bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary urachal carcinoma: A systematic review.
Authors: Findakly Dawood , Wang Jue
Published: June 2021

e16502

Background: Primary urachal carcinoma (PUC) is a rare cancer of unknown definite cause, and various treatment approaches given its very low incidence and the scarcity of prospective studies. This review aimed to assess the clinicopathologic findings, treatment, and outcomes of PUC cases reported in the literature. Methods: We performed PubMed, Medline, ScienceDirect, and Scopus literature search for "urachus cancer" in adults (19+ years) from data inception through 2020, pooled with six cases from our institution. Results: We included 152 patients with a male: female ratio of 1.61:1 and mean age at diagnosis (±SD, range) of 50.0 (±13.5, 20–86) years. Most common presenting symptoms were hematuria, irritative voiding, abdominal pain, mucinuria, and a palpable mass in 49.5%, 17.3%, 10.2%, 8.7%, and 6.6% of patients, respectively, with a median duration of symptoms of 3 (range 0.25-240) months. Most common locations were the urinary bladder dome (83.6%), supero-anterior (7.03%), and the anterior wall (3.9%), with a median size of 4.9 (range 0.5–96) cm. Subgroups, according to tumor size, were divided into < 4 cm (n = 54, 35.5%) vs ≥4 cm (n = 98, 64.5%) with a significant survival differences according to a log-rank test (p-value < 0.0001). Histologically, the most common diagnoses were urachal adenocarcinoma (43.4%), followed by mucinous adenocarcinoma (24.1%), adenocarcinoma of enteric type (8.9%), and adenocarcinoma with signet ring cell (6.9%). 17.5% and 72.2% of patients were diagnosed at an early stage (stage I and II) while 82.5% and 27.8% were diagnosed at an advanced stage ( III and IV) using Sheldon staging system and Mayo staging system, respectively. Only 9.9% of patients lived for more than five years after their diagnosis. Early Sheldon stage is associated with a high survival probability based on a log-rank test (p-value: 0.003). Overall, most common treatment modalities included surgery alone (71.0%), followed by surgery with chemotherapy (18.6%), and surgery with chemoradiation (4.1%). Patients underwent partial cystectomy (65.4%), en bloc radical resection/exenteration (25.7%), local resection (8.8%), pelvic lymphadenectomy (38.2%), and umbilectomy (16.9%). Almost 79% of patients were alive with an average duration of follow-up of 12 (range 0.9-240) months, and 20.9% were deceased with an average time to death of 23.9 (range 5-139) months. Conclusions: Early Sheldon stage and smaller tumor size were notable predictors of higher survival probability in PUC patients. Hence, early and correct diagnosis is crucial in improving outcomes. This review serves as real-world evidence to promote our understanding of this rare entity and shed light on future clinical trial design.
Clinical safety and activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) after platinum chemotherapy (ARCADIA): Preliminary results from a nonrandomized, open-label, phase 2 trial.
Authors: Giannatempo Patrizia , Franza Andrea , Marandino Laura , Raggi Daniele , Calareso Giuseppina , Alessi Alessandra , Colecchia Maurizio , Bevilacqua Liana , Russo Giusy , Del Re Marzia , Anichini Andrea , Sgambelluri Francesco , Sepe Pierangela , Zimatore Matteo , Claps Melanie , Verzoni Elena , Guadalupi Valentina , Ottini Arianna , Procopio Giuseppe , Necchi Andrea
Published: June 2021

e16529

Background: Combining anti-VEGFR drugs with checkpoint inhibitors have shown synergistic effect in pts with UC. ARCADIA is a phase 2 trial evaluating the safety and efficacy of combination of CABO, a multikinase inhibitor, with the anti-PDL1 DURVA in pts with platinum-refractory advanced UC or variant histology (NCT03824691). Herein we report the preliminary results. Methods: Pts received CABO 40 mg daily, orally, in combination with DURVA 1500 mg, intravenously, every 28 days, until disease progression or unacceptable toxicity. Key inclusion criteria were: ECOG-PS 0-1, UC or variant histology, failure of 1 or 2 platinum-based regimen for metastatic disease, non-measurable disease was permitted. Response was evaluated by RECIST criteria v.1.1 every 2 cycles by CT and 18FDG PET/CT scans. The primary endpoint of the study was overall survival (OS). Other endpoints included safety, objective response-rate (ORR), duration of response, progression-free survival (PFS). PD-L1 expression was assessed by Ventana SP142 assay. Next-generation sequencing tests (FoundationOne) on pre-therapy tumor samples were performed. Results: From September 2019 to February 2021, 26 pts were enrolled with a median follow-up of 5 mo. Median age was 64 yrs (range 44-74), 69% were male, and 23% had ECOG PS 1. 8 pts presented variant histology. Five pts (19%) had received 2 prior systemic anticancer therapies. In pts evaluable for efficacy analyses, 3 (11.5%) complete responses (CR) and 6 (23.1%) partial responses (PR) were observed. The ORR and DCR were 34.6% and 57.7% respectively. Treatment-related AEs (TRAEs) occurred in 17 pts (65%), including 2 (8%) grade 3 TRAEs, within the first 2 cycles. 7 pts (27%) discontinued CABO due to toxicity, no interruption of DURVA was observed. The most common AEs by any grade were transaminase increase (35.7%), asthenia (27%), diarrhea (27%), and hypertension (15%). Conclusions: Combination of CABO and DURVA demonstrated promising preliminary activity and a manageable safety profile in pts with advanced UC and variant histology. More mature results according to biomarkers and histology will be presented. Clinical trial information: NCT03824691.
Retrospective analysis of multiparametric MRI to predict complete pathologic response after neo-adjuvant chemotherapy for muscle invasive bladder cancer.
Authors: De Maeseneer Daan , De Visschere Pieter , Van den Broecke Mats , Villeirs Geert , Verbeke Sofie , Decaestecker Karel , Rottey Sylvie
Published: June 2021

