bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravesical therapy with the trifunctional anti-EpCAM/CD3 bsAb Catumaxomab is well tolerated and shows encouraging preliminary efficacy in patients with high-risk NMIBC (CATUNIBLA phase I trial).
Authors: Albert Felix , Antoniewicz Aleksander , Grantzow Tobias , Fingerle-Rowson Guenter , Ruf Peter , Lindhofer Horst , Kriegmair Maximilian , Oberneder Ralph
Published: June 2022

e16555

Background: Tx of high-risk NMIBC is challenging due to a high risk of recurrence. Novel therapeutic options are highly anticipated to avoid cystectomy and disease progression. Malignant transitional cells express EpCAM. The trifunctional anti-EpCAM/CD3 bsAb Catumaxomab (CAT) mediates cell killing against human BC. This dose escalating Phase I trial (NCT04819399) investigates the safety of intravesical CAT in high-risk NMIBC. Methods: Following first TUR-B, pts with newly diagnosed high-risk NMIBC were enrolled and received 6 x weekly intravesical CAT instillations, each of 2h duration) at a dose of 50 or 70μg. Subsequently, 2nd TUR-B and adjuvant instillation therapy (tx) was performed as SoC. Here, we report the safety and preliminary efficacy of dose cohorts 1 and 2. Results: 7 Pts are included, 5 with pTa, 2 with pT1 disease. There were 5 concomitant pTis. 6/7 pts received the planned 6 x weekly CAT instillations. 1 pt discontinued after 1 instillation due to recurrent UTI. No DLTs occurred. 28 AEs were observed in 6/7 pts, all of gr 1-2 except two unrelated gr 3 AEs . 2/7 pts had an unrelated SAE each (1 hydronephrosis, 1 recurrent fever after BCG). For 6/7 pts cytokines were below LLQ. In one pt of cohort 2 low amounts of IL-6 and IL-8 were detectable. Weak HAMA responses in 5/6 pts transiently occurred at days 29 and 43. CAT instillations led to transient increases of urinary leukocytes. During and after CAT treatment, there was a strong trend towards reduction of EpCAM+ cells in urine. At 2nd TUR-B tumour persistency was observed in two patients only. Remarkably, 3/5 pTis were no longer detected at 2nd TUR-B. So far, 5/7 pts received adjuvant BCG, 2 pts declined. 7/7 pts achieved CR as best response. While 2/3 pts in the 50 μg cohort had a recurrence, no recurrence was observed in the 70 μg cohort. Conclusions: Intravesical instillations with the trifunctional, anti-EpCAM/anti-CD3 bsAb Catumaxomab are well tolerated in pts with high risk NMIBC. CAT does not enter systemic circulation and elicits only low and transient immunogenicity. The MTD is not reached and dose escalation is still ongoing with cohort 3 (100 μg)(updated results will be presented at meeting). The reduction in EpCAM+ urine cells indicates potential activity of this novel immunotherapy and the high CR rate of Tis at the end of CAT therapy is promising. Clinical trial information: NCT04819399. [Table: see text]
Endoscopic balloon cryoablation against single instillation after transurethral resection of bladder cancer: A multicenter, randomized, controlled noninferiority trial.
Authors: Xu Chenyang , Jiang Haowen , Guo Jianming , Shi Guowei , Xu Danfeng
Published: June 2022

e16561

Background: Cryotherapy is a prevalent percutaneous ablative therapy for solid tumors. However, studies on the clinical practice of endoscopic cryotherapy for intraluminal malignancies are lacking. We aim to explore the feasibility of endoscopic cryotherapy for bladder cancer. Methods: In this multicenter, randomized, parallel controlled, non-inferiority trial, we compared endoscopic balloon cryoablation (EBCA) with a single instillation (SI) of pirarubicin after transurethral resection (TUR).Men or women aged 18-85 years with a clinical diagnosis of bladder cancer (tumor number no more than 3 and maximal tumor size no more than 3 cm) were included. The exclusion criteria were as follows: locally advanced urinary bladder cancer (clinical stage T3 or T4), lymph node involvement (N1) or distant metastasis (M1), severe organ dysfunction, severe coagulation disorder, sepsis, concomitant neoplastic malignancy and other conditions unsuitable for surgery or intravesical chemotherapy. Women in pregnancy or lactation were also excluded. Eligible participants were randomly assigned (1:1) to the TUR-EBCA or TUR-SI group. The primary endpoint was the residual-free rate at repeated TUR. A non-inferiority test was used to compare the primary endpoint with a chosen margin of 10%. The secondary endpoints included the recurrence-free survival (RFS), progression-free survival (PFS) and adverse events. Results: We recruited 227 participants between November, 2017, and September, 2020. In total, 205 patients received EBCA or SI after TUR, of whom 163 completed all the required interventions and follow-up. In the per-protocol analyses, 75 (91.5%) of 82 patients had no residual tumor in the TUR-EBCA group compared with 61 (76.5%) of 81 in the TUR-SI group (risk difference 14.9%; 95% confidence interval [CI] 0.03 to 0.27, P < 0.001), meeting the criteria for non-inferiority. Similar results were found in the after intention-to-treat analysis. After a median follow-up of 21 months, the TUR-EBCA group had better RFS(HR = 0.49; 95% confidence interval [CI] 0.24 to 0.99; Log-rank P = 0.046) and PFS (HR = 0.25; 95% confidence interval [CI] 0.08 to 0.77; Log-rank P = 0.0092). There were no significant differences in the SAEs rate (3.0% vs. 3.9%, p = 0.52). Conclusions: EBCA is a safe and effective adjuvant alternative to TUR for bladder cancer with the potential advantage of “energetically resecting” the tumor base. Clinical trial information: NCT02760953.
An extracellular vesicle-based assay for noninvasive detection of metastases and monitoring prostate cancer.
Authors: Wang Jasmine Jiemei , Sun Na , Lee Yi-Te , Kim Minhyung , You Sungyong , Di Vizio Dolores , Tseng Hsian-Rong , Chen Jie-Fu , Zhu Yazhen , Posadas Edwin Melencio
Published: June 2022

