bluuebunny/crossref_metadata_2025 huggingface dataset:
A morphological subset of circulating tumor cells in advanced prostate cancer reveals a potential biomarker for clinical outcomes.
Authors: Wang Jasmine Jiemei , Cavassani Karen Angelica , Teng Pai-Chi , Chen Jie-Fu , Jan Yu Jen , Chu Gina Chia-Yi , Lee Yi-Te , Gao Allen , Di Vizio Dolores , Chung Leland WK , You Sungyong , Zhu Yazhen , Freeman Michael , Rogatko Andre , Yang Ju Dong , Tseng Hsian-Rong , Posadas Edwin Melencio
Published: June 2021

e17008

Background: A morphological subset of prostate cancer (PCa) circulating tumor cells (CTCs) with particularly small nuclei (< 8.5 μm), named very-small-nuclear CTCs (vsnCTCs), were found to be correlated with the presence of visceral metastases. It is reported that the depletion of nuclear envelope protein emerin promotes PCa metastasis and is associated with nuclear shape instability. In this study, we hypothesize vsnCTCs as prognostic biomarkers in metastatic castration resistant PCa (mCRPC), and aim to investigate the correlation between emerin level and vsnCTCs. Methods: PCa CTCs were enriched using the NanoVelcro CTC Assay from 76 patients with mCRPC. The Kaplan-Meier analysis and log-rank test were used to estimate and compare the overall survival (OS) and progression free survival (PFS) of androgen receptor signaling inhibitor (ARSI), taxanes and other therapy in patients stratified by the presence of vsnCTCs. The correlation between the presence of vsnCTCs and OS and PFS were evaluated using the Cox proportional hazard regression. The expression level of emerin in patients with and without vsnCTC were compared using Mann-Whitney U test, and the correlation between emerin level and CTC nuclear size was tested by Pearson correlation coefficient. Results: Patients with vsnCTC (i.e, vsnCTC+) had significantly shortened OS and PFS compared with those without vsnCTC (i.e, vsnCTC-). The median OS was 34 (vsnCTC+, n= 49) vs. 149 (vsnCTC-, n= 27) weeks (hazard ratio [HR] = 2.6, 95% confidence interval [CI]: 1.5-4.5, P< 0.001). The median PFS was 12 (vsnCTC+, n= 32) vs. 26 (vsnCTC-, n= 18) weeks (HR = 2.2, 95% CI: 1.3 -4.0, P= 0.004). The emerin expression level was significantly higher in vsnCTC+ compared to vsnCTC- ( P= 0.009). In addition, we observed a significantly positive correlation between emerin expression and CTC nuclear size (r = 0.52, P< 0.001). Conclusions: This study casts light on the importance of the vsnCTCs in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for mortality. vsnCTC represents a new hallmark of an aggressive subtype of mCRPC and is related to emerin dysregulation, which promotes lethal progression and metastasis of PCa.
Nationwide trends in in-patient chemotherapy hospitalizations, cost, and mortality for patients with testicular carcinoma.
Authors: Abbasi Saqib , Wulff-Burchfield Elizabeth Marie , Parikh Rahul Atul
Published: June 2021

e17012

Background: Salvage therapy for advanced Testicular Carcinoma involves patients receiving ifosfamide are treated in hospital for risk of neuro-toxicities. We evaluated annual trends to assess the health care burden of testicular patients admitted for chemotherapy, as well as co-morbidities and complications associated with mortality. Methods: The National Inpatient Sample is a nationwide sample of all US hospital discharges. We collected data from the years of 2002 to 2017 on patients with Testicular Carcinoma who were receiving chemotherapy, to capture patients recieving ifosfamide and cisplatin in an in-patient setting. Patients undergoing an autologous stem cell transplant were excluded. Annual trends for inpatient mortality, length of stay, and total costs of admission were assessed. A univariate logistic regression analysis was used to calculate odds ratios (OR) for the effect of comorbid conditions and acute inpatient complications on in-patient mortality. Results: Hospitalizations for ifosfamide and cisplatin based treatment among patients with Testicular Carcinoma remained stable from a weighted national estimate of 2,261 in 2002 to 2,160 in 2017. Length of stay increased from 4.6 days to 5.5 days (p=0.01). Cost of stay increased from $26,140 to $53,193 (p <0.001) when adjusted for inflation. The average age of patients was 32.6 years. In-patient mortality was low at 0.2% in 2002 to <0.1% in 2017. Among comorbid conditions, heart failure was associated with increased mortality (OR 21.9). Among acute complications – acute kidney injury (OR 32.6), infection (OR 15.3), neurotoxicity (OR 12.3) were associated with significantly higher mortality. Conclusions: The increase in cost of stay is out of proportion to increases in length of stay. Indicating a disproportionate increase in financial toxicity for these patients. Patients with underlying heart disease are at increased risk of complications. Care needs to be taken to specifically identify patients at risk for renal failure and infectious complications.[Table: see text]
Phase 2 analysis on Covid-19-adopted etoposide (E) and cisplatin (P) regimens for patients (pts) with an advanced germ cell tumor (GCT): The CovGCT study.
Authors: Naban Nabeel , Tiemeier Gesa , Kocache Arwa , Taylor Rory , Keogh Georgina , Hennah Lindsay , Sarwar Naveed , Seckl Michael , Gonzalez Michael
Published: June 2021

