bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world associations between bone-targeted agents and palliative bone radiotherapy in prostate cancer decedents: A province-wide population study.
Authors: Phillips William James , Jooya Alborz , Mahdavi Roshanak , Leigh Jennifer , Tawagi Karine , Webber Colleen , Milani Christina , Morgan Scott Carlyle , MacRae Robert Malcolm , Bourque Jean-Marc , Tanuseputro Peter , Ong Michael
Published: June 2022

e17043

Background: Palliative bone radiation is the predominant skeletal-related event (SRE) reported in advanced prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to both prevent and delay SREs including bone radiation. This study evaluated real-world use of BTA in a large provincial database in relation to palliative bone radiotherapy prior to prostate-cancer related death. Methods: Linked, province-wide administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646), who received continuous androgen deprivation therapy (n = 29453), died between 2013-2018 (n = 4184), and qualified for Ontario Drug Benefits (OBD; 65 years or older, n = 3788). Patients receiving novel life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC; abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223) were selected, and use of BTA (denosumab, zoledronic acid) was identified. Demographic, health, and treatment characteristics were collected over a 2-year observation window looking back from the date of death. Multivariable analyses were conducted to identify factors important in use of palliative bone radiation. Results: 1769 patients received LPT for mCRPC, including abiraterone (n = 1094, 62%), docetaxel (n = 881, 60%), enzalutamide (n = 480, 27%), radium-223 (n = 250, 14%) and cabazitaxel (n = 108, 6%). Amongst patients receiving LPT, 57% received BTA and 60% received palliative radiation to bone. Factors associated with palliative bone radiation were receipt of BTA (OR 1.46; 95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (OR 1.48; CI: 1.11-1.97), radiation oncologist involvement (OR 103.11; CI: 47.03-226.25), whereas patients with fewer chronic diseases (OR 0.73; CI: 0.54-0.98) and who had prior prostatectomy (OR 0.54; CI: 0.36-0.84) were less likely to receive radiation. This relationship was maintained for both zoledronic acid (OR 1.68; CI: 1.09-2.58) and denosumab (OR 1.35, CI: 1.03-1.77). No specific LPT was associated with use of palliative bone radiation. Conclusions: Despite clinicians prescribing BTAs to prevent SREs, in this cohort, radiotherapy to bone was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but that patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of primary (before bone radiotherapy) versus secondary (after bone radiotherapy) BTA prescriptions will be presented, as well as timing of BTA initiation in relation to death.
Impact of therapeutic strategy on disease-free and overall survival of early-stage cervical cancer: Surgery alone versus preoperative radiotherapy.
Authors: Mahiou Katia , Vincent Laura , Peignaux-Casasnovas Karine , Costaz Hélène , Padeano Marie-Martine , Amet Alix , Dabakuyo Tienhan Sandrine , Bengrine-Lefevre Leila , Coutant Charles
Published: June 2022

e17517

Background: At present, there is no international consensus for management of early-stage cervical cancer. This study aimed to retrospectively investigate disease-free survival (DFS) and overall survival (OS) in patients with early cervical cancer according to the therapeutic strategy used, surgery alone versus pre-operative radiotherapy following by surgery. Methods: Data from patients with early-stage cervical cancer were retrospectively collected from January 1998 to December 2015 using the Breast & Gynecological Cancer Registry of the Côte d’Or, regrouping data from 7 centers. The inclusion criteria were: FIGO 2009 stage IB1 or lower; epidermoid, adenocarcinoma or adenosquamous type. The exclusion criteria were: history of pelvic radiation; concomitant radiochemotherapy; adjuvant radiotherapy; total radiation dose less than 50 Gy, or more than 66 Gy or not documented. In the surgery group, patients had only a surgical treatment for early-stage cervical cancer. The surgical treatment was either a hysterectomy, a trachelectomy or a conization. In the radiation group; patients had radiotherapy, brachytherapy and/or radiotherapy followed by surgery. DFS and OS were determined using the Kaplan-Meier method .Survival curves were compared using the log-rank test. Results: A total of 126 patients were included. Median survival in the whole population was 90 months (47-148); 72 months for those receiving primary surgery, and 135.5 months for those receiving primary radiation therapy. There was no significant difference in DFS between the surgery and radiation groups (HR=2.82, 95%CI (0.82-9.65), p=0.08). Similarly, there was no significant difference in OS between groups (HR=1.35, 95%CI (0.6-3.05), p=0.5). In the sub-group of patients with stage IB1 (FIGO 2009), there was no significant difference in DFS (HR=3.26, 95%CI (0.4-26.76), p=0.2) or in OS (HR=3.87, 95%CI (0.49-30.35), p=0.2) between groups. Conclusions: Cervical cancer counts among the only solid tumors for which increasing mortality has been observed in recent years. Radiation therapy is still a major source of morbidity for young patients. Therefore, key issues remain outstanding for the future management of young patients with cervical cancer and include reducing the morbidity of existing therapeutic options by identifying subgroups of patients at low or intermediate risk, and facilitating fertility-sparing surgery.
Gestational trophoblastic neoplasia: 14-year experience from a single institution.
Authors: Roque Perez Katia , Castro-Mollo Melanie Wendy , Vallejos Heberth Daniel , Ruiz Rossana , Galvez-Nino Marco , Valdivieso Natalia , Coanqui Ofelia , Olivera Hurtado de Mendoza Mivael , Perez Joan , Lopez Aldo , Velarde Carlos , De Mello Ramon Andrade , Mas Luis
Published: June 2022