e17004

Background: Optimizing outcomes in prostate cancer (PCa) requires timely detect of metastatic progression of prostate cancer patients. We aim to optimize an extracellular vesicle (EV)-based Digital Scoring Assay for detecting PCa metastasis and noninvasive monitoring disease progression. Methods: PCa EV Digital Scoring Assay was developed by combining EV Click Chip, a nanotechnology-enabled microfluidic device for purifying PCa-derived EV and reverse-transcription droplet digital PCR for profiling disease-relevant mRNAs. A panel of 11 PCa-relevant mRNA markers were selected from The Tissue Atlas and a blood-based biomarker study. Plasma samples from 20 localized, 20 metastatic PCa patients, and serial plasma from three PCa patients were used to assess the performance of PCa EV Digital Scoring Assay with the 11-gene panel. mRNA expression of the panel was computed using weighted Z score method. ROC analysis was applied to discriminate localized from metastatic PCa. Results: After optimization, the capability of EV Click Chips (92.5 ± 5.4%) for capturing PCa-derived EVs from artificial plasma samples spiked with EVs outperformed ultracentrifugation (41.0 ± 3.2%) or precipitation methods (34.9± 2.2%; P< 0.001). Strong signals of the 11-gene panel, i.e., ACP3, FOLH1, HOXB13, KLK2, KLK3, KLK4, MSMB, RLN1, SLC45A3, STEAP2, and TMPRSS2, were detected from three PCa cells (LNCaP, C4-2B, and 22Rv1) and their derived EVs, while rare signals were detected in either WBCs or EVs purified from male healthy donor. In the clinical study, the Z scores calculated from the 11-gene panel were significantly higher in metastatic than localized PCa with an area under the ROC curve of 0.88 (95% CI: 0.78-0.98). Finally, longitudinal analyses of three PCa patients with clinical progression, response, and stable diseases, respectively, showed the Z scores can precisely reflect the disease status even when it is undetectable by imaging. Conclusions: We demonstrate a sensitive PCa EV Digital Scoring Assay to identify metastatic PCa and dynamically monitor disease states in a noninvasive manner. This assay may augment current imaging tools for timely detection of PCa progression and provide a means to better personalized care.
Pan-cancer analysis of BRAF alterations and tumor-specific mechanisms of activation.
Authors: Bergom Hannah E. , Toye Eamon P. , Shi Xiaolei , Ryan Charles J. , Antonarakis Emmanuel S. , Hwang Justin
Published: June 2022

e17005

Background: BRAF is a proto-oncogene that is altered in various cancers and is a druggable target. Particularly, the selective BRAF kinase inhibitors Dabrafenib and Vemurafenib are FDA approved for melanoma and thyroid cancer that harbor the activating BRAF V600 hotspot mutations. In pre-clinical studies, activated BRAF promotes tumor cell function across many additional cancer types in which therapeutics have not been considered. We propose that identifying BRAF-activated cancers will guide future pre-clinical investigations and potentially expand the usage of existing BRAF-targeting therapeutics. Methods: We utilized bioinformatics to investigate the molecular profiles of pan-cancer cohorts from two platforms based on distinct sequencing technology. This included a custom curated dataset (whole exome, 6 studies, 39 cancer types, n = 12,019) and GENIE9.1 (targeted gene panel, 62 cancer types, n = 78,619). Studies were included based on genomic modalities (copy number alterations, mutations, gene fusions). We cataloged the frequency and all types of BRAF genomic alterations pan-cancer. We also examined other genomic features, including tumor mutational burden (TMB) and fraction of the genome altered (FGA), and their association with types of BRAF alterations across cancer types. Results: In both platforms, we found that BRAF alterations were observed across over 80% of cancer types. Melanoma, thyroid, and colorectal tumors exhibited the greatest rates of mutations. Regarding gene body rearrangements, we noted endocrine-driven cancers including ovarian and metastatic prostate tumors (mPC) exhibited relative robust rates of amplification. In addition, thyroid carcinoma and mPC harbored recurrent BRAF gene fusion events. In mPC, we found that the BRAF gene fusions often included an N-terminus gene fragment from known androgen-target genes (TMPRSS2 and SND1). These fusion events represented a dysregulated hormone-driven mechanism of BRAF activation. We also found that hotspot missense mutations were cancer-type specific, including K601 hotspots in mPC, G469 hotspots in non-small cell lung cancers, and G466 hotspots in ovarian cancers. Lastly, BRAF-amplified endocrine tumors harbored a 1.5-fold increase in FGA medians, whereas BRAF-mutated lung and colorectal tumors exhibited a 1.6-fold increase in TMB medians. Conclusions: Our molecular analysis revealed that cancers accrued activated BRAF through cancer-type-specific and divergent genomic mechanisms. These molecular features provide genomic evidence to expand the application of BRAF-targeted therapies in additional cancer lineages, including mPC. BRAF mutations were also associated with genomic biomarkers, such as TMB, which may predict response to immune therapies. This suggests that BRAF alterations can be considered as an additional feature to aid therapy selection.
Phase II therapeutic equivalence study of Abiraterone Acetate Tablets (I) vs. ZYTIGA® in patients with metastatic castration-resistant prostate cancer.
Authors: Ye Dingwei , Bian Xiaojie , Han Weiqing , Wu Bin , Chen Hui , Wu Jitao , Yu Dexin , Ge Huixin , Li Jian , Huang Houbao , Fan Tiwu , Cheng Linzhong , Zhang Xiaoping , Zhang Xuepei , Yao Xin , Wei Junli , Xu Zhenqiang , Mu Peilei , Huang Rong , Wang Huan
Published: June 2022