e17013

Background: The Covid19 pandemic has imposed risks to healthcare delivery for all cancer pts including young adults diagnosed with a GCT. Here, we examine Emergency EP (EmEP, Cohort A) and a novel 1-day Escalated-dose EP (EscEP, Cohort B) administered every 2 weeks as upfront or first-relapse therapy to minimise hospital days. Methods: Single-centre analysis in GCT pts receiving emergency and routine chemotherapy following our first National lockdown on 23rd March 2020. In Cohort A, eligible pts receive EmEP E100mg/m2, P20mg/m2 prior to EscEP within the acute setting as previously defined. In Cohort B, EscEP E500mg/m2, P60mg/m2 is compared to standard care chemotherapy BEP or POMB-ACE. Data collection includes demographics, treatment details, clinical outcome and Covid19 complications. Results: To date, we have accrued 19 pts with a median age 32 (range 18 to 65). In Cohort A, 7 pts with symptomatic high-volume disease received a median 1 cycle EmEP, 6/7 for a new GCT diagnosis and 1/7 for a first relapse, including 2 males with IGCCCG intermediate-prognosis disease, 5 females with FIGO Stage III (n = 2) and IV (n = 3) disease. One pt required higher-level support for organ dysfunction at presentation. In Cohort B, 19 pts including 7 pts from Cohort A received a median 4 cycles EscEP: 8 males (2 seminomas, 6 non-seminomas; IGCCCG good-prognosis in 4, intermediate-prognosis in 2, poor-prognosis in 2), 11 females (1 dysgerminoma, 10 non-dysgerminomas; FIGO Stage Ic in 6, III in 2, IV in 3). A majority (14/19, 74%) received EscEP for a new cancer diagnosis, 5/19 (26%) for a first relapse. Total median hospital stay: EscEP 5 days, BEP 21 days, POMB-ACE 28 days. Grade 3/4 neutropenic events: EscEP 28%, BEP 50%, POMB-ACE 43%. From April 2020, 16/16 pts were SARS-CoV-2 screened prior to each cycle: 3/19 (16%) testing positive, one prior to intubation and ventilation, 2 with asymptomatic infection. For Cohort B, at median follow-up 121 days (range 9-323 days), we have observed a complete response in 10 pts (53%), partial response in 3 pts (16%) and disease progression in 1 pt (5%). Five pts are still on treatment (26%). All pts remain alive. Conclusions: EmEP and EscEP represent safe options during the pandemic that minimise myelosuppression and total length in hospital days whilst bypassing the potential pulmonary toxicity from Bleomycin. Further follow-up will inform on long-term efficacy including a multicentre evaluation.
Burden of chemotherapy-induced peripheral neuropathy and associations with long-term sexual impairment in testicular germ cell tumor survivors.
Authors: Chovanec Michal , Galikova Dominika , Vasilkova Lucia , De Angelis Valentina , Rejlekova Katarina , Obertova Jana , Sycova-Mila Zuzana , Palacka Patrik , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: June 2021

e17014

Background: Chemotherapy-induced peripheral neuropathy (CIPN20) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. The association of CIPN with long-term sexual function in GCT survivors remains unclear. Methods: European Organization for Research and Treatment of Cancer (EORTC) CIPN20 and PROMIS modified sexual function (SexF) questionnaires were prospectively completed by GCT survivors (N = 128) at National Cancer Institute in Slovakia during their annual follow-up visit. The median follow-up after completion of treatment was 10 years (range 4-25). Upon obtaining the scores from each questionnaire per recommended guidelines, each score from SexF was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. Survivors were treated with cisplatin-based chemotherapy, radiotherapy to the retroperitoneum or both. Results: GCT survivors with CIPN reported a self-perceived sexual impairment. The overall perceived sexual impairment was higher in survivors with high vs low CIPN (mean score ± SEM: 7.44 ± 0.24 vs. 6.76 ± 0.21, P = 0.05). However, the overall perceived sexual abilities were not significantly different in CIPN high vs low (16.9 ± 0.68 vs. 16.8 ± 0.59, P = 0.97). The trend towards higher difficulty in maintaining erection was seen in CIPN high vs low survivors (3.94 ± 0.21 vs. 4.12 ± 0.18, P = 0.07). Furthermore, survivors with CIPN high were more disappointed with the quality of their sex life compared to those with CIPN low (1.96 ± 0.12 vs. 1.47 ± 0.11, P = 0.01). Patients with CIPN high had trend towards more anxiety from sexual relationships compared to CIPN low survivors (1.66 ± 0.11 vs. 1.33 ± 0.10, P = 0.06). The level of sexual desire, number of attempts to initiate sexual intercourse, ability to achieve erection, achieve orgasm were not different ( P all > 0.05). Conclusions: GCT survivors with higher burden of CIPN have certain impairment in sexual functioning. We hypothesize there may be a common pathogenetic mechanism of induction in these long-term toxicities of curative treatments.
The association of ATM alterations with clinical and molecular features in metastatic castration-resistant prostate cancer.
Authors: Xi Guo , WANG Qing , Zhang Qin , Duan Qianqian , Liu Yaqin
Published: June 2021