e17529

Background: Gestational trophoblastic neoplasia (GTN) is a rare tumor with an excellent prognosis. With the advent of multiagent chemotherapy, cure rate improved to nearly 100% in the low-risk group (LR). However, in developing countries it is lower, especially in the high risk (HR) group. Herein, we describe our experience with management and survival of GTN over a 14y period. Methods: Retrospective study based on case review of women with newly diagnosed GTN between 2005 and 2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima- Peru. Primary outcome measure was complete remission (CR) by 12 months following completion of therapy and 3y overall survival (OS). Risk score was established according to the International Federation of Gynecology and Obstetrics (FIGO) with patients with scores < 7 and ≥7 being classified as LR and HR, respectively. A subgroup with score ≥13 was defined as ultra-high risk (UHR) group. Results: 172 patients with GTN were included, median age was 30 years (range 18-54 y). Choriocarcinoma was the most frequent histology in 54.6%, however, in 38% it was not determined. The most common metastatic sites were lungs (66%) and brain (15%). Median FIGO risk score was 10 points (range 1- 21). Accordingly, 8% and 82% of patients belong to LR and HR group; 41% of patients with HR had a score ≥13. Regarding treatment, 5 patients (16%) in the LR group were treated with surgery only and 84% received oral methotrexate; while all patients in the HR group received multidrug chemotherapy: 85% received etoposide, methotrexate and dactinomycin (EMA)/ cyclophosphamide and vincristine (CO), 10.6% received etoposide, methotrexate, actinomycin-D (EMA)/ etoposide and cisplatin (EP) and 2% received other regimens. CR was ultimately achieved in 83% of cases overall (100%, 80% and 73% in LR, HR and UHR group, respectively). 16% had persistent disease and relapse occurred in 5% of patients who had previously achieved CR. Early death (within 4 weeks of initiating therapy) occurred in 4.6% (8/31). 3y-OS was 82%, after excluding early deaths, the survival rate was 86%. Conclusions: In our series, HR disease is the most frequent presentation and almost half of this cases correspond to the UHR group. Remission rate in the LR group is similar to that reported in other series, however it is lower in HR and UHR group. Having said this, it represents the data of a high-risk cohort of patients in a resource-constraint setting. This data is being used to identify strategies for improvement of results, especially in ultra-high risk group.
Anlotinib suppresses growth and metastasis through MAPK signaling pathway in cisplatin-resistant ovarian cancer cells.
Authors: Ji Yurou , Qu Pengpeng
Published: June 2022

e17542

Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Increasing evidence suggests that anlotinib exhibits effective anti-tumor activity in various cancer types. However, the functional roles of anlotinib on cisplatin-resistant ovarian cancer are yet to be elucidated. The objective of this study was to investigate the anti-tumor effects of anlotinib in the pathogenesis of cisplatin-resistant ovarian cancer cells and tried to explore the related molecular mechanisms. Methods: Human ovarian cancer cells (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cells proliferation were determined by CCK-8 assay and colony formation assay. To evaluate the invasion and metastasis of ovarian cancer cells, we conducted wound healing and trans-well assay. Cell cycle was detected by flow cytometry. Moreover, the xenograft mouse model was used for conducting in vivo studies to verify the effect of anlotinib. The expression of Ki-67 in the tumor tissue was detected by immunohistochemistry. In GSE15372, differential expressed genes (DEGs) between cisplatin-sensitive and cisplatin-resistant groups were analyzed and enriched pathways were identified. Real-time qPCR and Western blot were used to measure the mRNA or protein level. Results: In vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration, and invasion restraint. Meanwhile, xenograft cisplatin-resistant ovarian tumor models revealed that anlotinib treatment dramatically hindered in vivo tumor cells growth. HE and Ki-67 staining showed anlotinib markedly inhibited cisplatin-resistant ovarian cancer cells proliferation. Polo-like kinase 2 (Plk2) was identified as the main target gene of cisplatin-resistant ovarian cancer cells through bioinformatics analysis. Furthermore, we found that anlotinib upregulated the expression of Plk2 and suppressed the MAPK signaling pathway activation. The high expression of Plk2 might serve as a promising indicator when used to predict a favorable therapeutic response. Conclusions: In this study, we found that anlotinib had excellent anti-tumor effects in cisplatin-resistant ovarian cancer cells both in vitro and in vivo. These present results add to the growing body of evidence supporting anlotinib as a potential anti-cancer agent in ovarian cancer.
ChosenHRDw: A novel tool for the detection of homologous recombination deficiency(HRD) using low-pass whole-genome sequencing.
Authors: Zhang Xiaotian , Tian Weiwei , Wang Yakun , Bing Wang , Pengyan Chen , Yukai Hu , Zhang Yiqun , Cheng Wu , Xiumin Huang , Wan Qianhui , Xinying Shi , Pei Zhihua , Qiming Zhou , Wang Dongliang , Shen Lin
Published: June 2022