e17040

Background: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the originator abiraterone acetate (ZYTIGA) is observed to be with relatively low bioavailability and high pharmacokinetic variability. Abiraterone Acetate Tablets (I), in which Sodium N-[8-(2-hydroxy-benzoyl) amino] caprylate (SNAC) was added in the formulation as an absorption enhancer, was therefore developed by using nanocrystal technology to enhance the dissolution rate of pharmaceutical compounds, leading to the improvement of the low oral bioavailability and significant food effects. Methods: Patients with mCRPC were randomized (1:1) to receive either Abiraterone Acetate Tablets (I) 300 mg daily plus 5 mg prednisone orally twice daily, or ZYTIGA 1000 mg once daily plus 5 mg prednisone orally twice daily for 84 days. The primary endpoint was serum testosterone concentration (Day 9/10). Secondary endpoints included serum prostate-specific antigen (PSA), pharmacokinetics and adverse events. Results: 68 patients with a median age of 71 (52-84 yrs) (n = 34 in each group) were enrolled in the full analysis set (FAS). The least square geometric mean of Day 9/10 serum testosterone concentration (rounded-up by 1 ng/dl) in Abiraterone Acetate Tablets (I) and ZYTIGA groups was 1.053 (95% CI, 1.006-1.102) and 1.000 (95% CI, 0.956-1.046), respectively. The geometric mean ratio between two groups was 1.053 (90% CI, 0.998-1.110) and the 90% CI fell within 80.0% to 125.0% equivalence limits. The PSA-50 response rate was also similar on Days 28, 56 and 84 (46.9% vs 50.0%, 65.6% vs 57.6%, 71.9% vs 67.7%). Compared with ZYTIGAlabel, no new safety concerns were observed in Abiraterone Acetate Tablets (I). In addition, Abiraterone Acetate Tablets (I) group was observed to be with lower frequency of treatment-emergent adverse events (TEAEs) of any grade (76.5% vs 85.7%), grade ≥3 TEAEs (8.8% vs 22.9%), and grade ≥3 treatment-related adverse events (TRAEs) (5.9% vs 14.3%). Conclusions: Therapeutic equivalence between Abiraterone Acetate Tablets (I) 300 mg and ZYTIGA 1000 mg was confirmed by Day 9/10 serum testosterone concentration in mCRPC patients. Abiraterone Acetate Tablets (I) also showed a trend of improvement in safety profile. Clinical trial information: NCT04862091.
National trends in incidence of prostate cancer by age, ethnicity, region, and rurality from 2000-2018: An analysis of US NPCR Database.
Authors: Somasundaram Eashwar , Lang Jacob , Jambunathan Sree , Hadziahmetovic Mersiha , Ukaegbu Oke Oluchi , Petros Firas G. , Ekwenna Obi
Published: June 2022

e17054

Background: Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related death among males in the United States. Screening recommendations and treatments for PC have changed considerably over the past two decades, with differential effects across sociodemographic groups. This study aims to characterize trends in incidence of PC from 2000 to 2018 by age, race, region, and rurality to better understand these effects on incidence. Methods: Data were obtained from the National Program of Cancer Registries (NPCR), which represents patients for all 50 states. Incidence rates and average annual percent change (AAPC) were calculated using SEER*Stat software. Incident rates were calculated as the number of new cancers arising in the prostate (ICD-O-3 Site Code: C619) per 100,000 males. Trends across sociodemographic groups were analyzed and visualized in R. Results: PC incidence decreased significantly for all ages 40 and above from 2000 to 2018. Ages 85+ experienced the sharpest decline with an AAPC of -5.5% (95% CI: -6.0% to -5.1%). However, for all 5-year age brackets between 60 and 85, incidence reaches a minimum in 2014 before rising again as shown by segmented regression analysis. All race/ethnicity groups experienced a significant decline in incidence from 2000 to 2018 with sharpest decline in Hispanics -3.9% (95% CI: -4.5% to -3.3%). All regions also experienced a significant decline, with the greatest decline in the West at -4.0 (95% CI: -4.7 to -3.3). Metropolitan counties experienced a greater decline than nonmetropolitan. Patients ages 65 to 79, of Black race/ethnicity, and metropolitan groups had the highest overall incidence over the study period in their respective categories with 2018 incidences of 663, 181, and 115 per 100,000 males respectively. Conclusions: Nearly all sociodemographic groups have experienced a decline in the incidence of PC from 2000 to 2018. However, PC incidence increased from 2014 to 2018 for several sociodemographic groups. Importantly, 65 to 79 year olds, Black Americans, and metropolitan groups had the highest incidence over the study period. This study demonstrates a sustained rise in incidence of PC for several sociodemographic groups, as well as identifies groups at higher risk of PC. These trends may be due to evolving PC screening guidelines and merit further investigation.
ctDNA in treatment response monitoring in patients with relapsed gynecologic malignancies.
Authors: Williams Jason Russell , Grzankowski Kassondra , Castaneda Kayla , Saldivar Jose Salvador , Diaz-Arrastia Concepcion , Azzi Georges , Sindhu Hemant , Chae Young Kwang , Kalashnikova Ekaterina , Nicosia Brittany , Tekula Shilpa , George Giby V. , Malhotra Meenakshi , ElNaggar Adam , Aleshin Alexey
Published: June 2022