e17019

Background: Ataxia telangiectasia-mutated（ATM）is a serine/threonine kinase involved in DNA-damage repair (DDR) system and regulating cell cycle checkpoints, senescence, and apoptosis. Several clinical studies provide evidence about the DDR-mutated metastatic castration-resistant prostate cancer (mCRPC) benefit from PARP inhibitors (PARPi). However. the efficacy of PARPi was limited for mCRPC patients harboring ATM aberrations. We aimed to determine the association of ATM mutations with clinical and molecular features in patients with mCRPC. Methods: A total of three independent prostate cancer cohorts (MCTP, N = 61; SU2C-PCF, N = 429; MSKCC, N = 451) were used for analysis. We selected patients with characteristics “mCRPC” and “histology type: prostate adenocarcinoma”. Both the somatic and germline pathogenic alterations were analyzed, including single nucleotide variations (SNVs), in-frame insertions or deletions (Indels), frameshifts, homozygous deletions and fusions. The statistical analysis was conducted by R software (v.3.6.2). Results: We merged the three mCRPC cohorts, generating a new cohort consisting of 507 mCRPC patients. The median age was 62 (range, 38.6-89). The number of biopsies was 1-3 per patient. Of the 527 sequenced specimens, 39% were lymph node, 27% were bone, and 14% were liver. Forty percent of the patients had exposed to or on-treatment with next-generation androgen receptor signaling inhibitor (ARSI). A total of 44 patients (8.7%) harbored deleterious variations in ATM, including 10 homozygous deletions. The coexistence mutations were most commonly located in androgen receptor ( AR), followed by TTN/KMT2C/MUC16/TP53. Furthermore, we explored the association of pathogenic ATM alterations with clinical features. Compared with noncarriers of ATM mutations , carriers were diagnosed at a younger age (median: 59 vs 62.4, P = 0.022). In the subgroup from SU2C-PCF cohort, prostate specific antigen (PSA) at diagnosis and the proportion of Gleason score between 8-10 were analyzed, both showed no significant differences between the two groups. Notably, we observed a statistically significant higher TMB in ATM-altered group than ATM wildtype group (median, 2.04 vs 1.61, P = 0.013). Overall survival (OS) was not compared because of the limited clinical outcomes in ATM-mutated population. Conclusions: This study involving 3 cohorts identified the prevalence of pathogenic somatic or germline ATM mutations and explored the association of ATM alterations with both clinical and molecular features. Patients with ATM mutations tended to diagnose prostate cancer at an earlier age. Meanwhile, significantly higher TMB might imply potential immunotherapy opportunities in ATM-altered mCRPC without standard-of-care approaches.
Prostate cancer intensive, non-cross reactive therapy (PRINT) for CRPC: Interim analysis of efficacy endpoints.
Authors: Liaw Bobby Chi-Hung , Zhong Xiaobo , Tsao Che-Kai , Bakst Richard Lorne , Stewart Robert , Stock Richard , Galsky Matt D. , Oh William K.
Published: June 2021

e17027

Background: The standard mCRPC treatment paradigm, with sequential single agents administered until resistance, may be limited due to heterogenous tumors comprised of clones differentially sensitive to available therapies. An alternative approach involves rapid cycling of non-cross resistant therapies in an attempt to efficiently eradicate sensitive clones, mitigate resistance, and minimize toxicity. Methods: Patients with mCRPC received 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month study regimen, patients continued ADT alone. The primary endpoint is time to progression (TTP). A sample size of 33 patients will provide 90% power for a one-sided test at the 5% level to detect increase in TTP compared with historical control. Secondary endpoints include PSA response (>90%, >50%) with each module, and changes to alkaline phosphatase levels. Results: From 3/2017 to 11/2020, 40 mCRPC patients were enrolled. As of the data cut-off of 1/03/2021, 31 patients have completed the 9-month study regimen and are evaluable for TTP analysis. With a median follow up of 20.7 months, the median time to PSA progression is 3.8 months (95%CI; 2.1-6.3 mo). PSA declines >90% from baseline was achieved in 35.5% after module 1, 41.9% after module 2, 58.1% after module 3. Of the patients with bone metastasis and elevated alkaline phosphatase levels at baseline (9/31), 78% had normalization of alkaline phosphatase upon completion of study regimen. Five of 31 patients (16%) were able to be maintained on ADT alone for over a year during the post-study surveillance period: three patients were subsequently restarted on a mCRPC agent at time of disease progression (14.4 mo, 17.0 mo, 24.8 mo), two patients demonstrate sustained disease control and remain on ADT alone (16.3+ mo, 21.5+ mo). Shared baseline clinical features of the 5 patients with prolonged control include PSA of <10 ng/mL and normal alkaline phosphatase levels (< 126 IU/L); Gleason score and presence of bone and nodal metastases varied. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross resistant regimen is feasible and a subset of patients achieve prolonged disease control on ADT alone after completion of study treatment. Rapid cycling of available CRPC therapies may eliminate castration-resistant clones in a subset of patients, a concept warranting further preclinical and clinical evaluation. Clinical trial information: NCT02903160. [Table: see text]
Effect of immunotherapy on survival outcomes in prostate cancer: Systematic review and meta-analysis.
Authors: solipuram Vinod , Pokharel Kishor , Venkatesulu Bhanu Prasad , Samanapally Harideep
Published: June 2021

e17030

Background: Prostate cancer is one of the leading cancers in men with an estimated 191,930 new cases in 2020 in the USA alone. Treatment options for metastatic castration resistant prostate cancer (mCRPC) have evolved in recent years. Immunotherapy involving vaccines like sipuleucel-T, PROSTVAC and immune checkpoint inhibitors have been evaluated in these patients. We present a systematic review and meta-analysis of the randomized controlled trials (RCTs) testing the effect of immunotherapy in mCRPC. Methods: A systematic search was performed using PubMed, Embase and the Cochrane library without language limitations from inception to January 3, 2021. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), prostate specific antigen (PSA) reduction ≥ 50% and incidence of grade 3-4 adverse events. The analysis of OS, PFS was done using random effects hazard ratio (HR) by generic inverse variance method and analysis of PSA reduction ≥ 50% and grade 3-4 adverse events was done using random effects risk ratio (RR) by the Mantel-Haenszel method. Results: 12 RCTs comprising 4109 patients were included in the analysis. There was a statistically significant improvement in OS (HR 0.89; 95% CI (0.81, 0.97)) and PFS (HR 0.83; 95% CI (0.76, 0.92)) in the immunotherapy arm compared to placebo or standard treatment arms with moderate quality of evidence. Patients in the immunotherapy group had significant reduction in PSA ≥ 50% (RR 1.71; 95% CI (1.09, 2.68)) but also had statistically significant increased risk of grade 3-4 adverse events (RR (1.25; 95% CI (1.02, 1.54)) when compared to placebo and the standard treatment group. Subgroup analysis showed that the use of vaccine therapy in prostate cancer leads to significant improvement in OS (HR 0.83; 95% CI (0.74, 0.93)) and PFS (HR 0.80; 95% CI (0.67, 0.95)) compared to placebo and standard treatment. The use of immune checkpoint inhibitors was not associated with statistically significant improvement in OS (HR 0.98; 95% CI (0.88, 1.09)) but is associated with improvement in PFS (HR 0.87; 95%CI (0.81, 0.94)). Conclusions: This meta-analysis showed that immunotherapy led to significant improvement in OS, PFS and PSA reduction of ≥ 50%. However, there is an increased incidence of grade 3-4 adverse events with the use of immunotherapy when compared to other standard therapies and placebo. The improvement in overall survival is limited to the use of vaccine therapy and not to immune checkpoint inhibitors. Careful use of selective forms of immunotherapy in mCRPC can lead to greater improvement in survival.
The impact of COVID-19 on delivery of systemic anti-cancer treatment in urological cancer patients: A comparison with 2019 data from Guy’s Cancer Center.
Authors: Karampera Christina , Khan Muhammad , Russell Beth , Moss Charlotte , Monroy-Iglesias Maria J , Dolly Saoirse , Thillai Kiruthikah , Josephs Debra Hannah , Pintus Elias , Rudman Sarah , Van Hemelrijck Mieke , Enting Deborah
Published: June 2021

