp., Staphylococcus spp., Gardnerella vaginalis+Prevotella bivia+Porphyromonas spp., Eubacterium spp., Sneathia spp.+Leptotrichia spp.+Fusobacterium spp., Megasphaera spp.+Veillonella spp.+Dialister spp., Lachnobacterium spp.+Clostridium spp., Mobiluncus spp.+Corynebacterium spp., Peptostreptococcus spp., Atopobium vaginae, Candida spp., Mycoplasma hominis, Ureaplasma (urealyticum+ parvum), Mycoplasma genitalium. Results: Vaginal biocenosis was assessed as normocenosis in 12 (24%) women in group 1 and 12 (54.5%, p = 0.012) women in group 2; conditional normocenosis - 2 (4%) and 3 (13.6%, p > 0.05); dysbiosis - 36 (72%) and 7 (31.8%, p = 0.0017), respectively. Anaerobic bacteria prevailed in women with dysbiosis in both groups (46% and 22.7%, p = 0.005); aerobic dysbiosis was registered in 16% and 4.5% (p > 0.05), mixed dysbiosis – in 10% and 4.5% (p > 0.05) of women of groups 1 and 2, respectively. Normal flora ( Lactobacillus spp.) was observed in 23 (46.0%) in group 1 and 17 (77.3%, p = 0.02) in group 2. Streptococcus spp. >10% of TBM were found in 9 (21.9%) women in group 1 and not found in group 2 (p = 0.049). Gardnerella vaginalis+Prevotella bivia+Porphyromonas spp. >10% of TBM were found in 27 (54.0%) in group 1 and 6 (27.3%, p = 0.031) in group 2; Staphylococcus spp. - 13 (26.0%) in group 1 and 12 (54.5%, p = 0.031) in group 2. Conclusions: Development of gynecological tumors was accompanied by a sharp decrease in Lactobacillus spp., a significant increase in Gardnerella vaginalis+ Prevotella bivia+ Porphyromonas spp. and Streptococcus spp., vaginal dysbiosis with a predominance of anaerobic and mixed microflora.
Cachexia in treatment-naïve gynecological cancer patients: Prevalence, predictors, and clinical associations.
Authors: O'Donoghue Niamh , Sullivan Charlie , Thompson Claire , Abu Saadeh Feras , Kamran Waseem , D’Arcy Tom , Gleeson Noreen
Published: June 2021

e17576

Background: Cancer cachexia is associated with considerable morbidity and mortality, yet its prevalence in gynaecological malignancy is unknown. Prevalence of cachexia in de novo gynaecological cancer patients and the impact of cachexia on clinical parameters and patient-reported outcomes were investigated. Methods: A prospective, exploratory study of newly diagnosed gynaecological cancer patients was conducted at St. James’s Hospital, the largest treatment provider for gynaecological malignancy in the Republic of Ireland. Patients recently diagnosed with a gynaecological cancer were eligible. Demographics, oncological history, Clavien Dindo Classification and length of stay were collected from participants’ medical record. A questionnaire completed by participants on 3 consecutive days collected data on height, weight, weight history, recent dietary intake, nutritional impact symptoms and functional status. Cachexia was defined using the criteria established in 2011 (Fearon and Strasser et al, 2011). Participants’ staging computed tomography scans were utilised for body composition analysis. Descriptive statistics, Mann Whitney U tests and Chi-square were used to summarise and identify significant associations between variables. Logistic regression was used to model predictors of cachexia. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire in conjunction with EORTC gynaecological cancer-specific modules assessed quality of life. Results: A total of 94 participants were recruited. All five gynaecological cancers were represented. Prevalence of cachexia was 21.4% and was highest in patients with cervical cancer. Any weight loss in the previous month was predictive of developing cachexia. Low albumin and anorexia were associated with cachexia, although neither reached significance. Median post-operative length of stay for cachectic patients was 5 days (range 1-57) compared to 4 days (range 0-27) for non-cachectic patients (p = 0.682). 60% of cachectic patients had some post-operative complication. Cachectic patients were more symptomatic and had lower functional status in all quality of life categories, with the exception of emotional function. Conclusions: As prevalence of cachexia in this population is at least 22%, we strongly recommend screening for cachexia at all clinical assessments. Although weight loss and body mass index can identify the majority of cachectic patients, skeletal muscle mass index should also be included where possible. Its incorporation into standard radiology assessment of cancer patients would be optimal. Further research is warranted in a larger population to fully elucidate the predictors of cachexia. Quality of life is a useful means to monitor symptoms and functional status which may contribute to or exacerbate cachexia.
Real-world outcomes for patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with nivolumab: A Galician multicentric study (Spain).
Authors: Iglesias Rey Leticia , Vilchez Simo Rocio , Aguin Losada Santiago , Garcia Arroyo Francisco Ramon , Pena Carolina , Carral Maseda Alberto , Huidobro Vence Gerardo , Molina Díaz Aurea , García-Gómez Jesus , Covela Rúa Marta , Costa Rivas Marinha , Medina Ana
Published: June 2021