e17501

Background: The role of immunotherapy in gynecologic malignancies continues to evolve. Use of immune checkpoint blockade (ICB) agents have consistently demonstrated less than a 15% response rate in ovarian, cervical, and subsets of endometrial cancer. Given the limited number of responders, a novel approach to treatment monitoring is needed to better sequence therapies. Circulating tumor DNA (ctDNA) surveillance in patients treated with ICB is one such approach that has been shown to predict clinical benefit. We sought to evaluate this approach in patients with recurrent gynecologic malignancies managed with ICB therapy. Methods: In this retrospective analysis of real-world data, plasma samples (n = 208) from 28 patients with recurrent/metastatic ovarian (n = 8), endometrial (n = 14), and cervical (n = 6) cancers were identified as having received ICB therapy. A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection of ctDNA in plasma samples. Serial time points were collected to monitor ctDNA levels in response to immunotherapy. Results: Response assessment results and longitudinal plasma samples were available for 19 patients. Pre-ICB plasma samples were available for 11 patients. Of these ctDNA was detected in 73% (8/11) of patients. All patients with progressive disease (10/10) had rising ctDNA levels that preceded radiological findings by a median of 2.8 months. One patient with rising ctDNA concentration presented with stable disease by imaging at the last follow-up. The remaining 8 patients demonstrated response to therapy that coincided with a declining or negative ctDNA level; 5 with partial response had a decline in ctDNA level prior to imaging (n = 3) or lack of ctDNA detection (n = 2), and 3 with complete response remained ctDNA negative, prior to imaging. Patients that exhibited a rise in ctDNA concentration (n = 11) (consecutive time points) while undergoing ICB therapy were associated with resistance to treatment (HR = 4.58 95%CI: 1.048-20.03, p = 0.04). TMB and MSI status (binary) were not predictive of response in univariate (p = 0.8, p = 0.9) analyses. Conclusions: ctDNA monitoring during the course of immunotherapy for relapsed gynecologic malignancies allows for accurate determination of therapeutic response and early prediction of disease progression. This enables timely assessment with imaging, and change in treatment plan. Our data suggest that patients with gynecologic malignancies may benefit from personalized, tumor-informed ctDNA testing to guide treatment decisions. Prospective studies are needed to establish the clinical utility of ctDNA monitoring in patients with gynecologic malignancies undergoing systemic therapies.
Impact of Silva classification system on the survival of HPV-related cervical adenocarcinoma patients with stage I ̃ IIIc1p.
Authors: Li Jiehui , Li Fenghu , Junyu Mu , Li Ran , Mei Fan , Hu Lili , Du Yanjun , Tian Xue , Wei Hong , Yang Feiyue , Wanli Mao , Yao Qin , Meng Li , Shuishui Yin
Published: June 2022

e17505

Background: The incidence of cervical adenocarcinoma is increasing progressively in recent years and shows a younger trend that seriously threatens human health. However, the conventional pathological type of cervical adenocarcinoma is insufficient to predict the prognosis and therapeutic effect. Recently,the Silva classification system, a new pathological classification system was introduced and considered to have a better potential impact on the survival of HPV-related cervical adenocarcinoma patients. Methods: The clinical data of 102 patients with cervical adenocarcinoma from January 2010 to September 2021 were retrospectively included. All patients underwent radical resection of cervical cancer and were diagnosed as cervical adenocarci.noma by pathology.The HE staining sections of the patients were divided into SilvaA, SilvaB, and SilvaC types according to the Silva typing system. SPSS26.0 software was used for statistical analysis, Kaplan-Meier calculation was used for single-factor analysis, and COX stepwise regression model was used for multi-factor analysis. Results: Of the 102 patients with cervical adenocarcinoma who could be graded according to the Silva system, 14 (13.7%, 14/102) were SilvaA, 23 (22.5%, 23/102) SilvaB, and 65 (63.8%, 65/102) SilvaC. SilvaA type cervical adenocarcinoma patients were all stage I (IB1-IB3), no lymphatic or vascular invasion, and all patients were in a survival state by the end of follow-up. All patients with SilvaB cervical adenocarcinoma were stage I (IA2-IB3), without lymphatic or vascular invasion. Among 23 patients with Silva B, 2 patients died due to tumor, and the 5-year PFS and OS were 91.3%. Sixty-five patients with SilvaC type cervical adenocarcinoma (IB1-IIIC1P) and 15 patients died of tumor-related causes. FIGO stage, tumor size, lymph node invasion, and paralegal invasion were the influencing factors for survival and prognosis of SilvaC patients (P <0.05). Conclusions: In the Silva typing system, SilvaC type has the worst prognosis, SilvaA type and SilvaB type are both stages I, without lymph node invasion, and the prognosis is better. Patients with SilvaC type are at the Ib1-IIIC1P stage and may have a lymphatic and vascular invasion. Late FIGO stage, lymph node metastasis, and paralegal infiltration are the influencing factors for survival and prognosis of SilvaC type.
Salvage high-intensity focused ultrasound for residual or recurrent cervical cancer after definitive chemoradiotherapy.
Authors: Tang Fei , Zhong Qin , Ni Tingting , Chen Yanping , Liu Yuncong , Wu Jing , Feng Zhiyu , Lu Xiaokai , Tan Shisheng , Zhang Yu
Published: June 2022