e17057

Background: The provision of cancer services has been strongly impacted by the outbreak of SARS-CoV-2. Our Cancer Centre in South-East London treats approximately 8,800 patients annually and is one of the largest Comprehensive Cancer Centres in the UK. When dealing with the second wave of COVID-19, it is important to further evaluate the safety of cancer treatments whilst balancing the risks of COVID-19 infection and complications. Here, we report on the patient/tumour characteristics of those patients undergoing SACT for a urological cancer diagnosis during the first wave, so as to help establish clinical guidelines for the management of these patients in a SARS-CoV-2 epidemic. Methods: All urological cancer patients receiving at least one SACT between 1st March- 31st May 2020 (COVID-19 period) were compared to the same timeframe in 2019. SARS-CoV2 infection was defined as a positive RT-PCR test; patients with symptoms or radiological changes alone were excluded. As part of Guy’s Cancer Cohort, we collected information on demographics, and cancer type, stage, and treatment. Results: A total of 455 patients (305 prostate, 102 renal, 38 bladder, and 10 testicular) received SACT in 2020 as compared to 535 (353 prostate, 129 renal, 37 bladder, and 15 testicular) in 2019 (15% overall decline). Patient characteristics in terms of demographics were fairly comparable, with 10% female patients in 2019 and 9% in 2020; 49% aged 70+ vs 45%; and 77% in the low socio-economic category vs 78%. There was an increase in patients with stage 4 (89% vs 95% in 2020) and a slight change in distribution of SACT types (2019 vs 2020): chemotherapy (18% vs 14%), immunotherapy (7% vs 10%), biological or targeted (63% vs 66%), combination of biological/targeted (6% vs 5%), other combinations (5% vs 5%). The proportion of SACT delivered as part of radical treatment declined from 3% to 0.2% in 2020. A total of 5 patients (1%) developed COVID-19 (2 prostate, 2 renal, and 1 bladder). All were male and aged 60+; three had 2+ comorbidities. One patient was on immunotherapy and four on biological or targeted treatment. Four patients had severe pneumonia and one died of their COVID-19 (bladder cancer). Conclusions: Whilst there was a decline of number of patients receiving SACT during COVID-19, we were still able to provide a safe high-quality urological cancer SACT pathway during the peak of the COVID-19 pandemic, with very few COVID-19 positive patients. In a next step we will evaluate oncological outcomes at 6 months follow-up
Morbidity and mortality of pelvic exenteration for cervical cancer at a German referral center.
Authors: Boekhoff Jelena , terGlane Luisa , Wagner Uwe , Hegele Axel
Published: June 2021

e17505

Background: The purpose of this study was to evaluate data regarding the outcome of pelvic exenteration (PE) when performed for advanced or recurring cervical cancer. Methods: A total of 24 patients underwent PE for cervical cancer at the University Hospital Marburg between 2011 and 2016. Their data were retrospectively assessed and statistically analyzed. Survival was evaluated using the Kaplan-Meyer method. Results: Mean age was 52.2 years (29.7 to 72.6 years), mean BMI was 23.4 kg/m2. Most common indication was squamous cell carcinoma, whereas 3 patients underwent PE for adenocarcinoma. The majority of the tumors (62.5%) were stage pT4. Negative margins could be achieved in 70.8%. Lymph nodes could be assessed in 55% and were tumor-afflicted in 20.8%. 45.8% were treated for recurrent cancer; median recurrence free time between previous treatment and PE was 16 months. Up-front PE was performed in 20.8%. Another 79.2% received treatment prior to PE: 20.8% received all 3 treatment modalities whereas 37.5% had two treatments before (29.2% underwent chemo- and radiotherapy, 8.3% had surgery and radiotherapy) and 20.8% underwent one type of treatment. Anterior PE (APE) and total PE (TPE) were performed in 62.5% and 37.5%, respectively. Median operation time was 324min. Blood products were administered perioperatively in 75%; 37.5% needed 2 or more. Median hospital stay was 25 days. Major complications (Clavien Dindo≥3) were observed in 41.7% and 16.7% had no complications. Overall Survival (OS) was 29.2%; median overall survival was 19.1 months. 2- and 3-year survival rates for curative PE were 50% and 35% respectively. 4 patients underwent PE with palliative intent. Overall survival correlated significantly with R1- (p = 0.012), N1- (p = 0.047) and M1-status p < 0.01), TPE (p = 0.034) and surgical time > 6 h (p = 0.003). Conclusions: In cases of advanced or recurrent cervical cancer gynecologists struggle to find suitable therapeutic options, especially since most patients have already received radio- and/or chemotherapy. PE is a valid option for selected patients that may represent a cure with tolerable complication rates.
A retrospective study of anlotinib in patients with cervical cancer after chemoradiotherapy.
Authors: Tan Liu , Chu Alan , Yang Yu , Yuan Jinjin , Hou Ge , Song Rui , Wang Cheng , Xiao Chenhu , Chai Ting , Liu Shijia , Zhang Pan , Liu Zongwen
Published: June 2021