e16535

Background: Muscle invasive bladder cancer (MIBC) is a life-threatening disease. Treatment is multimodal combining neo-adjuvant cisplatin-based chemotherapy (NAC) and radical cystectomy (RC). Accurately predicting complete pathologic response (pCR) using multiparametric MRI (mpMRI) could impact peri-operatively treatment. Methods: MIBC patients receiving NAC were evaluated at our institution with mpMRI before, after 2 cycles and after 4 cycles of dose dense MVAC (ddMVAC). Response after 4 cycles was retrospectively assessed using the method earlier described by Necchi et al with blinding of the readers for the pathological result of RC. Two radiologists independently evaluated 3 questions: residual disease at T1/T2-weighted images, presence of spots of restrictive diffusion within the bladder wall on diffusion-weighted imaging, and presence of focal contrast enhancement in the bladder wall on dynamic contrast enhanced images. Radiographic complete response (rCR) was defined as “No” on all three questions. Results: A total of 46 patients were identified having received ddMVAC for urothelial MIBC. Six patients did not undergo RC after NAC and were excluded from this analysis. Eleven out of 40 (28%) patients showed a complete pathologic response (ypT0). Baseline characteristics were similar compared to non-complete pathologic responders ( > ypT0), with the exception of hydronephrosis (9% in ypT0 vs. 52% in > ypT0). mpMRI questions could be assessed in 37 of 40 patients (93%). rCR was seen in 5 patients and was significantly associated with pCR (1-sided p value 0.021). Although sensitivity was low (36%), specificity was very high (96%) of this 3-step assessment. Positive likelihood ratio was 9.45, negative likelihood ratio 0.66. Concordance of assessment was very high. Conclusions: Using the 3-step imaging approach of Necchi et al, mpMRI can predict pCR after neo-adjuvant cisplatin-based chemotherapy with high specificity but low sensitivity. mpMRI should be included in future trials of multimodal management of MIBC and is an important predictive asset in routine clinical management.[Table: see text]
Association of BMI, body composition and outcomes in Chinese patients with metastatic renal cell carcinoma treated with immunotherapy: A retrospective, multicohort analysis.
Authors: Wang Jun , Qu Yuanyuan , Xu Wenhao , Yu Chunping , Zhang Zhiling , Ye Dingwei , Zhou Fangjian
Published: June 2021

e16563

Association of BMI, body composition and outcomes in Chinese patients with metastatic renal cell carcinoma treated with immunotherapy: a retrospective, multicohort analysis. Background: Obesity (body-mass index [BMI] ≥30 kg/m) is associated with a higher risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with better outcome in renal cell carcinoma (RCC) patients treated with immunotherapy. Whether BMI associate outcomes in Chinese RCC patients treated with immunotherapy considering Asian population has a lower BMI? In this study, we aimed to investigate the relationship between BMI, body composition and outcomes of Chinese patients with RCC treated with immunotherapy. Methods: We evaluated clinical data of metastatic RCC patients treated with immunotherapy from five major centers in China. Despite using the Chinese standard, only 6 people met the obese standard (BMI ≥28 kg/m, as per WHO's BMI categories), so we divided the patients into high BMI gourps (BMI ≥24.0 kg/m), and normal weight groups (BMI 18.5-23·9 kg/m). We assessed overall survival, defined as the time from treatment initiation to the date of any-cause death or of censoring on the day of the last follow-up, in high BMI patients and in patients with a normal weight. We also investigative the relationship between body composition (skeletal muscle index (SMI = skeletal muscle area/height2), skeletal muscle density (SMD), and subcutaneous adipose distribution index (SADI = subcutaneous adipose tissue area / subcutaneous adipose tissue area + visceral adipose tissue area) of each patient at the third lumbar vertebrae) and overall survival using CT or MRI scan at the treatment initiation. Results: Out of a total of 222 patients, 203 had evaluable CT or MRI radiographs, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 4 (1.7%) underwetight patients, leaving a final cohort of 199 patients from this study for our analyses. There were 79 (39.7%) high BMI patients and 120 (65.3%) normal weight patients. There was no difference in overall survival between the high BMI and normal weight groups (HR:1.36, CI 0.83-2.21). In addition, SMI and SMD were not associated with outcome of patients. Interestingly, although there was no statistical difference, subcutaneous fat was associated with better outcomes, while visceral fat was associated with poor outcomes. Thus, the combination of the two indicators, SADI, showed a significant prognostic correlation after adjustment for International Metastatic RCC Database risk score (aHR:0.314, CI 0.19-0.51). Conclusions: BMI is not a good predictor of the outcome of immunotherapy in Chinese patients with RCC. Evaluation of body composition may be a better tool for predicting prognosis in RCC patients treated with immunotherapy.
What happened to the preserved renal parenchyma after partial nephrectomy?
Authors: Campbell Steven , Xiong Longbin , Jane Nguyen , Zhou Fangjian , Zhang Zhiling , Peng Yulu
Published: June 2021