e17524

Background: Approximately 30%-65% of patients have residual disease or subsequent recurrence after completion of chemoradiotherapy (CRT) treatment. The treatment of residual/recurrent cervical cancer in previously irradiated field is challenging and generally associated with a poor prognosis. Local treatments such as salvage surgery and re-irradiation are usually traumatic and have limited efficacy. High intensity focused ultrasound (HIFU) treatment can directly ablate solid tumors without damaging neighboring healthy tissue. However, the HIFU studies for these patients are limited. Over 10 years of experience gained with the management of HIFU in cervical cancer patients with residual disease or recurrence after CRT is reported here. Methods: 153 patients with residual or recurrent cervical cancer in previously irradiated field who received HIFU treatment between 2010 and 2021 were retrospectively analyzed. Adverse effects, survival benefit, and factors affecting prognosis were given particular attention. Results: A total of 36 patients (23.5%) achieved a partial response following HIFU treatment and 107 patients (69.9%) had stable disease. The objective response and disease control rates were 23.5% and 93.5%, respectively. The median progression-free survival (mPFS) and median overall survival (mOS) were 17.0 months and 24.5 months, respectively. Moreover, patients with lesions ≥ 1.40 cm before HIFU treatment and a shrinkage rate ≥ 30% after treatment had a higher mPFS and mOS, and patients with lesions ≤ 1.00 cm after HIFU treatment had a higher mPFS (P < 0.05). All of the treatment-related adverse events were limited to minor complications, which included skin burns, abdominal pain and vaginal discharge. Conclusions: Many cervical cancer patients have few efficacious treatment options following chemoradiotherapy. This study demonstrates that HIFU treatment is likely a preferred option that can safely improve the local control rate and extend survival.
Endocervical adenocarcinoma biomarkers for immunotherapy: Descriptive analysis.
Authors: Cerda Victoria , Karamzadeh Nooshin , Scott Marla , Kinne Nolan , Mayer Christopher , Taylor Kristin , Li Andrew John , Kim Kenneth H. , Medeiros Fabiola , Balzer Bonnie , Rimel Bj
Published: June 2022

e17526

Background: Adenocarcinoma and adenosquamous carcinoma of the cervix are subtypes of HPV related cervical cancer. As virally mediated tumors, they have become an obvious choice for immunotherapy treatment approach. Currently, there is little information about the presence of immunological tumor markers among patients with endocervical adenocarcinomas. We hypothesized cervical adenocarcinomas highly express immunotherapy markers. Here we characterize the protein status of immunotherapy markers in a large single institution dataset. Methods: An IRB approved retrospective review of cervical adenocarcinoma and adenosquamous carcinoma was performed. We gathered original slides for each patient and performed immunohistochemistry (IHC) for tumor markers CD8, PDL1, TIM3 and LAG3. Demographic and pathologic data was captured. Patients were categorized by positivity percentage for each marker. Descriptive statistics and univariate analysis were used. Results: A total of 97 patients met criteria for the study and slides were available for staining in 68 patients. Demographic data showed a median age of 42 years old with majority of patients identifying as White at 66%, followed by Hispanic (13%), Asian (10%), other (7%) and Black (1%). Of the entire cohort, 75% were adenocarcinoma, 25% were adenosquamous carcinoma. Among those with recorded status, 82% were HPV positive, 14% had metastasis, and 13% had recurrence. On univariate analysis, adenocarcinoma was significantly more common in patients who were LAG3 < 1% or PDL < 1% (p = 0.002, p = 0.007). Patients who were LAG3 < 1% or PDL < 1% were also less likely to have Grade 1 tumors (p = 0.006, 0.03). When analyzing by respective immune marker percentage group there were no statistically significant differences in LVSI, depth of invasion, stage, or recurrence rate. By IHC, 68% were PDL1 > 1% positive, 63% were LAG3 > 1% positive, 100% were TIM3 > 1% positive, 100% were CD8 > 1% positive. Seven of the 68 patients had a recurrence. Of those patients with recurrence, one was treated with immunotherapy. Conclusions: A large proportion of cervical adenocarcinomas displayed immunotherapy targets by IHC suggesting that combined immunotherapy agents may be useful in this population. Further study is needed to assess whether IHC is predictive of outcome or response.[Table: see text]
Comparison of survival outcomes between dostarlimab and comparator treatments (tx) in patients (pts) with advanced/recurrent (A/R) endometrial cancer (EC) in England: Matching-adjusted indirect comparisons (MAICs).
Authors: Goulden Scott , Heffernan Kiera , Sen Nikitas Fulya , Shukla Urmi , Knott Craig , Hunger Matthias , Pahwa Ankit , Schade Rene
Published: June 2022

e17534

Background: Limited tx options exist for pts with A/R EC who progress on/after platinum-based chemotherapy (PBCT). This study compared survival outcomes of pts with A/R mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC receiving dostarlimab in Cohort A1 of the single-arm, Phase I GARNET trial, with an equivalent real-world (RW) cohort receiving current tx in England. The primary objective compared second-line (2L) overall survival (OS) between cohorts; a secondary objective was time to tx discontinuation (TTD; proxy for progression-free survival). Methods: An overall-2L-tx RW cohort was established using National Cancer Registration and Analysis Service data. Five tx-specific RW cohorts were identified (tx received at 2L in > 5% of pts) (Table). Clinical outcomes between GARNET and RW cohorts were compared using MAICs. Relevant prognostic variables were used to create 3 matching scenarios (SC): SC1: grade, histology, PBCT number; SC2: histology, PBCT number; SC3: race/ethnicity, stage at diagnosis, histology, prior surgery (MMR/MSI status not considered). OS was time from first dostarlimab dose (GARNET) or 2L RW tx (RW cohorts) to any-cause death; MAIC-adjusted hazard ratios (HR, 95% confidence interval [CI]) were estimated by weighted Cox proportional-hazards models. TTD after MAIC was summarized descriptively. Results: Effective sample size (ESS) assessed matching capacity; lower ESS in SC1 reduced its robustness (Table). Following matching, distributions of baseline characteristics were similar between cohorts. Across most matching scenarios, there was a lower risk of death in pts treated with dostarlimab compared to the overall RW cohort and for tx-specific RW cohorts (Table). Median TTD (months, 95% CI) was longer for pts treated with dostarlimab across all matching scenarios (SC1: 7.8 [4.1, not estimable (NE)]; SC2: 9.7 [5.5, NE]; SC3: 14.0 [6.4, 17.9]) than the overall RW cohort (3.4 [3.2, 3.4]). Conclusions: Results suggest that pts in GARNET with dMMR/MSI-H A/R EC receiving dostarlimab had better OS and longer TTD compared with pts receiving current 2L tx in England. Funding: GSK (217216; scott.r.goulden@gsk.com).[Table: see text]
Detection of early-stage ovarian cancer using a liquid biopsy test based on extracellular vesicle proteins.
Authors: Hinestrosa Juan Pablo , Lewis Jean , Schroeder Gregor , Balcer Heath , Billings Paul R.
Published: June 2022