e18002

Background: Nivolumab has demonstrated efficacy in clinical trials of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). These results have been corroborated in real world studies in different populations. We describe the outcomes of 116 patients with R/M SCCHN in our clinical practice treated with Nivolumab in the main hospitals of the Galician health network (Spain). Methods: This multicenter study was carried out in nine hospitals that belong to the Galician Group of Head and Neck Cancer (GGCC). A total of 116 patients with R/M SCCHN who received nivolumab were recruited between January 2017 and June 2019. These patients were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS) and the disease control rate (DCR) of the overall patient and specifically in the first, second and third lines, as well as toxicity, were evaluated. Results: Data from 116 patients were available. Most of them were males (91.37%) with a median age of 60 years (41-84 years). The primary tumor sites were oral cavity, oropharynx, hypopharynx and larynx. At first diagnosis, the majority of the patients had advanced disease (stage IV a/b/c 74.12%) and a performance status (PS ECOG) rate of 1 (64.65%). Owing to the real-world nature of the study, patients with poor performance status were also included (ECOG 2: 13.79% and ECOG 3: 0.86%). HPV and PDL1 status were not available for the majority of patients. The use of nivolumab in the first, second and third line was carried out in 20 (17.24%), 76 (65.52%) and 20 (17.24%) patients respectively. With a median follow-up of 14 months (1-69), in all patients (n = 116) the median progression-free survival (mPFS) was 2.30 months (95% CI 1.45 – 3.14) and the median overall survival (mOS) was 8.08 months (95% CI 5.93 – 10.23). DCR was 43% with 5% complete response (CR), 25% partial response (PR) and 15% stable disease (EE). The mPFS of the patients who received nivolumab in the first, second and third line was 3.9 (IC 95%1.01- 6.93), 3.6 (IC 95% 0.82-6.47) and 2.3 months (IC 95% 0.72-3.87) and the mOS was 6.8 (IC 95% 2.36-11.43), 8.5 (IC 95% 5,9 - 11.62) and 7.2 months (IC 95% 4.51-10.07) respectively. Drug-related adverse effects (grade 3/4) were observed in 21.27% and were controlled with steroid treatment. Conclusions: in this real-life study, the population is broader than the represented in the phase III CheckMate 141 trial, including patients with higher ECOG PS (0-3). These concordant results in the real-world setting in both efficacy and safety, support the use of nivolumab in this group of patients with R/M SCCHN.
Novel biomarkers for head and neck squamous cell carcinoma: A retrospective study.
Authors: Dou Shengjin , Zhang Lin , Li Rongrong , Sun Debin , Wu Lijia , Zhu Guopei
Published: June 2021