e17573

Background: Homologous recombination deficiency(HRD) as a promising biomarker holds predictive and prognostic value in anticancer therapies, especially in ovarian cancer. Although next-generation sequencing techniques such as whole-exome sequencing (WES) and targeted sequencing have proven to be powerful detection of HRD, the latest low-pass (1x) whole-genome sequencing (WGS) with characteristic large-scale patterns for HRD detection status, as a cost-effective screening strategy, have established feasibility. In this study, we developed the ChosenHRDw, a comprehensive algorithm, which utilizing low-pass WGS to effectively classify the HRD status by defining the high or low HRD score. Methods: In this work, a correction method base on GC-content was applied. Then we took a window size of 1Mb resolution, and removed the error alignments genome bins basing on the healthy cohort data. Baseline of each bins was constructed from the data of 100 healthy volunteers. We characterized and quantified 8 HRD-related signatures: LOH score, TAI score, LST score, chromosomal instability index(CIN index), wGII(weighted genome instability index), CNV ratio (copy number ratio in bins), HRR index (HRR gene instability index), TFBS ratio (copy number ratio in transcription factor binding sites) as the variables in a random forest model. Results: A total of 140 patients (pts) were enrolled in the discovery cohort, which including 70 high HRD score and 70 low HRD pts were confirmed by HRDetect on paired tumor/normal samples via 1123plus-genes panel targeted sequencing. The AUC was 0.93. Independent validation was conducted in a validation cohort of 60 pts, which HRD high or low pts were 30 and 30, respectively. The sensitivity = 0.87 and specificity = 0.9. Conclusions: We classified HRD into high vs low using ChosenHRDw, which showing strong concordance. Our analyses demonstrated that the prediction of HRD status can be achieved from low-pass WGS. Due to the limitation of relatively small sample size, real-world studies with a larger number of patients are needed to verify our algorithm in the future.
Exploratory hrd and PD-L1 analysis of l-MOCA study: Olaparib maintenance monotherapy in Asian patients with platinum-sensitive relapsed ovarian cancer.
Authors: Ma Ding , Gao Qing-lei , Zhu Jianqing , Zhao Weidong , Huang Yi , An Ruifang , Zheng Hong , Qu Pengpeng , Wang Li , Zhou Qi , Wang Danbo , Lou Ge , Wang Jing , Low John , Kong Beihua , Yin Rutie , Xie Xing , Liu Jihong , Sun Wei , Zang Rongyu
Published: June 2022

e17578

Background: Olaparib demonstrated its efficacy to prolong progression-free survival (PFS) in platinum-sensitive relapsed ovarian cancer (PSROC) patients (L-MOCA study). Almost half of OC patients harbor homologous recombination deficiencies (HRD). However, there is lack of the HRD prevalence in Asian PSR population. Meanwhile, Immunological processes play a key role in tumorigenesis and PD-L1 status may hinder an effective antitumor immune response in OC. Herein, we analyzed HRD and PD-L1 status in Asian patients with PSROC, and explored Olaparib response to different HRD status. Methods: In this exploratory analysis of L-MOCA trial, HRD and PD-L1 status were analyzed from patients with PSROC. Residual DNA samples of 193 patients were analyzed for HRD status with a local developed HRD assay (Teddy Laboratory, Shanghai, China, which determines two major components, tBRCA1/2 status and LOH score, HRD positive indicates the presence of a deleterious or suspected deleterious BRCA mutation or LOH score ≥0.4). The remaining formalin fixation and paraffin embedded samples were used for PD-L1 expression analysis by immunohistochemistry with SP263. Descriptive statistics were summarized for HRD status, PD-L1 expression status and PFS by different HRD status subgroups. Results: 193 of 224 patients had residual DNA for HRD test. Patients clinical characteristics were similar between those with and without residual DNA for HRD test, in terms of age (mean age 55.5y Vs 54.2y), FIGO stage (stage III 68.9% Vs 61.3%, stage IV 12.4% Vs 22.65%), and time to disease progression to Last prior Platinum Based Chemotherapy (6-12m: 39.9% Vs 41.9%; > 12m: 59.6% Vs 54.8%). Among 193 patients with HRD test conducted, proportion of HRD+ BRCAm, HRD+ BRCAwt, HRD- and HRD unknown were 37.3%, 28.0%, 14.5% and 20.2%, separately. mPFS of the above subgroups was 20.1 months, 15.8 months, 9.2 months and 16.4 months, respectively (Table1). 200 of 224 patients were available for PD-L1 expression analysis. 184 (92%) with TC＜1%, 12 (6%) with TC among 1-25%. These results showed TC expression in all patients were less than 25%, suggesting that ovarian cancer may be an immunologically cold tumor. Conclusions: This is firstly showing the HRD and PD-L1 status in Asian OC patients. The results showed all the PSR patients could benefit from Olaparib treatment, regardless of HRD status. Meanwhile the numerically different mPFS observed across different HRD status subgroups also indicated potential clinical utility of locally developed HRD assay. Clinical trial information: NCT03534453. [Table: see text]
Exploring the mechanism of PARPi resistance in ovarian cancer by integrated analyze of pre- and post-progression samples in 5 patients.
Authors: Li Qingli , Song Liang , Lin Xiaojuan , Zhang Wenhao , Cheng Peng , Zhu Changbin , Yin Rutie
Published: June 2022