e17509

Background: Anlotinib is a novel small molecule antiangiogenic drug, which can inhibit multiple tyrosine kinase receptor activity. Its antitumor activity has been proved in various cancers, including gynecological tumors. This retrospective study explored the efficacy and safety of anlotinib monotherapy or anlotinib combined chemotherapy in cervical cancer patients who have disease progressed or metastasis after chemoradiotherapy. Methods: 28 patients with cervical cancer admitted to the Second Affiliated Hospital of Zhengzhou University were enrolled. These patients who had received radiotherapy and at least one line chemotherapy had tumor progression or metastasis. 13 patients received anlotinib monotherapy (12mg/d from day 1 to day 14 in a 21-day cycle) and 15 patients received chemotherapy combined with the anlotinib. Treatment was continued until disease progression or death or intolerable adverse events. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec 31 2020, no one was lost follow up. 2 patients were still under treatment, and 26 patients were evaluable. 1 CR, 6 PR, 13 SD, 6 PD, yielding the ORR of 26.92%, and the DCR of 76.92%. The median PFS for receiving anlotinib monotherapy was 4.57 (95% CI, 3.85-5.29) months, and 8.47 (95% CI, 5.09-11.85) months for combination group. The most common adverse events (AEs)were grade 1, including hypertension (46.43%), anemia (42.85%) and fatigue (39.29%). Grade 3 AEs were hypertension(10.71%) and anemia(7.14%). No higher grade AEs occurred. Conclusions: Anlotinib is safe and effective for patients with advanced cervical cancer after chemoradiotherapy, and it is well tolerated.
Dynamics of oxidative blood status and activity of antioxidant system of erythrocytes in patients with cervical cancer receiving combination therapy with dendritic cell vaccine.
Authors: Goroshinskaya Irina A. , Menshenina Anna P. , Frantsiyants Elena M. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Nemashkalova Ludmila A. , Chudilova Anastasia V. , Cherkasova Anna A. , Chalabova Tatiana G.
Published: June 2021

e17516

Background: The combination treatment with plasmapheresis and non-specific immunotherapy for locally advanced cervical cancer (CC) is shown to be effective. We studied the effect of immunotherapy with dendritic cell vaccine (DCV) as a part of combination therapy on the intensity of the lipid peroxidation (LPO) and activity of antioxidant enzymes. Methods: Plasma and erythrocyte content of malondialdehyde (MDA), the activity of superoxide dismutase (SOD), catalase, glutathione dependent enzymes and the content of reduced glutathione (GSH) in erythrocytes were determined in 24 patients with CC of T2a-2bN0-1M0 stages and in 25 women without cancer. The patients underwent neoadjuvant chemotherapy (CT) with cisplatin and bleomycin, followed by 2 cycles of DCV, for a total of 6 courses of CT and 12 cycles of DCV. Results: Initially, patients demonstrated intensification of free radical processes enhancing after PCT and the first two DCV: MDA in erythrocytes elevated by 52.2-111.7%, in the blood plasma by 2.2-3.5 times. Subsequent DCV cycles normalized the LPO. MDA levels after 4 DCV cycles were lower than the initial values in erythrocytes by 30.4% (p = 0.04), in plasma by 55.6% (p = 0.007), i.e. were similar to the levels in healthy women. The SOD activity was decreased by 16.7-27.3% (p < 0.005) after 4-6 DCV cycles and normalized after the 7th cycle. The catalase activity in erythrocytes was decreased before treatment and after PCT by 42.4% (p = 0.000000), during vaccine therapy by 20.5-37.7% (p < 0.0005). In reduced catalase activity, inactivation of hydrogen peroxide was realized, apparently, by glutathione peroxidase (GPO), and its increased activity (by 37-102.3%, p≤0.00005) was supported by a high GSH content - by 11.6-52.4% (p < 0.02) above the norm at all stages after the 2nd DCV cycle. And only with the complete normalization of the erythrocyte MDA content, the GPO activity after the 7th DCV cycle decreased by 46.7% (p = 0.000000) relative to the levels before the treatment and did not differ significantly from the values in donors. Conclusions: Vaccine therapy helped to enhance the activity of the glutathione system becoming the most important component of antioxidant protection in the blood of CC patients. Already 3-4 DCV cycles normalized the LPO sharply increased in CC patients during CT. Multi-course vaccine therapy allowed maintaining the optimal oxidative status of the blood.
A multicenter analysis of treatment and outcomes in neuroendocrine carcinoma of the uterine cervix (NCUC).
Authors: Hickman Ashley Deanelle , McGarrah Patrick Walsh , Glaser Gretchen , Naraev Boris , Wahner Hendrickson Andrea Elisabeth , Halfdanarson Thorvardur Ragnar
Published: June 2021