e16581

Background: Partial nephrectomy (PN) is the standard therapy for small renal mass, despite various degree of ischemia reperfusion injury (IRI) is always inevitable as the renal artery is usually clamped during PN. In mouse IRI model, unilateral renal artery clamped for 21 minutes results to sever kidney fibrosis in one year. However, what happened to the preserved renal parenchyma after several years since PN is still a mystery. The aim of the study is to compare the pathological chronic kidney disease (CKD) score of normal renal parenchyma before and several years after PN, as well as to explore the factors that associated with CKD score increase and GFR decline. Methods: We retrospectively collected the clinicopathologic data of 114 renal cell carcinoma (RCC) patients who underwent PN and subsequent radical nephrectomy (RN) due to tumor recurrence in 19 Chinese centers and Cleveland clinic. Macroscopic normal renal parenchyma was sampled at least 5 mm away from the tumor border in PN specimen and at distal portion of the kidney in RN specimen. Pathological CKD score is a summary of glomerular, tubular, interstitial, and vascular score. MDRD2 equation was used to estimate the glomerular filtration rate (GFR). Predictive factors for CKD score increase were evaluated by logistic regression. Results: A total of 64 patients that have all the required data were included in the analysis. The median duration warm ischemia (n = 41) and hypothermia (n = 23) were both 23 min. In a median interval of 2.44 years, the CKD score arose in 73.4% (47/64) patients, with 45.3% (29/64) cases increased by ≥3. Even so, no kidney fibrosis was observed in this cohort including in those with extend warm ischemia (≥45min). There was no significant difference in the change of CKD score during patients with different ischemia time and type. However, patients with comorbidities such as hypertension, diabetes mellitus or CKD (HTN/DM/CKD) showed higher rate and extent of CKD score increase. In multivariate analysis, HTN/DM/CKD was found to be an independent predictor for the CKD score increase [OR:4.24 (1.23-14.64)]. However, the decline of GFR was mild and analogous between patients with or without CKD score increase (23.03±22.53ml/min/1.73m2 vs. 24.27±21.79ml/min/1.73m2, p = 0.856). Conclusions: In majority, preserved renal parenchyma after PN suffered pathological deterioration. Ischemia time and type seem to have limited impact on the change of CKD score of preserved renal parenchyma during PN. Patients with HTN/DM/CKD have higher risk of CKD score increase in despite of similar mild GFR deterioration.
Post radical prostatectomy prostate-specific antigen doubling-time kinetics: Observations of increasing versus decreasing doubling times.
Authors: Huynh Linda My , Huang Erica , Skarecky Douglas , Ahlering Tom Edward
Published: June 2021

e17002

Background: Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of distant metastatic progression or prostate cancer (PC) death, consequently resulting in overtreatment. Further, little has been published about active surveillance (AS) specific management recommendations. Herein, we validate the practicality of using the kinetics (change) of PSA doubling time (PSADT) to direct continued observation versus intervention. Methods: In a retrospective cohort analysis of 406 men with BCR (defined as adjuvant therapy or PSA > 0.2 ng/dl, x2), 284 men were monitored post RP with PSADT graphs for all patients, and the PSADT was characterized as increasing vs decreasing. Receiver-operator characteristic (ROC) curves were generated to assess the sensitivity/specificity/positive predictive value/negative predictive value of PSADT progression on treatment and prostate cancer specific mortality at 10 years post-RARP, respectively. Results: The median follow-up was 7.6 (IQR: 4.6-10.6) years. Of 284 men, 109 (38%) and 175 (62%) were in the no treatment versus treatment groups, respectively. 87% of men receiving treatment had a decreasing PSADT and 100% men with PCSM had a decreasing PSADT. ROC analysis showed 0.870 sensitivity and 1.0 specificity when predicting secondary treatment (AUC = 0.935) and 0.857 sensitivity and 0.50 specificity when predicting PCSM (AUC = 0.679). Conclusions: A decreasing PSADT is a sensitive and specific metric for predicting the need for secondary intervention. We also found all men who died of PC had a decreasing PSADT. Lastly an increasing DT predicts a benign course without need for treatment. The current findings suggest that the kinetics of PSADT, increasing versus decreasing, is an accurate metric for the need of treatment. A direct comparison between PSADT kinetics and PSADT is needed.
Genomic characteristics of homologous recombination deficiency in prostate cancer.
Authors: Wei Yu , Yao Zhu , Cui Lina , Zhao Xiaochen , Bai Yuezong , Ye Dingwei
Published: June 2021