e17582

Background: PARP inhibitors (PARPi) have been widely used in the treatment of homologous recombination repair-deficient tumors. Comprehensive investigations on the resistance mechanisms of PARPi and tumor microenvironment alterations after PARPi therapy are largely insufficient. Methods: 5 ovarian cancer patients (pts) treated with PARPi at West China Second University Hospital were enrolled in this study (Ethical Lot Number: 20200076). Clinicopathological information of the pts are shown in table below. Paired PARPi treatment-naive surgical samples (TNS) and the biopsy samples that progressed after PARPi maintenance therapy (PPS) were obtained. Multi-omic profiling was conducted by an NGS panel (Master Panel, AmoyDx) containing DNA exon regions of 563 genes and RNA expression of 1831 genes analyzing genetic mutations and dynamics of gene expression profile in these paired tumor samples. Results: Median duration of treatment with PARPi was 18 months (11-22). Comprehensive genomic profiling discovered MYC amplification (n = 3), ZFHX4 mutation (n = 2) and IDH1 mutation (n = 1) in PPS. One PPS harbored simultaneous amplification of PDCD1, FGF3, MYC, FGF19 and ZFHX4 mutation. In addition, BRCA1 intron11: c.4096+1G > T mutation was detected in one PPS carrying germline BRCA1 mutation (E1066*), which putatively resulted in restoration of BRCA1 function. At RNA level, single-sample enrichment analysis showed that B cells, T cells, and co-activation factors were significantly up-regulated in PPS. In addition, expression of CXCL13 and activation of CCL19/21-CCR7 axis were significantly increased, which indicated a PARPi-triggered “hot” immune-microenvironment. Moreover, immune-checkpoint TIGIT was significantly upregulated, paved the way for immunotherapy. Nevertheless, stromal remodeling, and tumor proliferation signatures were also up-regulated in PPS. In parallel, cancer-related pathways, PI3K/AKT, Epithelial-Mesenchymal transition, cell-cycle as well as G2M checkpoint were observed in the pathway enrichment analysis, which further verified the aforementioned findings. Conclusions: This small sample size study confirmed the complexity of the resistance mechanisms to PARPi, including BRCA reversion mutation, oncogene activation and bypass signaling activation. The activation of both positive and negative immune regulators in the tumor microenvironment shed light on future clinical management for patients with PARPi resistance.[Table: see text]
Changes in focal adhesion protein Talin-1 expression during malignant transformation leading to ovarian high-grade serous carcinoma.
Authors: Paris Elizabeth , Bitterman Pincas , Sharma Sameer , Basu Sanjib , Bahr Janice M , Barua Animesh
Published: June 2022

e17586

Background: Ovarian high-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, is often detected at late stages due to the lack of an early detection test resulting in low 5-year survival rates. Information on factors associated with malignant transformation and early metastasis is critical in developing interventional strategies to reduce the incidence and death due to HGSC. Talin-1, a focal adhesion protein, regulates cell–cell adhesion, and induces cytoskeletal remodeling leading to tumor cell migration and adhesion. Destabilization of the cell membrane during malignant development may shed Talin-1 in circulation which may be a potential early marker of progression of HGSC. Objective: The goal of this study was to examine the changes in Talin-1 expression during malignant transformation in ovaries and fimbria of the fallopian tube and its prevalence in serum. Difficulty in accessing patients with early-stage HGSC is a significant barrier to study malignant transformation and progression. Laying hen model of spontaneous ovarian HGSC was used together with clinical specimens. Methods: Two experiments were conducted. Exploratory study:Archived normal ovaries (n = 10), ovaries with HGSC at early (n = 10) and late (n = 10) stages from patients and their serum samples were used. Prospective study: Laying hens with no detectable abnormalities were selected and monitored using transvaginal ultrasound (TVUS) imaging at 10 week intervals for 10 months and sera were collected at each scan. Hens were euthanized at diagnosis of solid mass during scanning or at the end of the study; ovaries, fimbria and serum samples were collected. Normal hens (n = 10), hens with early (n = 7) and late-stage (n = 8) tumors were selected. Talin-1 expression in tissues and serum was determined by immunohistochemistry (IHC), Western blotting (WB), gene expression (qPCR), and immunoassay (ELISA). Significant differences in Talin-1 expression among all groups were determined by ANOVA and/or paired/unpaired t-tests, significance was taken when P< 0.05. Results: Expression of Talin-1was detected in all tissues with various intensities. Compared with normal, ovarian HGSC tissues showed intense expression of Talin-1 in IHC, WB and qPCRs ( P< 0.05). Similar patterns were observed in serum levels in ELISA ( P< 0.01) in the exploratory study. Prospective study in hens showed significant increase in serum Talin-1 levels even before the formation of a solid tumor mass in the ovary or fimbria detectable by TVUS. Conclusions: Elevated Talin-1 expression in early-stage ovarian HGSC tumors suggests its association with malignant development. Serum prevalence of Talin-1 during malignant transformation makes it a potential marker for early detection of HGSC and its progression. These results will serve as foundation for a clinical study with larger cohorts. Support: NIH R01 CA210370 (AB)
Prognostic factors of stage I endometrioid or clear cell or mucinous ovarian cancer: Analysis based on surveillance, epidemiology, and end result program, 2000-2016.
Authors: Li Jing , Lin Zhongqiu , Qiao Huimin , Wang Lijuan , Liu Yunyun , Lu Huaiwu
Published: June 2022