e17558

Background: We have recently conducted a study to evaluate the predictive value of proteins associated with extracellular vesicles (EVs) isolated using an alternating current electrokinetic (ACE) system, for the detection of early stage (I & II) ovarian cancer cases. Ovarian cancer patients, typically, have few symptoms in stages I & II; the disease is often undetected until it is advanced. Currently, only 15% of cases are detected at early stages when clinical treatment outcomes are improved. Methods: We tested the feasibility of detecting the presence of early stage (I-II) ovarian cancer using protein biomarkers carried by EVs in patient blood. Using an ACE microelectrode array, EVs were purified from ovarian cancer patient plasma (N = 70; Stage I = 51, Stage II = 19) and female non-cancer donors (N = 290) and tested for the presence of cancer biomarker proteins with multiple bead-based multiplex immunoassay kits. An adaptive boosted trees machine learning algorithm with 100x cross-validation was developed to identify the most important features for differentiation between cases and controls. Results: The machine learning algorithm identified relevant biomarkers for the detection of ovarian cancer with a receiver-operator characteristic area under the curve (AUC) of 0.952 (95% CI: 0.918 – 0.985). Overall sensitivity was 72.9% at 99% specificity, rising to 84.3% at 95% specificity. When further stratified, Stage I sensitivity was 70.6% and stage II sensitivity was 78.9% at the 99% specificity level, as expected. We also separated the cases into endometroid carcinoma (N = 24) and serous carcinoma (N = 36). At the 99% specificity level, the sensitivity was 87.5% and 63.9%, respectively. Conclusions: These results suggest that it is possible to detect early-stage ovarian cancer by analyzing the EV-bound proteins isolated with the ACE technology. EVs may carry the earliest signals of cancer development and a blood-based EV-protein biomarker test can yield high sensitivity and specificity. Stable biomarker detection with small input volumes may be possible. These results require further investigation in larger datasets to validate the current observations with the potential application for general, routine screening, as well as for populations at elevated disease risk.
Impact of paclitaxel versus docetaxel on neuropathy in ovarian cancer patients with diabetes.
Authors: Kincaid Kaitlyn , Boitano Teresa KL , Leath Charles A. , Straughn J Michael
Published: June 2022

e17616

Background: Peripheral neuropathy is a common side effect of taxanes, particularly in diabetic patients, which can significantly affect quality of life. The objective of this study was to determine whether there was a difference in the incidence of new or worsening neuropathy between diabetic patients with ovarian cancer who received paclitaxel versus docetaxel as part of their primary therapy. Methods: This retrospective cohort study included ovarian cancer patients with Type I or Type II diabetes at a large academic institution who underwent surgery from 6/2016 to 5/2020 and received neoadjuvant and/or adjuvant chemotherapy. Individual chart review was performed to assess patient characteristics including race, body mass index (BMI), performance status (PS), Charlson Comorbidity Index (CCI), baseline hemoglobin A1c, current diabetic medications. The primary outcome was incidence of new or worsening neuropathy during primary therapy including adjuvant or neoadjuvant chemotherapy. New neuropathy was defined as no neuropathy prior to chemotherapy. Worsening neuropathy was defined as baseline neuropathy that worsened after initiation of chemotherapy. Secondary outcomes included chemotherapy treatment delay, increase of diabetic medications during therapy, and a change of chemotherapy regimen from paclitaxel to docetaxel. Statistical analysis was performed using SPSS v. 26. Results: 32 patients met inclusion criteria. Patient demographics including race, PS, BMI and CCI were similar between patients who received paclitaxel and those who received docetaxel. 24 patients (75%) received paclitaxel and 8 (25%) received docetaxel. The majority (93.8%) of patients had Type II diabetes. Patients who received paclitaxel were more likely to develop new or worsening neuropathy (81% v. 50%; p = 0.028) but less likely to require an increase of diabetic medications (0% v. 50%; p = 0.003) compared with patients receiving docetaxel. During primary therapy, 17% of patients were transitioned from paclitaxel to docetaxel due to treatment-related complications (i.e. neuropathy (50%), allergic reaction (50%)). There was no difference in incidence of treatment delays between the two treatment groups (25% v. 25%; p = 1.0). Conclusions: Patients with ovarian cancer who received paclitaxel were more likely to experience new or worsening neuropathy compared to patients who received docetaxel. There was no difference in treatment delays between the groups, but nearly one-fifth of patients receiving paclitaxel had to be transitioned to docetaxel because of treatment-related complications. Because of fewer side-effects, docetaxel is a reasonable chemotherapy alternative in ovarian cancer patients with diabetes.
Role of genetic ancestry in endometrial cancers: Understanding disparities in black women.
Authors: Lee Michelle Jeung-Eun , Shah Manan , Kollepara Sri Lakshmi Sudha , Jain Sanjay R.
Published: June 2022