e17004

Background: PARP inhibitors (PARPi) have been approved in the treatment of metastatic castration-resistant prostate cancer with deleterious or suspected deleterious alterations in homologous recombination repair (HRR) genes. Patients carrying alterations of different HRR genes showed diverse response to PARPi, while the underlying mechanism is unrevealed. Homologous recombination deficiency (HRD) score serves as a promising way to interpret the genomic instability by targeted next-generation sequencing (NGS). In this study, we analyzed HRD score and its relationship to genomic characteristics in a prostate cancer (PC) cohort. Methods: Tumor tissue and matched white blood cells from 295 PC patients were analyzed by NGS-based assays, which target over 10,000 single-nucleotide polymorphisms distributed across human genome to characterize genomic instability, as well as the whole coding region of 733 or 233 genes. HRD score was derived by the sum of three indexes, including loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions. Deleterious or suspected deleterious mutations were included for analysis. Tumor mutation burden (TMB) was calculated by the number of somatic single nucleotide variants and indels in examined coding regions, with driver mutations excluded. An ovarian and fallopian tube cancer cohort, carrying deleterious or suspected deleterious mutations in BRCA1/2, was also included. Results: In PC cohort, 25 patients (8.47%) had BRCA1/2 mutations, with additional 39 patients (13.2%) carrying mutations in HRR genes other than BRCA1/2. HRD score was similar among tumors with germline BRCA1/2 mutation (n = 9), somatic BRCA1/2 mutation (n = 14) or both (n = 2) (median HRD score 38.0, 32.5 and 49.5; P = 0.281). In BRCA1/2 mutation carriers, HRD score in PC cohort was lower than ovarian cancer (n = 222) and fallopian tube cancer (n = 8) (median HRD score 36, 54 and 67; P < 0.001). PC samples with CDK12 (n = 35), ATM (n = 13) and PALB2 (n = 2) mutations had lower HRD score compared with BRCA1/2 mutants (median HRD score 24, 14, 11 and 36; P < 0.001). In PC patients without HRR mutation, HRD score was higher in TP53 mutants compared with TP53 wildtype (median HRD score 25 and 14; P < 0.001), while tumors with ERG fusion had lower HRD score than ERG fusion absent tumors (median HRD score 8 and 18.5; P = 0.029). In four TP53 mutated PC patients treated with PARPi in our center, three patients achieved PSA response. Furthermore, no linear correlation was discovered between TMB and HRD score, while tumors with higher HRD score (HRD score ≥ 30) had a bit lower TMB (median TMB 3.07 vs 3.91, P = 0.002). Conclusions: HRD score was affected by alterations in different HRR genes, TP53 mutation and ERG fusion, which should be taken into consideration of the future clinical trials and research on intrinsic mechanisms. Patients carrying alterations other than HRR genes might benefit from PARPi. Further studies are needed.
Predictive factors for choriocarcinoma syndrome development in high-risk patients with germ cell tumors (GCTs).
Authors: Rejlekova Katarina , Kalavska Katarina , Makovnik Marek , Hapakova Nikola , Chovanec Michal , De Angelis Valentina , Obertova Jana , Palacka Patrik , Sycova Zuzana , Mardiak Jozef , Mego Michal
Published: June 2021

e17010

Background: Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of patients with super-high-risk characteristics can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS). CS is defined as a syndrome with hemorrhage from metastatic sites in patients with advanced GCTs with high-volume of choriocarcinoma elements, especially those with a choriogonadotropin level over 50,000 IU/l. CS typically develop shortly after the chemotherapy start with high mortality rate. Our retrospective study aimed to determine the risk factors of high-risk GCTs susceptible to CS development. Methods: Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated in NCI through 2000 to 2018, and 90 eligible patients with high-risk GCTs relying on IGCCCG classification, were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation to CS development. Results: Nine (10 %) of 90 patients developed CS in a median of 1 day (1- 9 days) after the chemotherapy administration. All patients died shortly after the chemotherapy start with median of 4 days (3-35 days) due to consecutive ARDS development. Predictive factors for CS development were metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss and hemoglobin ≤100 g/l at the time of presentation. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS compared to 0% with one or zero of these predictive factors (P < 0.000001). Conclusions: In our study we identified predictive factors for CS development. These factors might improve the risk stratification of the patients susceptible to CS development connected with ARDS as well as to find optimal treatment approach for them.
Immune checkpoint inhibitor plus anti-EGFR target therapy plus chemotherapy in patients with locally advanced penile squamous cell carcinoma.
Authors: Han Hui , An Xin , Yan Ru , Guo Shengjie , Xue Cong , Liu Tingyu , Tian Li , Ma Huali , Li Yonghong , Qin Zike , Liu Zhuowei , Zhou Fang-Jian , Shi Yanxia
Published: June 2021