e17589

Background: Endometrioid (EEOC), clear cell (OCCC) or mucinous ovarian cancer (MOC) had the highest incidence of Less Common Ovarian Cancers (LCOC). The benefit of adjuvant chemotherapy, lymphadenectomy or fertility-sparing surgery (FSS) for Stage I of these rare cancers remains unclear. Methods: We conducted a retrospective case-controlled study examining the Surveillance, Epidemiology, and End Result (SEER) database between 2000 and 2016. Propensity score matching is used to avoid the selection bias caused by the heterogeneity of demographic and clinical characteristics. Adjuvant chemotherapy or lymphadenectomy or fertility-sparing surgery on overall survival (OS) was compared with log-rank tests. A univariate and multivariate Cox analysis was performed to control for confounders. A nomogram was developed and the discriminatory ability of the model was analyzed. Results: The study identified 4,681 patients with FIGO stage I EEOC, 2,450 with stage I OCCC, and 2,839 with stage I MOC. After the propensity score matching, there was an equally comparable number of patients with or without adjuvant chemotherapy. The results showed that adjuvant chemotherapy could not prolong the 5-year OS of patients with stage I OCCC (86.7% vs. 85.9%, p = 0.732) and MOC (87.6% vs. 88.2%, p = 0.843). Adjuvant chemotherapy was associated with a 5-year OS benefit only in the subgroup of patients with substage IC, grade 3 EEOC (85.2% vs. 67.7%, p = 0.008). We also found that lymphadenectomy improved the 5-year OS of stage I EEOC (93.5% vs. 86.3%, P = 0.000), OCCC (87.8% vs. 82.8%, P = 0.040) and MOC patients (91.8% vs. 84.2%, P = 0.000). Furthermore, we observed that the 5-year OS raised in stage I EEOC (91.9%vs. 87.7%, P = 0.029) and OCCC (87.6% vs. 81.3%, P = 0.051) patients when conducted the non-fertility-sparing surgery (non-FSS) rather than the FSS. However, FSS did not significantly impact the 5-year OS of MOC patients (91.3% vs. 88.8%, P = 0.181). The nomogram survival prediction model showed that the area under the receiver operating characteristic (ROC) curve (AUC) was 0.650, 0.640 and 0.710 in EEOC, OCCC and MOC, respectively. The C-indexes for the OS were 0.666 (95%CI:0.638-0.694), 0.613 (95% CI:0.575-0.650) and 0.677 (95% CI:0.637-0.716), respectively. Conclusions: Adjuvant chemotherapy was associated with a 5-year OS benefit for patients with stage IC, grade 3 EEOC, but it was unnecessary for patients with stage I OCCC and MOC. Lymphadenectomy was associated with a survival benefit for these early cancer patients. FSS is appropriate for stage I MOC but needs to be discussed for stage I EEOC and OCCC. We constructed predictive nomograms to evaluate the OS of patients with stage I EEOC, OCCC or MOC, and it will provide an individualized evaluation of OS for suitable treatments.
Molecular classification of endometrial cancer of Chinese population.
Authors: Kang Nan , Wang Zhiqi , Gai Fei , Su Wenqing , Shen Danhua , Wang Jianliu
Published: June 2022

e17623

Background: Endometrial cancer (EC) is one of the most prevalent gynecologic tumors. Current diagnosis and treatment of EC no longer rely solely on traditional histopathological classification. Nevertheless, molecular classification of EC demonstrated clear prognostic value and may guide clinical decision. Methods: In this study, archived tissue specimens from 240 EC patients from Department of Pathology, Peking University People’s Hospital. Four subtypes [POLE ultramutated (POLE mut), microsatellite instability high (MSI-H), copy number low (CNL), and copy number high (CNH)] were stratified by next-generation sequencing (NGS) panel (Amoy Diagnostics, Xiamen, China) targeting POLE, TP53, BRCA1, and BRCA2 genes and microsatellite instability (MSI) status. Immunohistochemistry (IHC) was applied to detect the expression of P53, MMR and other related proteins. Results: Distribution of the EC subtypes in 240 patients was 13 (5.42%) of POLE mut, 36 (15.00%) of MSI-H, 41 (17.08%) of CNH, and 150 (62.50%) of CNL. Compared to published results of EC subtypes in Caucasian including TCGA, ProMisE as well as TransPORTEC, real-world data on Chinese ECs displayed a significantly larger proportion of CNL. In addition, novel biomarkers such as DUSP1, MCF7 and BUB1, which were independent prognostic marker from our previous research were validated. Also, it was found that BRCA2 appeared to be more prevalent in EC than BRCA1. Further analysis revealed that the overall consistency for NGS-based and IHC-based TP53 abnormalities detection and MSI/MMR status assessment were as high as 87.5% and 100%, respectively. Conclusions: Chinese ECs have unique molecular characteristics. In order to perform accurate molecular typing of Chinese ECs, more molecular indicators that match the characteristics of the Chinese population need to be added to the existing classifiers. NGS-based panel is easy to operate and replicate with high accuracy. Thus, it is a viable alternative to IHC in EC molecular classification.
Five years survival outcomes of head and neck cancer patients treated with palliative metronomic chemotherapy.
Authors: Naidu Priyanka Dhanraj , Patil Vijay Maruti , Noronha Vanita , Nawale Kavita Prakash , Dhumal Sachin Babanrao , Jogdhankar Shweta , Menon Nandini Sharrel , Prabhash Kumar
Published: June 2022