e17631

Background: Endometrial cancer is the most common gynecological malignancy in the United States. Endometrial cancer disproportionately affects black women in terms of incidence and survival despite advancement in treatment, and preventive strategies. Identifying distinct tumor markers in patients with African ancestry will help distinguish biological determinants underlying the disparities in endometrial cancer. In this study, we investigated the genetic alterations in endometrial cancer in individuals of African (AFR) ancestry using The Cancer Genome Atlas (TCGA). Methods: The genomic and clinical data of TCGA PanCancer Atlas uterine corpus endometrial carcinoma (UCEC) were explored using CBioportal (http://www.cbioportal.org/). We utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral composition. This dataset contains 529 patients, including 357 self-reported whites and 107 blacks. For each case the proportion of European, West African, East Asian, Native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global genetic ancestry analysis identified 115 AFR ancestry cases with mean ancestry of 80.4%. The dominant AFR ancestry subject matched the self-reported race with 94% accuracy. We identified 23 subjects with ≥90% AFR ancestry, 43 subjects with 80-90% AFR ancestry, 34 subjects with 70-80% AFR ancestry, and 15 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene in patients with AFR ancestry(49.5%). ≥90% AFR ancestry had the highest rate of TP53 mutations (52.2%) compared with 80-90% AFR ancestry (51.2%), 70-80% AFR ancestry (43.8%), and 50-70% AFR ancestry (41.7%). PTEN was less commonly mutated in patients with higher proportion of AFR ancestry (47.8% in ≥90% AFR ancestry, 39.0% in 80-90% AFR ancestry, 59.4% in 70-80% AFR ancestry, and 66.7% in 50-70% AFR ancestry). PIK3CA mutation frequency was almost identical in all AFR ancestry groups studied. No significant differences in overall survival was observed between AFR ancestry groups. Conclusions: We aimed to investigate the etiology of endometrial cancer disparities by analyzing the effect of ancestry on genetic alterations in endometrial cancer. This study demonstrated differences in the mutation frequency among patients with AFR ancestry. We have shown that TP53 mutations were seen more frequently in patients with higher AFR ancestry, which may confer a poorer prognosis. Nonetheless, to validate the findings of this study, future studies should be conducted with larger sample sizes and more diverse ancestral groups to explore how genetic ancestry impacts tumorigenesis and cancer progression.
Molecular aberrations in late-stage dedifferentiated/undifferentiated endometrial carcinoma: A review of current literature.
Authors: Landry Ian , Sumbly Vikram , Vest Mallorie , Reed Mary K Smith
Published: June 2022

e17632

Background: Uterine cancer remains the fourth most common cancer diagnosed and seventh most common cause of cancer death in American women. Four molecular subtypes have been created to categorize and prognosticate endometrial carcinoma based on their molecular aberrations, but are often based on initial tumor presentation and are associated with high cost to the healthcare system. Methods: A comprehensive literature search was performed on PubMed, ClinicalTrials.gov, Embase, and WebofScience. Abstracts and publications from ASCO/ASH were also included. Results: 32 articles were included in our systematic review. A total of 388 women were analyzed in the main group analysis and nearly half of the patients were diagnosed as stage III or IV (n = 178, 46%). MSI was present in 66% of all tumors tested and PD-L1 was overexpressed in 78%. Eighty-four percent (84%) of the tumors were negative for ER, up to 44% had loss in SWI/SNF complex, and 64% lost expression of e-cadherin. Pax-8 and fascin proteins were over expressed in 29% and 88% of patients tested, respectively. In a sub-group analysis, evidence of progression and use of adjuvant radiotherapy were significantly associated with a later stage of diagnosis ( p = 0.052, 0.044). Conclusions: We found no statistically significant association between stage of diagnosis and unique mutation. Patients with evidence of progression or recurrence were found to have disease in atypical locations. Unique mutations which categorize patients at time of diagnosis may be different upon progression or recurrence of the tumor. While a novel classification system has been produced to assist with prognosis and treatment guidelines, these tests are not widely available in the community hospital setting.[Table: see text]
Neoadjuvent chemotherapy in rare sinonasal teratocarcinosarcoma: Long-term result from tertiary center.
Authors: Sharma Abhishek , Patil Vijay Maruti , Rai Rahul Kumar , Saha Saswata , Noronha Vanita , Menon Nandini Sharrel , Joshi Amit , Prabhash Kumar
Published: June 2022