e17016

Background: Locally advanced penile squamous cell carcinomas (PSCCs) have poor prognosis and limited therapeutic options. We aim to evaluate the safety and the efficacy of neoadjuvant therapy with anti-PD-1 immune therapy (toripalimab) plus anti-EGFR target therapy (nimotuzumab) plus chemotherapy (TIP) in locally advanced PSCCs. Methods: We retrospectively reviewed chemotherapy-naive, unresectable locally advanced PSCCs (T4NanyM0 or TanyN3M0) who received combined neoadjuvant therapy and subsequently radical surgery in Sun Yat-sen University Cancer Center between 2018 and 2020. All patients received toripalimab 240mg on day 1 plus nimotuzumab 400mg on day 1 plus standard-of-care TIP (Cisplatin 25mg/m2 on day 1 to day 3; ifosfamide 1.2g/m2 on day 1 to day 3; paclitaxel 175mg/m2 or albumin-bound paclitaxel 260mg/m2 on day 1) every 3-4 weeks. Pathologic complete response(pCR) rate and toxicity were evaluated. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier estimation. Results: We screened 12 patients in total who had performed toripalimab plus nimotuzumab plus TIP (TNTIP) as neoadjuvant treatment and subsequently radical surgery. Median age was 51 (95% confidence interval [CI]: 44-60.5) years old. 10(83.3%) patients received 3 or 4 courses of TNTIP neoadjuvant treatment. After neoadjuvant treatment and radical surgery, 8(66.7%) patients had a pCR. 2(16.7%) patients died of disease progress or recurrence, which 1(8.3%) patient occurred bone metastases after 2 courses of TNTIP, and 1(8.3%) patient appeared recurrence after 6 months of radical surgery. The median follow-up time was 21.3 months (95%CI 19.9-22.6). Median PFS and OS were not reached. The 1-year PFS rate was 83.3% and 1-year OS rate was 91.7%. 3(25%) patients experienced grade 3 treatment-related adverse events of fatigue, anemia and neutropenia. No grade 4 or 5 adverse events or death associated with treatment. Conclusions: Compared with other therapeutic options, our results suggest that TNTIP in neoadjuvant stage effectively improve the disease control and prognosis in locally advanced PSCCs. Based on this result, we are conducting a phase II study in Sun Yat-sen University Cancer Center to further validate the efficacy and safety of TNTIP neoadjuvant regimen in locally advanced PSCCs. (ClinicalTrials.gov No. NCT04475016).
Serial ctDNA profiling in patients with metastatic prostate cancer undergoing treatment with radium-223.
Authors: Blanding Dena , Drusbosky Leylah , Gourdin Theodore Stewart , Lilly Michael B.
Published: June 2021

e17018

Background: Assessment of the anti-tumor response to radium-223 (Ra-223) treatment is difficult in individuals. PSA levels seldom fall and imaging of existing bone metastases is imprecise. Circulating tumor DNA (ctDNA) is a non-invasive marker of prostate tumor DNA, with static measurements demonstrating high concordance rates with tumor DNA. Serial monitoring of ctDNA levels may provide insights into therapy response, targetable mutations, and progression of disease. We report changes in ctDNA profiles and clinical associations of 10 patients who had serial ctDNA profiles during Ra-223 treatment. Methods: Serial ctDNA analyses of mutations (73 genes) and amplifications (18 genes) were performed via a commercial provider (Guardant 360; Guardant Health). Assays were performed before treatment, after the third Ra-223 dose, and after the final Ra-223 dose. ctDNA data (minor allele frequencies for mutations, copy number for amplifications) were reviewed to identify clonal mutations with at least 50% change in highest allelic frequency or 30% change in copy number during treatment. Clinical data (performance status (PS), PSA, pain score, prescribed oral morphine equivalents (OME), imaging, progression free survival (PFS), and overall survival) were gathered via chart review. Clinical progression was defined by an increase in at least 2 bone lesions on bone scan, progression of soft tissue disease by RECIST, worsening PS, or at least 20% increase in OME. Results: Three of 10 patients had a reduction in the proportion of mutated or amplified tumor DNA as measured by ctDNA profiling, after receiving Ra-223 (response group). Median PFS defined by time to PSA rise of at least 25% in this group was 120 days (95% CI 83 to 237) compared to 29 days (95% CI 21 to 145) in the group without a reduction (no response group). Median clinical PFS defined as above was 266 days (95% CI 109 to 291) in the response group compared to 83 days (95% CI 33 to 182) in the no response group. There was no difference in baseline pain score between the two groups, though median baseline PSA was higher in the no-response group (97.14 compared to 20.05). Reductions in allelic frequency were noted in several mutated genes, including AR, ARID1A, CDK12, and TP53(G245C), during Ra-223 therapy of subjects in the response group. Decreases in copy number were also seen in several amplified genes, including AR, CCNE1, CDK6, FGFR1. In the no-response group, 4/7 patients had an increase in AR amplification; 3/7 patients had an increase in variant allele fraction of TP53 mutations. In the response group of 3 patients who had a reduction in clonal mutations, none had an increase in the AR amplification. Conclusions: A reduction in proportion of clonal mutations or gene amplification measured in ctDNA may be associated with a longer PFS in patients treated with Ra-223. Mutations in the TP53 gene and amplification of AR gene were associated with shorter PFS.
Evaluating the prevalence and nature of sleep disturbances in prostate cancer patients receiving androgen deprivation therapy using a combination of actigraphy and sleep questionnaires.
Authors: Mangar Stephen , Mondal Shalini , Edwards Steve , Ahmed Hashim Uddin , Wassersug Richard J , Falconer Alison , Iles Ray , Dimitriou Dagmara
Published: June 2021