e18009

Background: Palliative metronomic chemotherapy improved overall survival over intravenous chemotherapy in head and neck cancers. However, there is no data available about the 5-year outcomes with this regimen. Methods: This was a single-arm prospective study that enrolled head and neck squamous cell carcinoma patients warranting palliative chemotherapy. The chemotherapy administered was methotrexate 15 mg/m2 per oral weekly and celecoxib 200 mg per oral daily till the development of intolerable side effects or progression. Kaplan Meier method was used for estimation of OS and factors impacting the same were sought. A p-value of 0.05 was considered significant. Results: 200 patients were enrolled with a median age was 49.5 years (Range 22-85 years) and preponderance of male gender (175, 87.5%). The predominant site of malignancy was oral cavity in 144 patients (72.2%). Prior chemotherapy exposure was present in 78 patients (39%). The median FACT trial outcome index score was 43.7 (16.7-80.7). The median OS was 194 days (95%CI 181.7-206.3) . The 1-year, 3-years and 5-years OS were 17 %(Standard error-2.8%), 7.9% (Standard error-2.5%), and 3.9% (Standard error- 2%) respectively. The details of factors impacting OS are given in Table. Conclusions: Oral metronomic chemotherapy leads to a small proportion of patients having long term survival with metronomic chemotherapy. Clinical trial information: CTRI/2015/11/006392. [Table: see text]
Nomogram to predict duration of clinical benefit from nivolumab in platinum resistant, recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Feeney Laura , Rack Samuel , Mistry Hitesh , Bola Becky , McPartlin Andrew , Sykes Andrew , Metcalf Robert
Published: June 2022

e18016

Background: Immune checkpoint blockade of the programmed death-1 receptor (PD1) with nivolumab improves survival for patients with platinum resistant recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, response rates are only 15-20% and the majority of patients do not have prolonged clinical benefit. Established predictive biomarkers such as PDL1 are not reliable in this context and there remain no reliable predictors of response to nivolumab in R/M HNSCC. We therefore sought to evaluate a panel of clinical, haematology and biochemistry parameters to develop a nomogram to predict the duration of clinical benefit following treatment with nivolumab. Methods: Ninety-one patients treated with nivolumab for R/M HNSCC were included. Nivolumab was administered as standard of care management and tumour response was evaluated every 8-12 weeks using CT or MRI. The electronic clinical records were reviewed and all clinical and demographic data were extracted in addition to baseline haematology and clinical biochemistry values. Using Cox proportional hazard analysis these variables were used to create a predictive model for duration of clinical benefit. Patients were dichotomised based upon duration on nivolumab treatment. Backwards elimination with a p-value threshold of 0.05 was used to create a predictive nomogram. For the final model, patients were assigned to two groups (< 3 months and ≥ 3 months on therapy) calculated from the date of first nivolumab dose to the date of discontinuation. Progression free survival (PFS) and overall survival (OS) were calculated from the date of the first dose of nivolumab. Results: Of the 91 patients, 82 had stopped treatment at the time of analysis with a median time on treatment of 2.5 months (95% CI 1.8 to 3.6). Median PFS was 3 months with 1-year PFS rate of 15%. Median OS was 9 months with 1 year OS rate of 40%. Multivariable analysis identified multiple pre-treatment factors that correlate with time on treatment; age (HR 0.97; 95% CI 0.93-1.00, p = 0.029), oropharyngeal tumour location (HR 0.51; 95% CI 0.31-0.85, p = 0.01), N stage (HR 1.84; 95% CI 0.97-3.5, p = 0.061), M stage (HR 2.44; 95% CI 1.27-4.7, p = 0.007), and pre-treatment peripheral blood markers which included monocyte count (HR 2.83; 95% CI 1.05-7.6, p = 0.04), sodium (HR 0.94; 95% CI 0.88-1.00, p = 0.057) and calcium (HR 7.6; 95% CI 1.46-39.7, p = 0.016) levels. These were included in the final nomogram which had a concordance index of 0.69. Conclusions: We have developed a novel nomogram to predict the duration of clinical benefit from nivolumab in platinum resistant R/M HNSCC for subsequent independent validation. This may assist clinicians in counselling patients and clinical decision making and could also be used to identifying poor responders for whom alternative treatment options are required.
Factors associated with recurrence in oral cavity squamous cell carcinoma: A real-world experience from an Indian comprehensive cancer center.
Authors: Sood Siddharth , Mehta Prashant , Sharma Sakshi , Badola Amit
Published: June 2022

e18018

Background: Oral cavity squamous cell carcinoma (OCSCC) is the third most common malignancies in India with an estimated 72,000 deaths annually. The incidence is increasing owing to rising alcohol and tobacco consumption in last 2 decades. Methods: We performed a retrospective cohort study in patients with OCSCC to identify risk factors for local and metastatic recurrences following definitive treatment including surgery and/or radiation therapy or chemotherapy or both at our institute. Patient records were screened from 2016 till 2021. Eligible patients were followed up for disease status and outcome. Data included sociodemographic details, substance use, tumor differentiation, stage at diagnosis, LVI, PNI, margin status, treatment details and site of recurrence. All statistical analysis was performed on Microsoft excel 2016 and Jamovi version 1.6.23.0. Results: Out of 195 patients files screened, 90 were available for analysis. Demographic details, substance use pattern and tumor profile are highlighted in table. Tongue was the most frequent site involved and most of the tumors were well to moderately differentiated. Majority of the patients presented as locally advanced disease (Stage IVa). LVI and PNI were identified in 5.75% and 29.89% patients respectively while one of the patients had a positive margin after resection. Surgery followed by adjuvant chemo-radiation was the most frequently prescribed treatment (n = 46; 52.8%) whereas 27.59% patients (n = 24) underwent surgery alone. Fifty six (63.3%) patients experienced recurrence out of which 50% were local and 35% were metastatic recurrences. On multivariate analysis, the predictors of disease recurrence were male gender (OR- 3.2; 95% CI- 1.02-10.05; p-0.05), tobacco and alcohol use (OR- 1.93; 95% CI- 0.8-4.6; p- 0.14 and OR- 2.16; 95% CI- 0.82-5.65; p- 0.12 respectively), Stage IVb disease (OR- > 10; 95% CI- 0-10; p-1.0), presence of PNI (OR- 1.39 ; 95% CI- 0.55-3.70; p-0.497) and presence of LVI (OR- 2.54; 95% CI- 0.36-50.8; p- 0.414). Median disease free survival and overall survival of the cohort was 11.3 months and 15 months respectively. Advanced stage, tobacco consumption, presence of LVI and PNI negatively affected overall survival in our cohort. Conclusions: Oral cavity squamous cell carcinoma is among the most preventable malignancies and they contribute to significant morbidity and mortality. This study highlights the role of early detection and management of such patients. Patients may still experience disease recurrence after initial management which may be difficult to treat. Such patients should be encouraged to participate in a clinical trial as treatment options for recurrent disease are limited.[Table: see text]
Efficacy and tolerability of a low dose weekly paclitaxel, carboplatin, cetuximab (PCC) regimen for metastatic or unresectable head and neck squamous cell carcinomas.
Authors: Locke Margaret , Kohn Nina , Seetharamu Nagashree
Published: June 2022