e18010

Background: PDL-1 and tumor mutation burden are only useful to select a small portion of patients with head and neck squamous cell carcinoma for immunotherapy, more biomarkers are in an urgent need for the majority. Methods: Ninety-nine recurrent/metastatic patients were analyzed. PD-1 cohort including 78 patients; Non-PD-1(NPD-1) cohort including 28 patients received anti-EGFR antibody and harbored at least one of EGFR amplification/mutation, CCND1 amplification, FGF3/4/19 amplification, or CDKN2A/B mutations (including 7 patients received with both treatment). Patients were evaluated as no clinical benefit (NCB) if experiencing progressive disease or stable disease lasting < 6 months and were discontinued from immunotherapy within 3 months; otherwise, patients were evaluated as clinical benefit (CB). Tumor genomic DNA was isolated from formalin-fixed paraffin-embedded tissue for the targeted sequencing by a 769-gene panel. R package was used for fisher test to evaluate the variants. p < 0.05 was set as significant. Results: With median age of 57 years old, this study included 75 (75.8%) oral squamous cell carcinoma patients,17 (17.2%) oropharyngeal carcinoma patients and 7 others. Sixty-nine (69.7%) patients have PD-L1 CPS≥1, 27 (27.3%) patients have CPS＜1 and 3 (3.0%) have an unknown CPS. The estimated 10-month progression-free survival of the NPD-1 cohort and PD-1cohort were 60.0%and 47.6% (p = 0.06) respectively. In NPD-1 cohort, 23 patients were evaluated as CB (78.3%), and in PD-1 cohort, 41 were evaluated as CB (52.6%) (p = 0.00682), indicating EGFR amplification/mutation, CCND1 amplification, FGF3/4/19 amplification, or CDKN2A/B mutations may be negatively correlated with immunotherapies. There were 14 patients who harbored either EGFR amplification or SNV mutation. Of the 8 patients who received NPD-1 treatment, 7 were CB (87.5%); Of the 8 patients who received PD-1 treatment, 2 were CB (25%) Statistically, the difference between NPD-1 treatment group and PD-1 treatment group was significant with a p value of 0.04056. There were 16 patients who harbored CCND1 amplification, or FGF3/4/19 amplification. Of the 12 patients who received NPD-1 treatment, 10 were evaluated as CB (83.3%); Of the 7 patients who received PD-1 treatment, 1 was evaluated as CB (14.3%). The difference was significant with a p value of 0.00627. There were 44 patients who obtained CDKN2A/B mutations. Of the 12 patients who received NPD-1 treatment, 11 acquired CB (81.7%); Of the 33 patients who received PD-1 treatment, 18 acquired CB (54.5%). The difference was significant with a p value of 0.03325. Conclusions: We for the first time showed that genetic-altered EGFR, FGF3/4/19, CCND1 and CDKN2A/B were negatively correlated with anti-PD-1 therapy in clinical cohorts retrospectively and these genetic aberrations may serve as novel immune-negative biomarkers for immunotherapies.
Network meta-analysis (NMA) of pembrolizumab for first-line (1L) treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Ramakrishnan Karthik , Mojebi Ali , Ayers Dieter , Chirovsky Diana Romana , Borse Rebekah , Keeping Sam
Published: June 2021