e17046

Background: Sleep disturbances and cancer related fatigue are commonly associated. Prostate cancer patients may suffer from disturbed sleep as a result of their diagnosis and following treatment, especially with androgen deprivation therapy (ADT). Wrist actigraphy is a non-invasive objective method of sleep data collection. This feasibility study compares sleep data obtained by actigraphy with subjective data from sleep questionnaires in order to determine the nature and severity of sleep disturbances in patients with and without ADT use. Methods: A prospective cross-sectional pilot study was conducted on 74 patients with prostate cancer attending a regional oncology clinic. Two validated subjective sleep questionnaires namely the Pittsburgh Sleep Quality Index [PSQI] and the Epworth Sleepiness Scale [ESS] were used. Patients wore actigraphy watches for a minimum of five consecutive days. The parameters of interest included: actual sleep time, sleep efficiency, fragmentation index, daytime napping frequency and duration. The questionnaire and actigraphy data were compared between 20 patients receiving ADT and 41 who were treatment-naive. Results: The compliance rate for completed actigraphy was 85%. Complete data sets with actigraphy and questionnaires were available from 61 patients. Those already receiving ADT were on LHRH analogues for a median duration of 2.35 years. Poor sleep quality as self-identified by patients from the PSQI (cut-off > 5) was 49% in the treatment-naive group which increased to 70% for those on ADT. For daytime sleepiness as assessed by ESS (cut-off > 10) this was 16% and 20% respectively. Actigraphy showed that patients on ADT reported longer sleep duration (7.4 vs 6.5 hours, p = 0.02), higher levels of nocturnal wakings (51.1% vs 36.7%, p = 0.002), with greater daytime napping duration (80.7mins vs 53.0mins, p = 0.04), and frequency (8.6 vs 5.6, p = 0.02) compared to treatment-naive patients. Conclusions: Self-reported poor sleep quality is common in prostate cancer patients, which appears worse for those receiving ADT. In patients receiving ADT, data derived from actigraphy suggests that although they were sleeping for longer at night, the quality of sleep was poor which, in turn, may be responsible for an increase in the frequency and duration of daytime napping. Based on the current findings, we recommend the use of actigraphy to characterise patients’ sleep patterns and to assess if sleep treatment is needed. Actigraphic data may allow for direct comparisons of different hormonal agents on sleep whilst identifying those with specific sleep disorders amenable to therapeutic intervention.
Accelerated epigenetic age among HIV-infected Nigerian women with invasive cervical cancer.
Authors: Musa Jonah , Kim Kyeezu , Zheng Yinan , Travis Lois B. , Gursel Demirkan , Silas Olugbenga A. , Abdulkareem Fatimah Biade , Imade Godwin , Akanmu Alani , Wei Jian-Jun , Kocherginsky Masha , Kim Kwnag-Youn , Wehbe Firas Hazem , Achenbach Chad , Anorlu Rose , Simon Melissa A. , Sagay Atiene , Ogunsola Folasade , Murphy Robert , Hou Lifang
Published: June 2021

e17504

Background: Invasive cervical cancer (ICC) is one of the HIV-associated cancers with a high burden in Nigeria. ICC occurs at relatively younger age in HIV infected women, with HIV known to promote aging and related diseases, including cancer. DNA methylation changes with increasing age, various health-related exposures, and age-related health outcomes, suggesting a role of DNA methylation in biological aging and disease. We sought to understand the effect of HIV infection on epigenetic age acceleration (EpiAgeAccel) in Nigerian women with ICC. Methods: Epigenetic age (EpiAge) was estimated by Horvath’s calculator using genome-wide methylation data in 116 cervical tissue samples from three groups of women: a) HIV positive with ICC (n=39); b) HIV positive and cancer-free (n=53); and c) HIV negative with ICC (n=24). EpiAgeAccel was computed as the regression residuals of EpiAge against chronological age (ChronAge), representing the independent deviation of EpiAge from ChronAge. We compared EpiAgeAccel across the 3 HIV/ICC groups using multiple linear regressions adjusting for ChronAge, education, parity, employment, cancer stage, body mass index, and study site. Among the ICC women, we compared EpiAgeAccel between 26 tumor tissues and their surrounding normal tissues using paired t-tests, stratified by HIV status. Results: EpiAgeAccel among HIV positive women with ICC was 4.5 years higher than HIV positive and cancer-free women (p=0.019). We did not find substantial differences in EpiAgeAccel between HIV-positive women with ICC and HIV-negative women with ICC. EpiAgeAccel was 7.9 and 2.9 years higher in tumor tissues compared to the surrounding normal tissues among HIV positive women (p=0.021) and negative women (p=0.295), respectively. Conclusions: EpiAge is accelerated in cervical tissue of HIV-infected women with ICC. EpiAgeAccel may be a potential biomarker for ICC screening and early detection for women living with HIV in low- and middle-income countries.
The diagnostic value of core needle biopsy in cervical cancer: A retrospective analysis.
Authors: Lia Massimiliano , Horn Lars-Christian , Sodeikat Paulina , Höckel Michael , Aktas Bahriye , Wolf Benjamin
Published: June 2021