e18019

Background: The standard of care for metastatic or unresectable head and neck squamous cell cancers (HNSCCs) is 5-FU and a platinum doublet with cetuximab or pembrolizumab. However, these regimens are cumbersome as they involve hospitalization for continuous 5-FU infusion and carry a high toxicity profile. In addition, many patients are unfit for this regimen due to poor performance status (PS) or comorbidities. An alternative is paclitaxel, carboplatin, and cetuximab (PCC). PCC has been shown to be a promising induction regimen in small, mostly retrospective studies. Also, low dose chemotherapy may improve tolerability. Our study evaluates the tolerability and efficacy of low dose PCC with or without concurrent palliative radiation therapy (RT) in patients with metastatic or unresectable HNSCCs. Methods: This retrospective observational study included 40 patients with metastatic or unresectable HNSCCs at a single academic center who received PCC between August 2017 and January 2022. Included patients were not candidates for standard frontline therapies due to either PS, comorbidities, prior progression on these therapies, plan for RT, or patient preference. Chart review was performed to grade adverse events (AEs) according to CTCAE criteria. Progression free survival (PFS), overall survival (OS), and response to treatment were assessed per RECIST 1.1 guidelines. Results: Of the 40 patients, mean age was 69.6 years (SD 15.4), and 82.5% were male. Common primary sites were oral (13, 32.5%), oropharynx (12, 30%), hypopharynx (4, 10%), and sinus (4, 10%). Most patients had Stage IVa disease (16, 40%) followed by IVc (12, 30%) and IVb (6, 15%). The remainder (6, 15%) had stage III or unknown stage. Patients received weekly paclitaxel (30-50 mg/m2), carboplatin (AUC 1.5-2), and cetuximab 400 mg/m2 loading followed by 250 mg/m2 maintenance dose. 8 patients (20%) received concurrent RT. Most were treated with palliative intent (32, 80%) and a few induction intent (8, 20%). Prior to PCC, 11 patients had prior salvage surgery, 19 prior RT, and 18 prior systemic therapy. Baseline ECOG PS was 0-2 in 37 patients (92.5%). The most common AEs were skin rash (27, 67.5%), fatigue (22, 55%), and mucositis (12, 30%). 7 patients (17.5%) experienced a grade 3-4 AE, which were mostly hematologic. 2 of the 8 patients on concurrent RT experienced a grade 3-4 AE. 5 patients (12.5%) stopped PCC treatment due to toxicities. 8 patients (20%) had progression on initial follow up imaging. Median duration of response was 4.3 months. PFS was 7.8 months. Median OS was 19.2 months. Conclusions: Our study supports the use of PCC in metastatic or unresectable HNSCCs. This regimen can be considered in patients with suboptimal PS who are not candidates for standard frontline therapies or for those planned for palliative RT. PCC can be used safely and effectively with or without concurrent RT.
Anlotinib for patients with recurrent or metastatic nasopharyngeal carcinoma: A phase II study.
Authors: Cai Qingqing , SU Ning , Fang Yu , Zou Qihua , Xia Yi , Ma Shuyun , Cai Jun , Liu PanPan , Wang Jinni , Zhang Yuchen
Published: June 2022