e18005

Background: Sinonasal teratocarcinosarcoma (SNTCS) is a rare and highly aggressive disease entity having poor outcomes with available treatment modalities. Surgery followed by radiation or radical chemoradiation are considered standard therapy. However, in very locally advanced diseases surgery or radiation is not feasible and such patients are subjected to palliative therapy and have dismal outcomes. Methods: We identified 21 patients with very locally advanced SNTCS in our prospectively maintained head and neck cancer database over the last 8 years. All patients were seen in a multidisciplinary clinic prior to the start of therapy and were deemed unfit for local therapy. They were planned for 2 – 3 cycles of Neoadjuvant chemotherapy (NACT). They were then assessed in the multidisciplinary clinic for local therapy. Depending upon the response and performance status further therapy was planned. SPSS version 20 was used for the analysis. Descriptive statistics were performed and the Kaplan Meier method was used to evaluate overall survival(OS) and progression-free survival(PFS). Results: Median age was 50 years (range 27-80 Years) with male to female ratio being 6:1. ECOG PS was 0 in 3(14%), PS 1 in 14(67%) and PS 2 in 2 (9%) patients. 14 (67%) patients had Kadish C and the rest (33%) had Kadish D stage at presentation. Cisplatin & Etoposide was the chemotherapy of choice for the majority of patients (14/21 patients, 67%) with Docetaxel – Cisplatin (5/21 patients,19%), and Ifosfamide – Adriamycin (2/21 patients, 9%) being the other regimens. After NACT 14/21(66%) patients underwent surgery,1/21(4%) underwent radical Chemoradiation,1/21(4%) for palliative radiation therapy and rest for best supportive care. R0 resection was achieved in 11 out of 14 (78.6%) patients. The median PFS of the study was 17.5 months (95% CI 8.2 – 26.7) and the median OS was 19 months (95% CI = 0 -47). Those who underwent surgery after NACT have achieved a median OS of 37.3 months(95% CI 0-77.7) in comparison to 6.3 months (95% CI 0.3 -12.2) for those without surgery (p value 0.02). Conclusions: NACT in very locally advanced SNTCS achieves resectability in ⅔ patients who were unresectable upfront and would have received palliative therapy. This is important as patients who undergo surgery have prolonged overall survival.
Long-term outcomes of a randomized controlled clinical trial comparing the efficacy of cabazitaxel versus docetaxel as second-line or above therapy in recurrent head and neck cancer.
Authors: Nawale Kavita Prakash , Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Dhumal Sachin Babanrao , Bhattacharjee Atanu , Prabhash Kumar
Published: June 2022

e18008

Background: Long term outcomes (> 2 years or above) are rarely reported in studies with second line or beyond systemic therapies in head and neck squmouas cell carcinoma (HNSCC). Methods: Recurrent or relapsed adult HNSCC, with ECOG PS 0-2 who have been exposed to at least one line of chemotherapy were 1:1 randomized between Docetaxel (75 mg/m2) and Cabazitaxel (20 mg/m2). The chemotherapy was given till progression or development of intolerable side effects. The outcomes reported are long term overall survival(OS) and progression free survival (PFS) and factors impacting overall survival. Results: On the intention to treat analysis (n = 92), at the time of data censoring, 92 patients had died. The median overall survival was 112 days (95% CI 81 to 178 days) in the cabazitaxel arm versus 192 days (95% CI 153 to 259 days) in the Docetaxel arm (P = 0.048). In cabazitaxel arm, the one year OS was 6.5% (95% CI 1.6-16.06), 2 year OS was 2.17% (95% CI 0.17-9.95) and 3 years was 2.17% (95% CI 0.17-9.95). While the corresponding figures in the docetaxel arm were 21.7% (95% CI 11.23-34.46), 0% and 0%. The median progression-free survival was 21.0 days (95% CI 16.0-42.0 days) in the Cabazitaxel arm versus 57.5 days (95% CI 26.0-85.0 days) in the Docetaxel arm (P = 0.02). Among the tested factors age (p = 0.037) and site of primary(p = 0.023) had an impact on OS. Conclusions: In this phase 2 randomised study, cabazitaxel has inferior PFS and OS than docetaxel. Hence docetaxel remains the option of choice when cytotoxic chemotherapy needs to be used as second line or beyond setting in HNSCC. Clinical trial information: CTRI/2015/06/005848.
Real world data of neoadjuvant and adjuvant chemotherapy in head neck osteosarcoma: Experience from a tertiary care center in India.
Authors: Tongaonkar Arnav , Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Jogdhankar Shweta , Prabhash Kumar
Published: June 2022

e18012

Background: The head and neck (HN) region is a rare sub-site of osteosarcoma(OGS), with less than 10% of all cases of osteosarcoma and < 1% of all the head and neck malignancies . The evidence pertaining to the treatment of OGS of the head & neck region is limited. The role of adjuvant chemotherapy is evolving and research in this field is limited by the rarity of this tumour. However, in multiple small series, adjuvant or neoadjuvant chemotherapy has been found to be beneficial in head and neck OGS. To this end, we have audited our practice of the last 10 years to see the pattern of care, outcomes and advancements in the chemotherapy of HN OGS. Methods: We maintain a record at our outpatient department of patients receiving neoadjuvant and adjuvant chemotherapy. We conducted a database search spanning the data from 2010 to 2020, using the keywords: osteosarcoma, osteogenic sarcoma, OGS and head neck region, maxilla, skull base. Any adult patients who received chemotherapy in the adjuvant or neoadjuvant setting were selected for this study. The baseline demographics, patterns of chemotherapy administration and outcomes were documented. We analysed the data using SPSS descriptive statistical analysis. Survival analysis for progression-free survival and overall survival was done using the Kaplan-Meyer method. Results: 30 patients of HN OGS were treated with neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) at our centre from 2010 to 2020. The median age was 25 years, with a male preponderance (n = 21, 70%). The sites of disease were maxilla- 15(50%), mandible- 11 (37%), alveolus- 2 (6.6 %), orbit- 1 (3.3%), masticator space - 1 (3.3%). Out of the study population, 18 patients (60%) received NACT, 17 patients (56%) received ACT, 5(16%) patients received both NACT and ACT. 23 patients (76.6 %) underwent surgical resection, with R0 resection achieved in 17 (56.6%) and R1 in 3 patients(10%). 16 patients (53.3%) received adjuvant radiotherapy. Median progression-free survival was 16.10 months (95% CI: 10.30-21.89). Median overall survival (OS) was 22.56 months (95%CI: 11.16-33.96). 2 years OS was 49.1% (standard error 9.6). Conclusions: The patterns of use of neoadjuatnt and adjuvant chemotherapy in HN OGS are variable. Overall, the outcomes of HN OGS remain unsatisfactory. Further efforts are warranted in this direction to standardise an algorithm for chemotherapy. Further intensification of therapy may be required to improve patient outcomes.