e17512

Background: The aim of this retrospective study was to evaluate the accuracy, sensitivity, specificity, and predictive values of preoperative core needle biopsy (CNB) assessment of histological characteristics in primary cervical cancer. Methods: We reviewed 318 cases of primary cervical carcinoma with available pathology reports from preoperative CNB assessment and from final postoperative evaluation of the hysterectomy specimen. Setting the postoperative comprehensive pathological evaluation as reference, we analysed CNB assessment of histological tumor characteristics. In addition, we performed multivariable logistic regression to identify factors influencing the accuracy in identifying lymphovascular space invasion (LVSI) and tumor grade. Results: CNB was highly accurate in discriminating histological subtype. Sensitivity and specificity were 98.8% and 89% for squamous cell carcinoma (SCC), 92.9% and 96.6% for adenocarcinoma (AC), 33.3% and 100% in adenosquamous carcinoma respectively. Neuroendocrine carcinoma was always recognized correctly. The accuracy of the prediction of lymphovascular space invasion (LVSI) was 61.9% and was positively influenced by tumor size in preoperative MRI and negatively influenced by strong peritumoral inflammation. High tumor grade was diagnosed accurately in 73.9% of cases and was influenced by histological tumor type. Conclusions: CNB is an accurate sampling technique for histological classification of cervical cancer and represents a reasonable alternative to other biopsy techniques. Factors such as peritumoral inflammation, tumor size or tumor subtype may influence the accuracy of histologic Evaluation and should be taken into account when interpreting the results.
Expression of multidrug resistance marker MDR1 in patients with ovarian cancer and its possible predictive significance.
Authors: Ulianova Elena P. , Yakubova Darya Yu. , Sagakyants Aleksandr B. , Zhukova Galina V. , Nepomnyashchaya Evgeniya M. , Menshenina Anna P. , Shulgina Oksana G. , Ardzha Anna Yu. , Zhenilo Oksana E. , Verenikina Ekaterina V.
Published: June 2021

e17530

Background: Despite the progress made in diagnosis and treatment, ovarian cancer (OC) is still the third most common genital cancer. Poor results of therapy for various forms of OC stimulate the search for fundamentally new approaches to the treatment. One of the main reasons for resistance to chemotherapeutic agents includes multidrug resistance (MDR) of tumor cells. The most characterized of its various mechanisms is the elevated activity of the ABC family protein - ABCB1 (Pgp or MDR1). The purpose of the study was evaluation of the expression of this ABC transporter as a predictive factor in platinum-containing chemotherapy in OC patients. Methods: 100 patients aged 29-79 years with advanced stage IIIC - IV OC with/without ascites were recruited between 2016 and 2020. Depending on the treatment results, patients were divided into 2 groups: group 1 (n = 59) - patients with platinum sensitivity; group 2 (n = 41) - patients with platinum resistance during the treatment or within 6 months after its completion. IHC analysis was performed using rabbit polyclonal anti-MDR1 antibodies (Affinity Biosciences) diluted 1:600 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. MDR1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: Patients with MDR1+ prevailed in group 2 (98%), and patients with MDR1- in group 1 (32%). The average expression of MDR1 in tumor cells in group 2 (64.0±7.0) was statistically significantly higher by 1.7 times (p = 0.003) than in group 1 (37.2±6.8) by the Mann-Whitney U-test. When distributed according to Pearson's χ2 criterion, positive MDR1 as a risk factor in the platinum-resistant group increased the risks of refractory to platinum therapy by 19 times (95% CI 2.4-148.8). Conclusions: The study demonstrated predictive significance of the MDR1 biomarker in platinum treatment in patients with ovarian cancer.
Factors of VEGF, IGF, and TGF-β1 families in omentum tissues to mark premetastatic niches in ovarian cancer.
Authors: Menshenina Anna P. , Frantsiyants Elena M. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Cheryarina Natalia D. , Yakubova Darya Yu. , Adamyan Meri L. , Chernikova Natalia V. , Chalabova Tatiana G.
Published: June 2021

e17535

Background: Analysis of the nature of cancer cell release and interaction with the microenvironment determines the fundamental basis of ovarian cancer pathogenesis, which is necessary for the development of new methods for peritoneal dissemination treatment and prevention. The purpose of the study was to analyze levels of VEGF-A, VEGFR1, VEGF-C, VEGFR3, TGF-β, IGF-1, IGF-2 and IGFBP3 in omental tissues (O) with and without metastasis (Mts) in ovarian cancer patients. Methods: Samples of O tissues were obtained from 51 ovarian cancer patients aged 60±1.9 years (G2-G3 serous cystadenocarcinoma – AC, Т2-3NxM0-1). 17 non-cancer patients of similar age were controls (C). Levels of VEGF-A, VEGFR1, VEGF-C, VEGFR3, IGF-1, IGF-2, IGFBP3 and TGF-β1 were measured in Mts and O tissues by standard ELISA test systems. Results: VEGF-A levels in O of AC patients were 2.6 times higher than in C. In Mts, VEGF-A and VEGFR1 exceeded the levels in C (by 6.3 and 3.1 times) and O (by 2.5 and 2.8 times, respectively). VEGF-C in O was lower than in C by 5.5 times, while VEGFR3 was 2.2 times higher. In Mts, VEGF-C and VEGFR3 exceeded the levels in C (by 7.8 and 3.6 times) and O (by 43.3 and 1.6 times, respectively, p<0.05). Levels of IGF-2 and IGFBP3 in O were similar to the levels in C, while IGF-1 was twice higher. In Mts, IGF-1, IGF-2 and IGFBP3 exceeded the levels in C (by 4.9, 2.8 and 3.4 times) and O (by 2.5, 2.2 and 3.6 times, respectively). Levels of TGF-β1 were higher in O by 2.9 times and in Mts – by 2.3 times. Conclusions: The interaction between VEGF-A, IGF-1, and TGF-β can serve as a regulator of the metabolic state of the “soil” for tumor dissemination, marking the premetastatic niche and providing mesenchymal-epithelial transition of circulating tumor cells.
Chemotherapy response score: Validation of a three-tier system to quantify histopathologic response to neoadjuvant chemotherapy in ovarian carcinoma.
Authors: Kubalanza Kari , Kim Teresa , Zhang Mingyan , Cohen Joshua Garrett , Memarzadeh Sanaz , Zakhour Mae , Salani Ritu , Rao Jianyu , Konecny Gottfried E.
Published: June 2021