e17518

Background: Morbidity and mortality for patients with cervical cancer has improved significantly over the past few decades with modern multimodal therapy. However, neuroendocrine carcinoma of the uterine cervix (NCUC), which accounts for 1-2% of cervical cancers, remains a deadly subtype. In this study, we combine data from Mayo Clinic (MC) and the University of Iowa Hospitals and Clinics (UIHC) to provide information on tumor characteristics, treatment, and outcomes. Methods: The electronic medical record was reviewed for patients with NCUC from MC and UIHC. Data on diagnosis, treatment, and outcomes were collected through chart review. Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included median survival, survival at 1 year after surgery, and survival at 1 year by first line chemotherapy agent. Kaplan-Meier survival analysis was used to estimate median PFS, median survival, and OS. Fisher’s test analysis was used to calculate survival at 1 year after surgery and by first line chemotherapy agent. Results: There were 62 patients (MC: 26, UIHCC: 36) with NCUC stage I-IV (stage I: 29, stage II: 9, stage III: 7, stage IV: 14, unknown: 3). Median age of diagnosis was 47 years (range 21-77 years). By subtype, 47 were small cell (76%), 9 were large cell (15%), and 6 were unknown/undetermined (9%). The initial treatment modalities for each patient are outlined in the table. 28 patients had complete/partial response or stable disease from first line treatment, while 10 patients had disease progression. Of the patients who initially responded or had stable disease, 16 later progressed (57%) with a median time to progression of 15 months. Median follow up was 65.1 months with a median OS of 28.5 months. Median survival for those with stage I was 40.9 months, stage II: 54.6 months, stage III: 8.75 months, and stage IV: 11.7 months. There was a significant difference in overall survival at 1 year between those who received surgery and those who did not in stage I/II ( p = 0.01). There was no significant difference in overall survival at 1 year for those who received surgery in stage III/IV. There was no statistical difference in survival at 1 year for carboplatin or cisplatin in combination with etoposide as first line chemotherapy agent. Conclusions: NCUC is an aggressive malignancy that is usually progressive despite multimodal therapy. Our study demonstrated a median overall survival of 28.5 months and 5-year survival rate of 21%. Our study showed a survival benefit at 1 year for those who receive surgery with stage I/II NCUC. There was no significant survival benefit at 1 year between carboplatin or cisplatin in combination with etoposide as first line agent.[Table: see text]
Cervical cancer screening: Twelve years experience of the Kazakhstan National Screening program.
Authors: Bolatbekova Raikhan , Kaidarova Dilyara , Zhylkaidarova Alma , Sadykova Tolkyn , Kukubassov Yerlan , Satanova Alima , Aidarov Askar
Published: June 2021

e17520

Background: Cervical cancer (CC) is the most common gynecological cancer in Kazakhstan (KZ). Standardized incidence rate of CC was 16.7 per 100, 000, while the mortality rate was 5, 9 per 100, 000, in 2020. The National Cervical Screening program in KZ uses cytology (Pap test) from 2008, which is free of charge for women aged 30 to 70 years of age with an interval of 4 years. In 2017 Experts from ImPact Mission and analyzed existing CC screening revealed a number of recommendations aimed at reducing the screening interval and increasing the coverage. The purpose of this study was to analyze results of CC screening in KZ and his impact on CC incidence and mortality. Methods: Coverage, the number of screened women, the level of pre-cancer detection and cervical cancer during screening have been obtained from specific reports (form № 025, № 08) for 2008-2020. Results: The total number of screened women for 2008 were 554 283 women. There is a decrease in screening coverage to 45.9% in 2017 due to a decrease in funding. in this regard, in 2017, a number of changes were made to the existing screening program. In 2020 after the CC screening improvement 786 690 women were examined during the screening program, coverage rate was 66, 2%, . Analysis of screening results showed a marked increase in the detection of precancerous lesion from 0, 136 in 2008 to 0, 87 with an increasing by 37%. The analysis of CC incidence revealed significant changes: after the introduction of screening, an increase in the incidence rate is noted from 15.5 in 2008 to 20.1 per 100, 000 female population in 2015. Since 2015, there has been a significant decrease to 16.7 per 100, 000 women. Conclusions: Despite the positive results of screening, an increse the screening coverage, improvement in the detection of the initial stage of CC, mortality rate from CC and a one-year mortality remain high, which makes it necessary to improve the screening of CC in KZ through the introduction of HPV-screening
Investigating reasons for discontinuation of first-line adjuvant chemotherapy among ovarian cancer patients in the midwestern United States.
Authors: Weeks Kristin S. , Stewart Sherri L. , West Michele , Carnahan Ryan , Oleson Jacob , Lynch Charles F.
Published: June 2021

e17523

Background: Receipt of surgery and adjuvant chemotherapy greatly impact survival outcomes for ovarian cancer, the deadliest gynecologic malignancy with a high recurrence/progression rate. Most patients receive first-line, platinum-based chemotherapy. Platinum-based chemotherapy causes severe side effects, including nephrotoxicity and myelosuppression. Evidence for other chemotherapeutic agents is lacking and options are limited for women who cannot tolerate first-line chemotherapy. We aimed to determine the prevalence of premature first-line chemotherapy discontinuation and to detail reasons for discontinuation. Methods: We used the population-based cohort, Patterns of Ovarian Cancer Care and Survival in the Midwestern Region of the United States—a CDC Investigation, comprised of women diagnosed with histologically confirmed, stage IB-IV ovarian cancer in 2010-2012 in the Midwestern United States (i.e., Iowa, Kansas and Missouri) between the ages of 18 and 89 years. We limited the cohort to patients who received cancer-directed surgery and initiated adjuvant chemotherapy. Chemotherapy lines, completion, and reasons for discontinuation were abstracted from patient medical records by cancer registrars using standardized protocols. Results: Nineteen percent (N= 107/559) of ovarian cancer patients who initiated adjuvant chemotherapy did not complete first-line treatment. Reasons for chemotherapy discontinuation included toxicity or other kinds of intolerance (39%), poor quality of life or comorbid conditions (19%) or exhibited no response (17%) (Table). No significant differences were observed between gynecologic oncologists and non-gynecologic oncologist chemotherapy providers (p=0.109). Conclusions: One in 5 women who initiated did not complete first-line chemotherapy. Reasons were varied and suggested that lack of tolerance is not the only factor in discontinuation. Lack of response and the presence of comorbid conditions are considerations that can be taken into account during decision-making processes for treatment. More clinical research into additional chemotherapy options that may be useful in these patients is necessary.[Table: see text]
Anlotinib in patients with recurrent platinum-resistant or refractory ovarian carcinoma: A prospective, single-arm, single-center, phase II clinical study.
Authors: Wang Huaying , Shen Wenbin , Shan Boer
Published: June 2021