e18012

Background: In the KEYNOTE-048 trial, pembrolizumab as monotherapy (P) and in combination with platinum+5FU chemotherapy (P+C) versus cetuximab+platinum+5FU (EXTREME regimen) significantly improved overall survival (OS) in the combined positive score (CPS) ≥1 (hazard ratio: 0.74; 95% confidence interval: 0.61-0.90) and total (0.72; 0.60-0.87) R/M HNSCC populations, respectively, and was approved by the FDA in these patient populations. While the EXTREME regimen is considered standard of care in 1L R/M HNSCC, other systemic treatment options including cetuximab+platinum+docetaxel (TPEx regimen), platinum+paclitaxel/taxane (Pt+T), and platinum+5FU (Pt+F) are also commonly used. Due to lack of head-to-head comparisons with pembrolizumab, an NMA was conducted to estimate the comparative efficacy of P and P+C versus these interventions in 1L R/M HNSCC. Methods: A systematic literature review (SLR) was conducted on November 13, 2019 to identify randomized controlled trials for the relavant interventions. Data were extracted for the OS and progression-free survival (PFS) outcomes. NMA analyses were conducted for the total population and for the CPS ≥1 and CPS ≥20 subgroups in a Bayesian framework using proportional hazards (base case) and time-varying (sensitivity analysis) treatment-effect models. The deviance information criterion was used to compare the goodness-of-fit of the alternative survival models. Results: The SLR identified 28 trials, of which six trials matched the trial eligibility criteria of KEYNOTE-048 and were included in the NMA. Results from the fixed-effects NMA for P and P+C are summarized in table below for the FDA indicated population. Improvement in OS was noted for P and P+C versus EXTREME, Pt+T, and Pt+F, and a trend in improved OS versus TPEx was observed. The sensitivity analysis showed improved OS over time across all comparisons. PFS was improved with P and P+C versus Pt+F and comparable versus other interventions. These results were generally consistent for P and P+C in the CPS (CPS ≥1 or CPS ≥20) patient subgroups. Additionally, NMA results versus EXTREME were consistent with the KEYNOTE-048 trial results. Conclusions: Pembrolizumab (P or P+C), showed improved OS and comparable PFS outcomes versus alternative 1L R/M HNSCC interventions, consistent with the efficacy results versus EXTREME observed in the KEYNOTE-048 trial. [Table: see text]
Treatment patterns for patients with metastatic or recurrent head and neck cancer in a large integrated health-care system.
Authors: Seto Tiffany , Samant Navendu D. , Shah Nina , Shirazi Aida , Colevas A. Dimitrios , Katzel Jed Abraham
Published: June 2021

e18015

Background: Since publication of the landmark KEYNOTE-048 Trial, pembrolizumab alone or with platinum-based chemotherapy and 5-fluorouracil (5FU) was established as a standard of care for the frontline treatment of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), replacing the EXTREME regimen of Cetuximab with platinum and 5FU. In clinical practice, some clinicians modify the KEYNOTE-048 regimen by substituting a taxane for 5FU (i.e., Paclitaxel + Carboplatin + Pembrolizumab, PCT). Within the Kaiser Permanente Northern California (KPNCAL) network, we identified a cohort of 123 patients who received palliative first-line therapy for metastatic HNSCC to identify practice patterns in a real-world setting within a large health care delivery system. Methods: This is a data-only cohort study of all adult KPNCAL members diagnosed with metastatic HNSCC treated with palliative combination chemotherapy and/or immunotherapy between January 1, 2018 and July 31, 2020. Results: Among a cohort of 123 patients, 28 patients received the EXTREME regimen (platinum + 5FU + cetuximab), 10 received modified EXTREME (platinum + taxane + cetuximab), 14 received platinum + 5FU + pembrolizumab, 9 received platinum + taxane + pembrolizumab and 62 received single agent immunotherapy. From 2018 through mid-2020, there was an apparent shift away from cetuximab based regimens and a concurrent rise in immunotherapy-based regimens. By mid-2020, the majority of patients received an immunotherapy-based regimen (28 patients), while only 5 patients received a cetuximab based regimen (Table). Conclusions: Data from our cohort reported clinical practice patterns within a large multispecialty integrated health-care system in Northern California. Our findings highlight the marked variability in practice patterns within a single health care system for first-line metastatic therapy. While we identified trends away from cetuximab based therapy and toward immunotherapy-based therapy in clinical practice there remained wide practice variations among clinical oncologist treating patients with newly diagnosed metastatic HNSCC. This further emphasizes the need for prospective clinical trials to identify the optimal regimen or to confirm clinical equipoise between regimens among patients with metastatic or recurrent head and neck cancer. [Table: see text]
Association of HLA loss of heterozygosity with allele-specific neoantigen expansion in response to immunotherapy.
Authors: Pyke Rachel Marty , Abbott Charles , Dea Steven , Bedi Nikita , Colevas A. Dimitrios , Levy Eric , Zhang Simo V. , Snyder Michael , Mellacheruvu Datta , Sunwoo John B. , Chen Richard , Boyle Sean Michael
Published: June 2021