e18020

Background: The prognosis of patients (pts) with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) is poor, especially for those who had failed two or more lines of prior systemic therapy. Anlotinib is a novel tyrosine kinase inhibitor that can inhibit tumor angiogenesis and proliferation by targeting VEGFR, FGFR, PDGFR, and c-Kit. A prospective, single-arm, phase 2 trial (NCT03906058) was performed to assess the efficacy and safety of single-agent anlotinib against R/M NPC and here we report the final results of this study. Methods: Eligible pts were aged 18-70 years old, diagnosed with histologically confirmed R/M NPC, had at least one measurable lesion and failed at least two lines of prior systemic treatments including chemotherapy, targeted therapy, or immunotherapy. Anlotinib was administered at 12 mg QD orally from day 1 to day 14 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was confirmed disease control rate (DCR). The second endpoints included confirmed objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Tumor response was assessed according to RECIST 1.1 and adverse events were assessed according to NCI-CTCAE v5.0. Results: From April 2019 to March 2021, 39 pts were enrolled. 33 were male and 6 were female. The median age was 46.7 years (range, 20-64). 24 pts (61.5%) had liver metastasis. 29 pts (74.4%) had previously received 2 lines of systemic treatments and others received 3 or more. 19 pts (48.7%) pts had been exposed to anti-PD-1 immunotherapy. The median treatment duration of anlotinib was 4 cycles (range, 0.5-20). At the data cutoff date of Feb.1st 2022, 36 pts have underwent tumor response evaluation and the best response to anlotinib was partial response for 8 pts and stable disease for 20 pts. The DCR was 77.8% and ORR was 22.2%. 28 patients have progressed. For the intent-to-treat population, the median PFS was 5.7 months (95% CI: 4.7-6.7). 21 pts have died and the median OS was 23.9 months (95% CI: 5.3-42.5). The most common treatment-related adverse event (TRAE) of any grade was hand-foot syndrome (HFS) (24 pts). Grade 3 TRAEs included HFS (9 pts), mucositis (7 pts), hypertension (21 pts), liver dysfunction (2 pts) and pneumonia (1 pts). Only one grade 4 TRAE (mucositis) was reported and no treatment-related death was observed. 13 pts experienced hemorrhage, all were grade 1 or 2. Conclusions: Anlotinib monotherapy seemed to be a promising option for pts with R/M NPC who were heavily treated. The survival benefits were impressive and the toxicity was tolerable. Clinical trial information: NCT03906058.
Long-term outcomes of phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early failure oral cancer.
Authors: Dhumal Sachin Babanrao , Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Nawale Kavita Prakash , Mahimkar Manoj , Prabhash Kumar
Published: June 2022

e18021

Background: Triple metronomic chemotherapy is one of the options of treatment in platinum-refractory/early failure oral cancer. However long term outcomes with this regimen are unknown. Methods: Adult patients with platinum-refractory/early failure oral cancer were enrolled in the study. Patients were administered erlotinib 150 mg once daily celecoxib 200 mg twice daily and methotrexate weekly (phase 1 in variable dose 15-6 mg/m2 & 9 mg/m2 in phase 2), all taken orally till progression of disease or development of intolerable adverse events. The primary objective was to estimate the long term overall survival and factors impacting it. Kaplan Meier method was used for time to event analysis. COX proportional hazard model was used to identify factors impacting OS and PFS. The factors included in the model were age, gender, ECOG PS, tobacco exposure, a subsite of primary and circulating endothelial cell levels at baseline. A p-value of 0.05 was considered significant. Results: A total of 91 patients were recruited (15 in phase 1 & 76 in phase 2), the median follow-up was 41 months and 84 events of death had occurred. The median OS was 6.67 months (95%CI 5.43-7.37). The 1-year, 2-years and 3-years OS were 14.07% (95%CI 7.75-22.2), 5.86% (95%CI 2.18-12.2) and 5.86% (95%CI 2.18-12.2) respectively. The only factor favourably impacting OS was the detection of circulating endothelial cells at baseline (HR = 0.459; 95%CI 0.28 -0.753, P = 0.002). The median PFS was 4.3 months (95%CI 4.1-5.1) and the 1-year PFS was 12.97% (95%CI 6.8-21.2). The factors with statistically significant impact on PFS were detection of circulating endothelial cells at baseline (HR = 0.479; 95%CI 0.3 -0.775, P = 0.002) and tobacco exposure at baseline (HR = 0.505; 95%CI 0.272 -0.937, P = 0.03). Conclusions: The long term outcomes with triple oral metronomic chemotherapy with erlotinib, methotrexate and celecoxib are unsatisfactory. Detection of circulating endothelial cells at baseline is a biomarker predicting efficacy of this therapy. Clinical trial information: CTRI/2016/04/006834..
Impacts of hepatitis b infection in patients with head and neck squamous carcinoma.
Authors: Lai Cheng-Lun , Su Yu-Chen , Lin Cheng-Hsien , Chou Cheng-wei
Published: June 2022

e18051

Background: Hepatitis B Virus (HBV) infection was known to be have impacts of occurrence and survival in different malignancies. We aim to evaluate the clinical association with head and neck squamous cell cancer (HNSCC) and HBV infection. Methods: A retrospective review was conducted on the medical records and cancer registry database at the Taichung Veterans General Hospital (Taichung, Taiwan) between January 2007 and December 2015. Patients with histologically proven squamous cell carcinoma of oral cavity, oropharynx, hypopharynx and larynx were enrolled in the study. HBV infection was defined as HBsAg seropositivity. Clinical features, hepatic function test and five-year overall survival (OS) were compared between patients with and without HBV infection. Results: A total of 1826 HNSCC patients were analyzed. 225 of them (12.3%) were proved HBV-infected. The HBV-infected patients was diagnosed at younger age (< 65 years; 76.1% vs. 65.5%, p< 0.012) and had a higher proportion of initial liver cirrhosis (11.6% vs. 3.6%, p< 0.001) and hepatic dysfunction (10.7% vs. 6.1%, p= 0.009) included elevation of alanine transaminase (ALT), aspartate transaminase (AST) and prothrombin time expressed as international normalized ratio (INR). The other baseline characteristics were similar. The five-year OS were 52.9% and 48.6% in the HNSCC patients with or without HBV infection, respectively ( p= 0.341). The incidence of later founded hepatic dysfunction during follow-up was similar (31.1% vs 26.2%, p= 0.122). Conclusions: Information from this study indicated that HBV-infected HNSCC patients may present in younger age, more initial liver cirrhosis, and hepatic dysfunction. However, HBV infection did not have negative impacts on survival outcome and later founded hepatic dysfunction in those patients. Characteristics and survival of HBsAg (+) vs. HBsAg (-) HNSCC Patients[Table: see text]