e17539

Background: Neoadjuvant chemotherapy (NACT) with interval debulking surgery is considered for patients with advanced-stage ovarian carcinoma (OC) who are not ideal candidates for primary debulking surgery due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally resected. Moreover, response to NACT may be a suitable surrogate end point for long-term clinical outcome in ovarian cancer. The aim of the present study is to evaluate the utility of a three-tier Chemotherapy Response Score (CRS) and validate whether residual disease or evidence of regression following NACT may provide prognostic information in ovarian cancer. Methods: We conducted a retrospective single-institution study of patients who received NACT with carboplatin and paclitaxel for FIGO stage III/IV ovarian cancer. Response to NACT was graded as no or minimal tumor response (CRS1); appreciable tumor response amid readily identifiable viable tumor (CRS2); or complete/near-complete response with no residual tumor or minimal scattered tumor foci (CRS3) as described previously (Böhm S, et al. J Clin Oncol 33:2457-2463). Multivariate progression free survival (PFS) and overall survival (OS) analyses were performed accounting for age, FIGO stage and BRCA status. Results: Of the 86 patients accrued to date, median age was 65 years, 62% had stage IV disease and 16% had a somatic/germline BRCA mutation. CRS scores 1, 2 and 3 were found in 26 (30%), 43 (50%) and 17 (20%) of cases, respectively, and were associated with PFS (log rank p = 0.002). A high CRS score predicted improved PFS and OS (CRS 2/3 vs 1; median PFS 17.3 vs. 11.8 mo, adjusted hazard ratio (HR), 0.33; 95%CI 0.17-0.62; p < 0.001; median OS 47.9 vs. 38.3 mo, adjusted HR 0.36, 95%CI 0.15-0.88, p = 0.026). Similarly, when comparing CRS 3 with 1/2, the high score predicted improved outcome for PFS but not OS (median PFS 17.3 vs. 14.7 mo, adjusted HR, 0.42; 95%CI 0.19-0.95; p = 0.037; median OS 48.6 vs. 46.5 mo, adjusted HR 0.43, 95%CI 0.14-1.35, p = 0.149). Conclusions: In this study, we validate a simple three-tier chemotherapy response scoring system for assessing histopathologic response of OC to NACT. Residual disease and evidence of complete/near complete regression following NACT provides prognostic information in OC. CRS may serve as a potential surrogate marker for long-term outcome and be a useful alternative intermediate end point in future clinical trials.
Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.
Authors: Chen Xiaoxiang , Ni Jing , Xu Xia , Guo Wenwen , Cheng Xianzhong , Zhao Qian , Zhou Rui , Gu Hongyuan , Chen Chen
Published: June 2021

e17543

Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.
Is age-related worsening in ovarian cancer prognosis linked to changes in body composition and pharmacokinetics?
Authors: Extermann Martine , Walko Christine Marie , Mishra Asmita , Thomas Kerry , Cao Biwei , Chon Hye Sook , Cristea Mihaela C. , Shahzad Mian M. , Chern Jing-Yi , Hoffman Mitchell S , Kim Jongphil , Marchion Douglas C. , Sansil Samer , Sehovic Marina
Published: June 2021

e17553

Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics and treatment tolerance limit the dosing of chemotherapy. And/or changes in tumor and host-tumor biology limit treatment efficacy. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin(C) AUC 5 every 3 weeks and paclitaxel(P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Total muscle mass, total fat mass, skeletal muscle index (SMI) and fat index were computed. Plasma concentrations were collected at pre-established time points for both C1D1 of C and P and concentration-time data was analyzed by non-compartmental methods. Area under the curve (AUC)0-INF, volume of distribution(Vd), clearance (Cl), half-life, and mean residence time were calculated. Free C concentrations were determined in plasma ultrafiltrate and assayed, along with P plasma concentrations, by liquid chromatography-tandem mass spectrometry. Toxicity was assessed as first cycle nadir ANC and G4 hematologic(H) or grade 3-4 non-hematologic(NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible. All patients but one received 3 cycles of chemotherapy and median dose intensity was 100% (range 33.3-100%). Mean 1st cycle nadir ANC was 1.29 (range 0.06-9.0). 10/17 (59%) patients experienced G4 H and/or G3-4 NH toxicity. SMI was associated with C AUC (r -0.50, p < 0.05), and both total muscle (r = 0.61) and total fat (r = 0.53) were associated with C Vd. We did not find a correlation of P pharmacokinetics with body composition. A lower SMI was associated with 1st cycle G4H toxicity (p = 0.02), while C AUC had a borderline trend only (p = 0.15). Age was associated with a lower Vd (r -0.63, p = 0.009) and Cl (r -0.67, p = 0.004) of C. There was no significant age trend in the body composition parameters. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Toxicity appeared driven by low skeletal muscle index, in part via affecting carboplatin pharmacokinetics, and showed no significant age trend. The explanation for age-related changes in prognosis is more likely to lay with changes in tumor and host-tumor biology, which are being analyzed.