e17524

Background: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and its anti-tumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and c-kit. This phase II study aims to evaluate the safety and efficacy of anlotinib monotherapy in patients with recurrent or refractory ovarian carcinoma. We have previously reported primary results (objective response rate (ORR) 35.7%, 95%CI: 12.8-64.9; and disease control rate (DCR) 85.7%, 95%CI: 57.2-98.2) in 14 patients), and we now present the updated ORR, DCR and safety data in more patients. Methods: Patients who have previously received second-line or more chemotherapy, with histopathologically confirmed ovarian high-grade serous gonadal ovarian carcer (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2 were considered eligible for enrollment. Anlotinib was administered orally (12 mg qd, d1-14; 21 days per cycle) till disease progression, death or intolerant toxicity. Therapeutic effects are evaluated every 6 weeks. The primary endpoint was ORR and the secondary endpoints included DCR, progression-free survival (PFS), overall survival (OS), safety and quality of life (QoL). Results: Between March 2019 and January 2021, 31 patients (female) with FIGO histopathological stage IC (1, 3.2%), IIC (1, 3.2%), IIIC (23, 74.2%) and IV (6, 19.4%) were enrolled and 24 patients were evaluable with a median age of 59 years (range: 37-73). The median treatment period was 4.96 months (95% CI: 4.50-7.56). Therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 4.2%, 25%, 45.8% and 25% respectively, yielding the ORR of 29.2% (7/24; 95% CI: 14.6-57.0) and the DCR of 75.0% (18/24; 95% CI: 53.3-90.2). The median PFS was 6.34 months (95% CI: 3.14-9.54). The median OS was not reached. Most of the occurring adverse events (AEs) were grade 1 and grade 2, and ≥10% grade 1 AEs included hypertention (45.83%), fatigue (29.17%), hand-foot syndrome (33.33%) and hoarseness (12.50%). Grade 2 AEs only included gingival bleeding (4.2%), hand-foot syndrome (4.2%), renal dysfunction (4.2%) and cancer pain (4.2%). No higher grade AEs were observed. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib showed a promising efficacy with an acceptable safety profile for patients with recurrent platinum-resistant or refractory ovarian carcinoma. Further evaluation of PFS and OS is ongoing. Clinical trial information: ChiCTR2000029654.
Impact of pleural effusion in ovarian cancer: A retrospective study in Lleida, Spain.
Authors: Murata Eleonor Paola , Bielsa Silvia , Pardina Marina , Salud Salvia Antonieta , Porcel Laura , Porcel Jm
Published: June 2021

e17534

Background: The presence of pleural effusion in the evolution of patients with ovarian cancer is not uncommon. In one series of 123 patients, malignant pleural effusion at the diagnoses was observed in 29%, and 70% during the course of the disease. Methods: This observational, retrospective study included patients with ovarian cancer and pleural effusion between July 2007 and December 2019 in Lleida, province of Catalonia, Spain. Data were collected from electronic medical reports. This study analyzed the clinical features of ovarian cancer patients with pleural effusion and its impact on their survival. Results: Data from 189 patients with ovarian cancer were collected. The median age was 63 years old. Pleural effusion was observed in 81 patients, 55 at the diagnosis and 26 in the disease evolution. Fifty five percent were confirmed as malignant etiology. Most of the patients were diagnosed with an advanced stage (38.3% stage IIIC, 12.3% stage IVA, 40.7% stage IVB), and 74.1% were high-grade serous carcinoma. When the pleural effusion was observed at the diagnosis, the median overall survival was 20.8 vs 69.3 months in the absence of it (p < 0.001). When the pleural effusion was observed at any time of the disease, the median overall survival was 26.7 vs 90.4 months without it (p < 0.001). Conclusions: In this study, patients with ovarian cancer and pleural effusion, at diagnosis or in the course of the disease, experienced reduced survival compared with the absence of it.
Variance of HRD score from primary to recurrent in high-grade serous ovarian cancer.
Authors: Chen Xiaoxiang , Ni Jing , Xu Xia , Guo Wenwen , Zhao Qian , Cheng Xianzhong , Zhou Rui , Gu Hongyuan , Chen Chen
Published: June 2021

e17540

Background: Homologous recombination deficiency (HRD) is an important biomarker of poly (ADP-ribose) polymerase inhibitor (PARPi) in patients with high-grade serous ovarian cancer (HGSOC). The stability of HRD in the recurrent HGSOC and its primary pair from Jiangsu Institute of Cancer Hospital was investigated. Methods: A total of paired 18 samples from 9 HGSOC patients were analyzed. HRD score was evaluated by loss of heterozygosity(LOH) and genetic mutations were also detected from next-generation sequencing.The student t-test evaluated the difference of HRD score between matched tumors. The functional annotation and clustering of affected genes in the recurrent tumor cells were analyzed by the KEGG Orthology (KO) database. Results: The HRD score of recurrent HGSOC tumors was significantly higher than that of the paired primary ones (p = 0.004). A total of 30 new somatic sequence variants at 27 genes presented in the recurrent tumors, were not found in any matched primary tumors. Of which, 19 (63.3%) were copy number variants (CNVs), 3 (10%) variants were rearrangement, and 8 (26.7%) were somatic point mutation. In these17 genes with CNVs, 14 genes had gene amplification variants, among them 50% (7/14) genes associated with the positive regulation of cell proliferation and cellular response to DNA damage stimulus. Four somatic point mutations involved in tumor suppressor pathway. Conclusions: Our data shed first light on the statistically significant changes of HRD score in paired recurrent HGSOC. The HRD score changes over time may imply further instantaneity assay strategy.
Identification of signal transduction pathway activity with potential clinical target in high-grade serous ovarian and tubal carcinoma.
Authors: van der Ploeg Phyllis , van Lieshout Laura A.M. , Wesseling-Rozendaal Yvonne J.W. , Van De Stolpe Anja , Bosch Steven L. , Lentjes-Beer Marjolein H.F.M. , van Diest Paul J. , Vos M.Caroline , De Hullu Joanne , Bekkers Ruud L.M. , Piek Jurgen M.J.
Published: June 2021