e18030

Background: Human leukocyte antigen loss of heterozygosity (HLA LOH) restricts immune recognition of tumors by limiting the major histocompatibility complex (MHC) presentation of neoantigens to T cells and correlates with reduced response to immune checkpoint blockade therapy (ICB) in non-small cell lung cancer. To explore the mechanism behind the impairment of HLA LOH on ICB, we analyzed the relationship between the antigen presentation pathway, neoantigen presentation and response to ICB in a head and neck squamous cell carcinoma (HNSCC) cohort. Methods: Following baseline sample collection, a cohort of 14 HNSCC patients recieved a single dose of PD-1 inhibitor. The primary tumor mass was definitively resected approximately one month later. If resection was impractical, a second biopsy was taken. Response to therapy was evaluated using RECIST criteria. Each pre- and post-intervention tumor sample and normal PBMC sample were profiled using Personalis’ ImmunoID NeXT Platform, an HLA-enhanced exome/transcriptome platform. HLA LOH was detected using a digital PCR validated machine learning algorithm (DASH). Neoantigen presentation was computationally predicted using a machine learning algorithm (SHERPATM) trained on mono-allelic immunopeptidomics data. Results: We found that 50% of the HNSCC cohort had HLA LOH, a larger percentage than in a large pan-cancer cohort (23%, n=611) and a distinct HNSCC cohort (40%, n=20). Further, two patients had B2M LOH and one patient had a deleterious mutation in an HLA allele. Despite the high frequency of somatic alteration in the antigen presentation pathway, we did not find an association between HLA LOH and ICB response. However, if HLA LOH was still shaping tumor evolution in response to ICB, we would expect to see immune pressure against subclonal tumor populations with neoantigens presentable by the retained HLA alleles but not the deleted HLA alleles. Indeed, we found that significantly more novel post-treatment neoantigens were predicted to bind to deleted HLA alleles compared to their homologous alleles (p=0.045). Conclusions: Given the high prevalence of HLA LOH across tumor types, a greater understanding is needed regarding the impact of HLA LOH on tumor evolution during ICB treatment. Though HLA LOH does not correlate with response to ICB, the consistent shift in neoantigen composition suggests that it acts as an evolutionary force in resistance to response during immunotherapy.
Analyzing the effects of depression among patients with head and neck cancer.
Authors: Zafar Muhammad Usman , Tarar Zahid , Ghous Ghulam , Farooq Umer , Anwar Masood
Published: June 2021