e17541

Background: High-grade serous carcinoma (HGSC) is the most common subtype of epithelial ovarian and tubal cancer. It has a high mortality rate, even after successful first-line treatment with debulking surgery and chemotherapy. Although therapeutic options for targeted therapy are rapidly expanding, identification of patients who respond to these therapies remains a challenge. In recognition of the importance of the functional phenotype of cancer cells, Verhaegh et al. (Cancer Res 2014) developed assays to measure functional activity of signal transduction pathways (STPs) based on mRNA expression levels of pathway-specific target genes. In this study, we aimed to identify HGSCs with STP activity with potential clinical target by comparing their activity assessment with STP activity in normal Fallopian tube epithelium (FTE), the tissue of origin of most HGSCs. Methods: We included 67 primary tumor samples taken prior to start of chemotherapy of postmenopausal patients diagnosed with advanced stage HGSC and 8 morphologically normal FTE samples of healthy postmenopausal women. Using OncoSignal pathway assays, we assessed functional pathway activity of the androgen receptor (AR), estrogen receptor (ER), PI3K, Hedgehog, TGF-𝛽 and Wnt pathways. Differences in STP activity between groups were compared with Mann-Whitney U tests. Cut-off value for aberrant STP activity was defined as two standard deviations above the mean value of STP activity measured in FTE samples. Results: In the HGSC group we observed lower median ER (p < 0.001) and Wnt (p = 0.046) pathway activity and higher median PI3K (p = 0.025) and TGF-𝛽 pathway (p = 0.030) activity as compared to the normal FTE group. In individual HGSC samples, aberrant activity was identified for the AR (n = 14), PI3K (n = 16), Hedgehog (n = 4), TGF-𝛽 (n = 36) and Wnt (n = 10) pathways. Frequently observed combinations of aberrant STP activity were AR/TGF-𝛽 (n = 8), TGF-𝛽/Wnt (n = 6) and PI3K/Hedgehog (n = 3). In total, we identified at least one STP with potential clinical target in 52 of the 67 HGSC samples. Conclusions: Our analysis enabled the identification of STP activity with potential clinical target in 78% of the analyzed HGSC samples. Differentiation between normal and aberrant STP activity could have clinical utility in the selection of HGSC patients for targeted therapy.
Stem-like markers in the circulating tumor cells assessment in ovarian cancer.
Authors: Gening Snezhanna , Abakumova Tatyana , Antoneeva Inna , Gening Tatyana
Published: June 2021

e17542

Background: Circulating tumor cells (CTCs) are a potential source of dissemination and relapse in ovarian cancer (OC). Stem cell properties can provide a survival advantage for CTCs. The clinical significance of stem-like CTCs in OC remains to be studied. We aimed to assess the quantities of the stem, epithelial, mesenchymal CTCs and their relationships with the clinical parameters in the OC. Methods: Peripheral blood samples (7.5 ml) were obtained from patients with primary epithelial OC before treatment. CTCs were isolated by flow cytometry (Cytoflex S (Beckman Coulter, USA)) using antibodies to CD45 (BioLegend, USA); CD44 (BioLegend, USA), CD133 (Miltenyi biotec, Germany), ALDH (Stemcell, Canada) to detect the stem markers; EpCAM (BioLegend, USA), cytokeratins 8, 18 (Abcam plc., UK), vimentin (BioLegend, USA) for epithelial and mesenchymal markers. Blood samples from patients with benign ovarian tumors served as a control. Informed voluntary consent was obtained from all the women. Statistical processing included Mann-Whitney U-test, linear regression, Cox proportional hazards model for progression-free survival (PFS) (Statistica 13.0 (TIBCO, USA)). Results: The study included 30 patients, median age 64 (34-76) years. 15 patients had a FIGO stage IV, 12 - stage III, 1 – stage II and 1 – stage I. The content of CTCs populations is presented in the table. The CTCs counts did not differ depending on age, platelet count, and stage 3 or 4. The amount of CD45-CK+Vim- was higher in the presence of ascites (p = 0.035). We found a regression relationship between the serum CA-125 and the number of CD45-CD44+CD133+ (R2= 0.220, p = 0.016); the leukocyte count in blood and CD45-CD44+ALDHhigh (R2= 0.234, p = 0.017); the number of CD45-Vim+ and CD45-CD44+CD133+ALDH+ (R2= 0.305, p = 0.014); CD45-CK-Vim+ and CD45-EpCAM+CK+ (R2= 0.717, p < 0.001). The Cox regression model for PFS included the number of CD45-CD44+CD133+ALDH+ (HR 1.51 95% CI 1.01-2.24 p = 0.043) and the cytoreductive surgery performance (HR 0.09 95% CI 0.01-0.89 p = 0.039) during the first line of treatment. Conclusions: Various populations of circulating tumor cells coexist in ovarian cancer patients. The use of a combination of stem markers in the CTCs detection can increase their prognostic value in OC. This work was supported by the RFBR grant No. 19-315-90011.[Table: see text]