e18038

Background: Patients with head and neck cancer carry the prospect of facial disfigurement in addition to the effects on speech, smell, sight, and taste. As such they are at a higher risk of acquiring emotional distress. Despite this, depression is underreported in this population. We review the National Inpatient Sample (NIS) to understand the effects of depression in patients admitted with any diagnosis of head and neck cancer. Methods: We designed a retrospective study and utilized NIS data for the year 2018. We identified patients with any history of Head and Neck cancer using their specific ICD-10 codes. We also identified codes for depressive disorders. Primary outcome was effect of depression on comorbidities. Secondary outcome was hospital length of stay. Utilizing STATA MP 16.1 we performed multivariate logistic regression analysis. Various comorbidities including previous history of coronary artery disease, congestive heart failure, stroke, smoking, hyperlipidemia, and chemotherapy were incorporated into the analysis. Results: The study population included 15,689 patients that were 18 years or older. Mean age was 64 years. Only 28% of the population was females. The mean hospital length of stay was approximately 7 days. In this group of patients, 12% had a history of depression. Among the different types of head and neck cancers oropharyngeal cancers had the highest percentage of depression rates (14%). In multivariable analysis, patients with depression had a higher comorbidity index but this result did not reach statistical significance (Odds Ratio (OR) 1.02, p = 0.054, 95% Confidence Intervals (CI) 0.999 – 1.045). Patients had higher odds of having depression if they also had a history of stroke (OR 1.4, 95% CI 1.13 – 1.73), prior history of chemotherapy (OR 1.25, 95% CI 1.09 – 1.43), history of hyperlipidemia (OR 1.31, 95% CI 1.16 – 1.48) or were admitted over the weekend (OR 1.21, 95% CI 1.07 – 1.38). Younger age was associated with lower odds of depression (OR 0.98, 95% CI 0.98 – 0.99). Women had higher odds of having depression (OR 1.68, 95% CI 1.51 – 1.88). When compared with white people, people from the following demographics had lower odds of depression – Black (OR 0.56, 95% CI 0.47 – 0.68), Hispanic (OR 0.64, 95% CI 0.49 – 0.83), Asian (OR 0.26, 95% CI 0.17 – 0.43), and others (OR 0.53, 95% CI 0.35 – 0.79). Hospital length of stay was higher among patients with depression (OR 0.7, 95% CI 0.2 – 1.15). Conclusions: Among patients with head and neck cancer, odds of having depression are higher in the white population, older patients, females and patients with prior history of chemotherapy. Depression is associated with higher hospital length of stay. These findings help understand the effect of depression on this susceptible population and identify at risk patients for appropriate screening.
Clinical outcomes, prognosis, and predictors of salvage surgery in oral cavity squamous cell carcinoma.
Authors: Lan Wen-San , Lu Hsueh-Ju , Chiu Yu-Wei , Peng Chih-Yu , Tseng Hsien-Chun , Hsin Chung-Han , Chuang Chun-Yi , Chen Chun-Chia , Huang Wei-Shiou , Yang Sung-Fa
Published: June 2021

e18040

Background: Salvage surgery (SS) is one of the curative options for oral cavity squamous cell carcinoma (OCSCC) patients with locoregional recurrence (LRR) or secondary primary, but the role of SS should be reevaluated between life expectancy, morbidity, and quality of life. Selecting suitable OCSCC patients receiving SS is important. Methods: From 2010 to 2018, newly diagnosed OCSCC patients who progressed to LRR or secondary primary were recorded. Clinical outcomes, prognostic factors, and predictors were analyzed for the patients receiving SS. Cox regression analyses were performed for PSS, defined from the date of SS to the date of death or last follow-up. Survival was estimated using the Kaplan–Meier method and log-rank tests. Results: A total of 263 newly diagnosed OCSCC patients progressing to LRR or secondary primary were recorded. Half (55.1%, 145/263) of them received SS, and one-third (29.7%, 43/145) of the SS group received twice and more times SS. Median survivals after disease progression were 65.6 and 10.6 months for patients with or without SS, respectively (P < 0.001). A total of 214 SS events were enrolled for analysis. Nearly twenty percentage (20.1%, 39/194) of SS events would progress to death within 1 year after surgery (PSS < 1 year). PSSs of the first, secondary, third, and fourth or more times SS were 64.2, 47.6, 40.9, and 18.9 months, respectively (P = 0.217). Surgical features of the last surgery (perineural invasion and depth of invasion), the interval between the last and current surgery, and clinical N staging of the current surgery were the four independent factors for PSS. To predict the patients with PSS < 1 year, a scoring system was established that each of the independent factors was scored one point. The area under the curve of the scoring system was 0.755, and sensitivity, specificity, positive predictive value, and negative predictive value were 66.7%, 76.0%, 39.0%, and 90.8%, respectively (Table). Conclusions: A scoring system with a high negative predictive value was established to predict PSS < 1 year.[Table: see text]